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EX-4.1 - EXHIBIT 4.1 - CoLucid Pharmaceuticals, Inc.d876348dex41.htm
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EX-4.2 - EXHIBIT 4.2 - CoLucid Pharmaceuticals, Inc.d876348dex42.htm
EX-10.8 - EXHIBIT 10.8 - CoLucid Pharmaceuticals, Inc.d876348dex108.htm
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EX-23.1 - EXHIBIT 23.1 - CoLucid Pharmaceuticals, Inc.d876348dex231.htm
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EX-10.9 - EXHIBIT 10.9 - CoLucid Pharmaceuticals, Inc.d876348dex109.htm
EX-10.2 - EXHIBIT 10.2 - CoLucid Pharmaceuticals, Inc.d876348dex102.htm
EX-10.7 - EXHIBIT 10.7 - CoLucid Pharmaceuticals, Inc.d876348dex107.htm
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Table of Contents

As filed with the Securities and Exchange Commission on March 30, 2015.

Registration No. 333-          

 

 

 

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

 

 

FORM S-1

REGISTRATION STATEMENT

UNDER

THE SECURITIES ACT OF 1933

 

 

COLUCID PHARMACEUTICALS, INC.

(Exact name of registrant as specified in its charter)

 

Delaware   2834   20-3419541

(State or other jurisdiction of

incorporation or organization)

 

(Primary Standard Industrial

Classification Code Number)

 

(I.R.S. Employer

Identification No.)

 

 

15 New England Executive Park

Burlington, Massachusetts 01803

(781) 365-2596

(Address, including zip code, and telephone number, including area code, of registrant’s principal executive offices)

 

 

Thomas Mathers

Chief Executive Officer

CoLucid Pharmaceuticals, Inc.

15 New England Executive Park

Burlington, Massachusetts 01803

(781) 365-2596

(Name, address, including zip code, and telephone number, including area code, of agent for service)

 

 

Copies to:

 

Daniel L. Boeglin

Jonathan R. Zimmerman

Faegre Baker Daniels LLP

2200 Wells Fargo Center

90 South Seventh Street

Minneapolis, MN 55402-1425

(612) 766-7000

 

Peter N. Handrinos

Nathan Ajiashvili

Latham & Watkins LLP

John Hancock Tower

200 Clarendon Street

Boston, MA 02116

(617) 948-6000

 

 

Approximate date of commencement of proposed sale to the public: As soon as practicable after the effective date of this registration statement.

If any of the securities being registered on this Form are to be offered on a delayed or continuous basis pursuant to Rule 415 under the Securities Act of 1933, as amended, check the following box.    ¨

If this Form is filed to register additional securities for an offering pursuant to Rule 462(b) under the Securities Act, check the following box and list the Securities Act registration number of the earlier effective registration statement for the same offering.    ¨

If this Form is a post-effective amendment filed pursuant to Rule 462(c) under the Securities Act, check the following box and list the Securities Act registration statement number of the earlier effective registration statement for the same offering.    ¨

If this Form is a post-effective amendment filed pursuant to Rule 462(d) under the Securities Act, check the following box and list the Securities Act registration statement number of the earlier effective registration statement for the same offering.    ¨

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, or a smaller reporting company. See the definitions of “large accelerated filer,” “accelerated filer” and “smaller reporting company” in Rule 12b-2 of the Exchange Act. (Check one):

 

Large accelerated filer   ¨    Accelerated filer   ¨
Non-accelerated filer   x  (Do not check if a smaller reporting company)    Smaller reporting company   ¨

 

 

CALCULATION OF REGISTRATION FEE

 

 

Title of Each Class of Securities to be Registered  

Proposed

Maximum

Aggregate

Offering Price(1)

 

Amount of

Registration Fee(2)

Common stock, par value $0.001 per share

  $86,250,000   $10,022.25

 

 

(1)  Estimated solely for the purpose of computing the registration fee pursuant to Rule 457(o) under the Securities Act of 1933, as amended. Includes shares of common stock that the underwriters have the option to purchase.
(2)  Calculated pursuant to Rule 457(o) under the Securities Act of 1933, as amended, based on an estimate of the proposed maximum aggregate offering price.

 

 

The registrant hereby amends this registration statement on such date or dates as may be necessary to delay its effective date until the registrant shall file a further amendment which specifically states that this registration statement shall thereafter become effective in accordance with Section 8(a) of the Securities Act of 1933, as amended, or until the registration statement shall become effective on such date as the Commission, acting pursuant to said Section 8(a), may determine.

 

 

 


Table of Contents

The information in this prospectus is not complete and may be changed. We may not sell these securities until the registration statement filed with the Securities and Exchange Commission is effective. This prospectus is not an offer to sell these securities and is not soliciting an offer to buy these securities in any state where the offer or sale is not permitted.

 

SUBJECT TO COMPLETION, DATED MARCH 30, 2015

 

                 Shares

 

COLUCID PHARMACEUTICALS, INC.

 

Common Stock

LOGO

$         per share

 

 

 

 

 

•  CoLucid Pharmaceuticals, Inc. is offering                 shares.

 

•  We anticipate that the initial public offering price will be between $         and $         per share.

  

•  This is our initial public offering and no public market currently exists for our shares.

 

•  We have applied to have our common stock approved for quotation on The NASDAQ Global Market under the symbol “CLCD.”

 

 

 

 

This investment involves risk. See “Risk Factors” beginning on page 12.

 

 

 

 

     Per Share    Total  

Initial public offering price

   $                    $                    

Underwriting discount(1)

   $                    $     

Proceeds, before expenses, to CoLucid Pharmaceuticals, Inc.

   $                    $     

 

 

 

(1)  See “Underwriting” for additional information regarding underwriting compensation.

The underwriters have a 30-day option to purchase up to             additional shares of common stock from us at the initial public offering price less the underwriting discount.

We are an “emerging growth company” under applicable Securities and Exchange Commission rules and will be eligible for reduced public company disclosure requirements. See “Summary—Implications of Being an Emerging Growth Company.”

Neither the Securities and Exchange Commission nor any state securities commission has approved or disapproved of these securities or passed upon the adequacy or accuracy of this prospectus. Any representation to the contrary is a criminal offense.

The shares of common stock will be ready for delivery on or about                 , 2015.

 

Piper Jaffray

Stifel

 

 

 

 

William Blair

The date of this prospectus is                 , 2015.


Table of Contents

TABLE OF CONTENTS

 

     Page  

Summary

     1   

Risk Factors

     12   

Information Regarding Forward-Looking Statements

     59   

Use of Proceeds

     61   

Dividend Policy

     62   

Capitalization

     63   

Dilution

     65   

Selected Financial Data

     68   

Management’s Discussion and Analysis of Financial Condition and Results of Operations

     69   

Business

     79   

Management

     119   

Executive Compensation

     125   

Certain Relationships and Related Party Transactions

     140   

Principal Stockholders

     144   

Description of Capital Stock

     146   

Shares Eligible For Future Sale

     152   

Material U.S. Federal Income Tax Consequences to Non-U.S. Holders

     154   

Underwriting

     159   

Legal Matters

     166   

Experts

     166   

Where You Can Find More Information

     166   

Index to Financial Statements

     F-1   

 

 

We have not authorized anyone to provide any information other than that contained or incorporated by reference in this prospectus or in any free writing prospectus prepared by or on behalf of us or to which we have referred you. Neither we nor the underwriters take responsibility for, and can provide no assurance as to the reliability of, any other information that others may give you. This prospectus is an offer to sell only the shares offered hereby but only under circumstances and in jurisdictions where it is lawful to do so. The information contained in this prospectus is current only as of its date, regardless of the time of delivery of this prospectus or any sale of shares of our common stock.

For investors outside the United States: Neither we nor any of the underwriters have done anything that would permit this offering or possession or distribution of this prospectus in any jurisdiction where action for that purpose is required, other than the United States. You are required to inform yourselves about and to observe any restrictions relating to this offering and the distribution of this prospectus.

 

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Table of Contents

CoLucid, the CoLucid logo and other trademarks or service marks of CoLucid appearing in this prospectus are the property of CoLucid Pharmaceuticals, Inc. Trade names, trademarks and service marks of other companies appearing in this prospectus are the property of the respective owners.

Certain industry data and market data included in this prospectus were obtained from independent third-party surveys, market research, publicly available information, reports of governmental agencies and industry publications and surveys. Our management’s estimates presented herein are based upon management’s review of independent third party surveys and industry publications prepared by a number of sources and other publicly available information. The market data used in this prospectus involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such estimates. We believe that the information from these industry publications and surveys that is included in this prospectus is reliable. The industry in which we operate is subject to a high degree of uncertainty and risk due to a variety of important factors, including those described in “Risk Factors.” These and other factors could cause results to differ materially from those expressed in the estimates made by the independent parties and by us.

 

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SUMMARY

This summary highlights information contained elsewhere in this prospectus and does not contain all of the information you should consider when making your investment decision. You should read this entire prospectus carefully, including the sections titled “Risk Factors” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations” and our financial statements and the notes thereto accompanying this prospectus, before making an investment in our common stock. As used in this prospectus, the terms “company,” “we,” “our,” and “us” refer to CoLucid Pharmaceuticals, Inc., except where the context otherwise requires.

Our Company

We are a Phase 3 clinical-stage biopharmaceutical company that is developing an innovative and proprietary small molecule for the acute treatment of migraine headaches. Our product candidates utilize the first new mechanism of action in the last twenty years, which we believe could address the unmet needs of migraine patients, including those with cardiovascular risk factors or stable cardiovascular disease and those who are dissatisfied with existing therapies. Lasmiditan, our lead product candidate, is an oral tablet for the acute treatment of migraine headaches in adults that does not have the clinical limitations associated with the most commonly used therapies. In our Phase 2b clinical trial of lasmiditan, we met our primary endpoint of headache relief with statistical significance as well as our secondary endpoint of freedom from the associated symptoms of nausea, sensitivity to sound and sensitivity to light. Headache relief is defined as reducing a moderate or severe headache at baseline to mild or none two hours after dosing. In our completed clinical trials, lasmiditan was well tolerated and had a favorable patient global impression of change, an indicator of patient satisfaction.

We are conducting our first pivotal Phase 3 randomized, double-blind, placebo-controlled clinical trial of lasmiditan, or SAMURAI, under a special protocol assessment, or SPA, agreement with the U.S. Food and Drug Administration, or FDA, with top-line data expected in the third quarter of 2016. We also plan to initiate a second pivotal Phase 3 clinical trial of lasmiditan in the first half of 2016. If we successfully complete our two pivotal Phase 3 clinical trials of lasmiditan, we expect to submit a new drug application, or NDA, to the FDA seeking marketing approval for lasmiditan in the United States with a product label that is differentiated from triptans. Triptan product labels include warnings and precautions against use in patients with cardiovascular risk factors or disease and triptans are not indicated to provide freedom from the most bothersome associated symptom. We are also developing intravenous lasmiditan, or IV lasmiditan, for the acute treatment of unspecified headache pain in adults in emergency room and other urgent care settings. We own or have exclusive rights to the intellectual property for lasmiditan and IV lasmiditan, including composition of matter protection. We have commercial exclusivity for lasmiditan and IV lasmiditan in the United States until 2025, which we expect will be extended up to five years to 2030 by obtaining a term extension under the provisions of the Hatch-Waxman Act.

According to the American Migraine Foundation, migraine affects 12% of the population in the United States and is the leading cause of disability among neurological disorders in the United States. The direct and indirect costs of migraine in the United States are estimated at over $20 billion annually. We believe that lasmiditan will be a first line therapy for the acute treatment of migraine in patients with cardiovascular risk factors or disease. Triptans, the current standard of care to treat migraine, use a vasoconstrictor mechanism of action associated with warnings and precautions against use in patients with cardiovascular risk factors or disease. Triptan product labels recommend that migraine patients with risk factors for cardiovascular disease be evaluated for silent myocardial ischemia before receiving a triptan dose, and should have their first dose administered in a medically supervised setting. Based on published studies, we estimate that more than 60%, or 21 million of the 36 million migraine patients in the United States, have cardiovascular risk factors and that triptans are contraindicated in 13%, or

 

 

 

 

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4.7 million. Further, we estimate that approximately 5% of migraine patients may be at risk for silent myocardial ischemia. We believe lasmiditan’s novel, centrally-acting mechanism of action could address this disadvantage of existing therapies because early studies have shown no evidence of vasoconstriction.

We believe that lasmiditan will also be a second line therapy for patients who are dissatisfied with existing therapies, either because of inadequate response or tolerability issues. If approved by the FDA, lasmiditan could also provide an alternative therapy for the more than 40% of patients who fail to respond to triptans or are dissatisfied with existing therapies.

We have completed seven clinical trials in which we dosed 393 migraine patients and 213 healthy subjects with lasmiditan or IV lasmiditan. Lasmiditan is designed to treat migraine using a novel mechanism by acting as an agonist at the 5-HT1F receptor. In contrast to triptans, which act peripherally, lasmiditan is designed to penetrate the central nervous system, or CNS, and to block the pathway that contributes to headache pain. Triptans were not designed to penetrate the CNS and have limited affinity for 5-HT1F receptors.

Migraine Overview

Current Treatment.    Migraine is a chronic and debilitating disorder characterized by episodic attacks of moderate to severe throbbing headaches, worsened by physical activity and associated with nausea, sensitivity to sound and sensitivity to light. Some people get migraine headaches only once or twice a year, but about 25% of sufferers experience an attack once or twice a week. Pain can last a few hours or up to 72 hours. More than 90% of sufferers are unable to work or function normally during a migraine attack, and depression, anxiety and sleep disturbances are common comorbid conditions for those with chronic migraine.

Products for acute treatment of migraine are used to alleviate pain and symptoms during the attack. Preventative products are used to reduce the frequency of migraine episodes, although most of these patients continue to develop migraine headaches and still require acute therapy. According to Decision Resources, prescription drug sales for migraine in the top seven countries were estimated to be $3.2 billion in 2013, and are expected to grow to $4.4 billion in 2020.

Triptans, a family of tryptamine-based drugs first sold in the 1990s, account for almost 80% of anti-migraine therapies prescribed at office visits. Generic sumatriptan, the most commonly prescribed triptan, has been available since 2009, and the entire class will be generic by the time we expect to launch lasmiditan. Other less commonly prescribed acute treatments include ergot alkaloids, analgesics including opioids, non-steroidal anti-inflammatory drugs, or NSAIDs, acetaminophen and antiemetics.

Limitations of Current Acute Migraine Treatments.    The vasoconstrictor mechanism of action of triptans confers a risk of serious cardiovascular adverse events, some fatal in patients with cardiovascular disease. Triptans are contraindicated in patients with cardiovascular, cerebrovascular or peripheral vascular disease. Triptan product labels include warnings and precautions stating that migraine patients with risk factors for cardiovascular disease (such as hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of coronary artery disease, women with surgical or physiological menopause and men over 40 years of age) should be evaluated for silent myocardial ischemia before receiving a triptan dose, and should have their first dose administered in a medically supervised setting. Confounding for the treating physician is the fact that up to 24% of patients taking oral triptans and 41% of patients taking subcutaneous triptans in controlled studies report triptan chest symptoms such as chest pressure. These symptoms may be troubling for prescribing physicians and patients because they may be unable to diagnose whether or not the patient is suffering a non-life threatening side effect of the triptan or a serious cardiovascular event.

 

 

 

 

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The need for an effective acute treatment for a migraine headache is only partially satisfied by triptans. Typically, only 50 to 60% of migraines respond to an oral triptan within two hours and even then symptoms commonly recur within 24 hours. Additionally, although the triptan drug class is the current standard of care for the acute treatment of migraine, more than 40% of patients fail to respond to triptan treatment or are dissatisfied with treatment. Additional triptan formulations have been developed, but they are all still vasoconstrictors and most of these products have had limited market success due to lack of perceived benefit, lack of patient acceptance and lack of compliance.

Annually, about 7% of migraine patients go to the emergency room due to headache pain, accounting for between 1% and 4% of all emergency room visits. The most commonly used treatments in emergency room management of headache pain include opioids, neuroleptics, NSAIDs, corticosteroids and antiepileptics. Opioids in particular present disadvantages for patients as well as hospitals because of their high abuse liability. The U.S. Centers for Disease Control and Prevention, or CDC, has recognized this growing issue and officially classified prescription opioid abuse as an epidemic.

Our Product Candidates

We are developing our product candidates to treat unmet needs of migraine and headache pain patients, including those with cardiovascular risk factors or disease and those who are dissatisfied with existing therapies, either because of inadequate response or tolerability issues. If approved, we believe that our product candidates could be an attractive option for the acute treatment of migraine and headache pain by providing:

 

   

relief of migraine pain and associated symptoms;

 

   

a novel, centrally-acting mechanism with no evidence of vasoconstriction;

 

   

physician and patient confidence to treat migraine in the presence of cardiovascular risk factors;

 

   

an alternative treatment option for patients not adequately managed with triptans;

 

   

favorable patient satisfaction and good tolerability; and

 

   

an additional non-opioid treatment option for headache in emergency room and other urgent care settings.

The table below summarizes the clinical phase of development for each of our product candidates:

 

LOGO

Lasmiditan.    We are evaluating lasmiditan in a Phase 3 clinical program for which the primary indication is acute treatment of migraine, with or without aura, in adults. Our completed, multi-site Phase 2b clinical trial of lasmiditan was a randomized, double-blind, placebo-controlled parallel group dose-ranging study in which we treated patients for a single migraine attack. Our Phase 2b clinical trial treated 305 patients with lasmiditan and achieved, with statistical significance, its primary endpoint of headache relief, defined as reducing a moderate or severe headache at baseline to mild or none, two hours after dosing, which is the regulatory time point for efficacy assessment. Headache relief was observed in 64% of patients receiving a 100 mg oral dose of lasmiditan and in 51% of patients receiving a 200 mg oral dose of lasmiditan as compared to 26% of patients receiving placebo.

 

 

 

 

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In addition to our primary endpoint of headache relief, a secondary endpoint in our Phase 2b clinical trial was freedom from headache pain two hours after dosing, which is a more rigorous endpoint. We achieved this endpoint with statistical significance and a dose response was observed in 14% of patients receiving a 100 mg oral dose of lasmiditan and in 19% of patients receiving a 200 mg oral dose of lasmiditan, compared to 7% of patients in the placebo group. Lasmiditan was well tolerated and had a favorable patient global impression of change, an indicator of patient satisfaction.

We believe we have clear guidance for the design of SAMURAI under our successfully negotiated SPA agreement with the FDA. We expect to begin enrolling patients in SAMURAI during the second quarter of 2015, with top-line data expected in the third quarter of 2016. The primary endpoint of SAMURAI is the proportion of lasmiditan patients who are free of headache pain two hours after dosing, which was a secondary endpoint of our Phase 2b clinical trial. The key secondary endpoint of SAMURAI is the proportion of lasmiditan patients who are free from their self-reported most bothersome symptom associated with migraine two hours after dosing: nausea, sensitivity to sound or sensitivity to light. Based on results from our Phase 2b clinical trial of lasmiditan, we believe SAMURAI is sufficiently powered to achieve its primary endpoint and key secondary endpoint.

Our clinical program is designed to support a request for a product label that is differentiated from triptans. Triptan product labels include warnings and precautions against use in patients with cardiovascular risk factors or disease and triptans are not indicated to provide freedom from the most bothersome associated symptom. SAMURAI and our second Phase 3 pivotal trial are expected to enroll migraine patients, including those with cardiovascular risk factors or disease. We plan to complete our two pivotal Phase 3 clinical trials for lasmiditan in the second half of 2017 and if successful, file for marketing approval in the United States.

IV Lasmiditan.    We are developing IV lasmiditan for the acute treatment of headache pain in adults, to be used in emergency rooms and urgent care settings. A significant number of patients seek treatment in an emergency room for an unspecified headache that may or may not be associated with migraine and that IV lasmiditan’s non-vasoconstrictive, non-addicting mechanism of action will be beneficial for these patients. In our completed Phase 2 clinical trial, IV lasmiditan achieved its primary endpoint of a statistically significant dose response relationship for headache relief two hours after dosing with numerical superiority of the 20 mg and 30 mg doses of IV lasmiditan over the placebo group.

Our Strategy

Our objective is to establish lasmiditan as a first line therapy in migraine patients with cardiovascular safety concerns and as a second line therapy in those patients who do not respond to existing treatments. To achieve this objective, our strategy is as follows:

 

   

Seek marketing approval from the FDA for lasmiditan with a product label that is differentiated from triptans, whose labels include warnings and precautions against use in patients with cardiovascular risk factors or disease and are not indicated to provide freedom from the most bothersome associated symptom.

 

   

Commercialize lasmiditan in the United States by building our own specialized sales force targeting neurologists, headache specialists and selected, high-prescribing primary care and women’s health physicians.

 

   

Seek marketing approval from the FDA for IV lasmiditan to treat headache pain in the emergency room and other urgent care settings after securing a collaboration to develop IV lasmiditan.

 

 

 

 

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Selectively establish collaborations for the development and commercialization of lasmiditan outside the United States and for IV lasmiditan in the emergency room and other urgent care settings.

 

   

Implement a life cycle management strategy to include development of additional formulations and possible new indications for lasmiditan and IV lasmiditan.

Sales, Marketing and Distribution

If we receive regulatory approval from the FDA for lasmiditan, we plan to commercialize lasmiditan in the United States by building our own focused, specialized sales force of approximately 200 sales representatives to target approximately 15,000 neurologists, 1,500 headache specialists and the top 10% of primary care and women’s health physicians, which we believe will cover physicians who together treat approximately 50% of migraine attacks. We expect to commercialize IV lasmiditan, if approved, through a collaboration and secure IV lasmiditan on hospital and urgent care formularies and support the subsequent launch of IV lasmiditan in the emergency room and other urgent care settings. We intend to control global development of lasmiditan and IV lasmiditan while collaborating with third parties who have expertise and resources to drive the development and commercialization outside of the United States. We expect to enter into additional arrangements with third parties for the development and commercialization of lasmiditan and IV lasmiditan if regulatory approval is received.

Series C Financing

In January 2015, we issued and sold shares of our Series C convertible preferred stock in a private placement, or our Series C financing, for gross proceeds of $36.9 million. All outstanding shares of our Series C convertible preferred stock will be converted into shares of our common stock upon the closing of this offering.

Intellectual Property and Proprietary Rights

We own or have exclusive rights to a significant patent portfolio related to the manufacture, sale and use of lasmiditan and IV lasmiditan. One portion of our portfolio is in-licensed from Eli Lilly and Company, or Eli Lilly, and the other portion is owned by us, through work-for-hire and through the activities of our employee inventors. The table below presents a brief summary of our patent portfolio directed to lasmiditan.

Key Intellectual Property

 

Family

  

Control by

  

Description

CLD01    Exclusive license from Eli Lilly    Claims issued for the compound lasmiditan; claims to a method of treating migraine; claims to the hemisuccinate and hydrochloride salts of lasmiditan
CLD02    Assignment under work-for hire agreement with Aptuit    Claims issued directed to process for making lasmiditan
CLD03    Assignment by our inventors    Claims pending for specific dosing regimens for lasmiditan in treating migraine, including amounts and routes of administration

Under the development and license agreement with Eli Lilly, we are also responsible for and have control over the filing and prosecuting of patent applications and maintaining patents, which cover making, using or selling lasmiditan under the agreement.

 

 

 

 

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Risk Factors

Our business is subject to a number of risks you should be aware of before making an investment decision. These risks are discussed more fully in the “Risk Factors” section of this prospectus immediately following this prospectus summary. These risks include the following:

 

   

We are highly dependent on the success of lasmiditan, which is still in clinical development, and we may not obtain FDA approval for lasmiditan or successfully commercialize lasmiditan or any other product candidates.

 

   

We have a limited operating history and have incurred significant losses since our inception, and we anticipate that we will continue to incur losses for the foreseeable future and may never achieve or maintain profitability.

 

   

We will require substantial additional financing to obtain regulatory approval of our product candidates and commercialize our product candidates, and a failure to obtain this necessary capital when needed on acceptable terms, or at all, could force us to delay, limit, reduce or terminate our product development, other operations or commercialization efforts.

 

   

If selected doses of lasmiditan do not meet the primary endpoint and key secondary endpoint in our SAMURAI trial, we may be required to conduct additional clinical trials, and will incur increased costs, and our ability to generate product sales could be delayed or limited.

 

   

Our strategy depends on securing a collaboration for the development and commercialization of IV lasmiditan prior to commencing a pivotal Phase 3 clinical trial, and if we fail to secure such a collaboration on acceptable terms, it could delay or limit our ability to successfully develop and commercialize IV lasmiditan.

 

   

Even if we obtain the required regulatory approvals in the United States and other territories, the commercial success of lasmiditan will depend on market awareness and acceptance of lasmiditan.

 

   

We have never commercialized a product candidate, and we currently have no marketing and sales organization.

 

   

We rely on a limited number of third parties to supply and manufacture our product candidates and our dependence on these third parties may impair the advancement of our research and development programs and the development of our product candidates.

Implications of Being an Emerging Growth Company

As a company with less than $1 billion in revenue during our last fiscal year, we qualify as an “emerging growth company” as defined in the Jumpstart Our Business Startups Act of 2012, or the JOBS Act. For so long as we remain an emerging growth company, we are permitted and intend to rely on exemptions from specified disclosure and other requirements that are applicable to other public companies that are not emerging growth companies. These exemptions include:

 

   

being permitted to provide only two years of audited financial statements, in addition to any required unaudited interim financial statements, with correspondingly reduced “Management’s Discussion and Analysis of Financial Condition and Results of Operations” disclosure;

 

   

not being required to comply with the auditor attestation requirements in the assessment of our internal control over financial reporting;

 

 

 

 

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not being required to comply with any requirement that may be adopted by the Public Company Accounting Oversight Board regarding mandatory audit firm rotation or a supplement to the auditor’s report providing additional information about the audit and the financial statements;

 

   

reduced disclosure obligations regarding executive compensation; and

 

   

exemptions from the requirements of holding a non-binding advisory vote on executive compensation and stockholder approval of any golden parachute payments not previously approved.

We may take advantage of these provisions for up to five years or such earlier time that we are no longer an emerging growth company. We would cease to be an emerging growth company if we have more than $1 billion in annual revenues, have more than $700 million in market value of our capital stock held by non-affiliates or issue more than $1 billion of non-convertible debt over a three-year period. We may choose to take advantage of some, but not all, of the available exemptions. We have taken advantage of some reduced reporting burdens in this prospectus. Accordingly, the information contained herein may be different than the information you receive from other public companies in which you hold stock.

In addition, the JOBS Act provides that an emerging growth company can take advantage of an extended transition period for complying with new or revised accounting standards. This provision allows an emerging growth company to delay the adoption of some accounting standards until those standards would otherwise apply to private companies. We have irrevocably elected not to avail ourselves of this extended transition period for adopting new or revised accounting standards and, therefore we will be subject to the same new or revised accounting standards as other public companies that are not emerging growth companies.

Corporate Information

We were incorporated in the State of Delaware on August 31, 2005. On December 16, 2005, we acquired or exclusively in-licensed the commercial and development rights to certain clinical and preclinical programs and intellectual property from Eli Lilly. Our principal executive offices are located in Burlington, Massachusetts and our telephone number is (781) 365-2596. Our website address is www.colucid.com. Information contained on our website is not a part of this prospectus, you should not consider information contained on our website in deciding whether to purchase shares of our common stock and the inclusion of our website address in this prospectus is an inactive textual reference only.

 

 

 

 

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THE OFFERING

 

Common stock offered by our company

                 shares

 

Underwriters’ option to purchase additional shares

The underwriters have the option to purchase from us an additional                  shares of common stock. The underwriters can exercise this option at any time within 30 days of this prospectus.

 

Assumed initial public offering price per share

$                 per share, which is the midpoint of the price range set forth on the cover page of this prospectus.

 

Use of proceeds

We estimate that the net proceeds to us from this offering, after deducting the estimated underwriting discounts and estimated offering expenses, will be approximately $         million, assuming an initial public offering price of $         per share, which is the midpoint of the estimated offering price range set forth on the cover page of this prospectus. We intend to use the net proceeds from this offering to fund our clinical trials of lasmiditan and to fund development of lasmiditan. We intend to use any remaining proceeds for working capital and general corporate purposes. See “Use of Proceeds” for a more complete description of the intended use of proceeds from this transaction.

 

Risk Factors

See “Risk Factors” beginning on page 11 and the other information included in this prospectus for a discussion of factors you should carefully consider before deciding to invest in our common stock.

 

Proposed NASDAQ Global Market symbol

“CLCD”

The number of shares of our common stock outstanding after this offering is based on                  shares outstanding as of                     , 2015, after giving effect to the conversion of all outstanding shares of our convertible preferred stock into                  shares of our common stock upon closing of this offering, excluding:

 

   

                 shares of common stock issuable upon the exercise of outstanding options to purchase our common stock at a weighted average exercise price of $         per share;

 

   

                 shares of common stock reserved for issuance under our 2015 Employee Stock Purchase Plan, which will become effective prior to the closing of this offering, as well as shares of our common stock that become available pursuant to provisions in our 2015 Employee Stock Purchase Plan that automatically increase the share reserve under the 2015 Employee Stock Purchase Plan on January 1 of each calendar year as described in “Executive Compensation”;

 

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                 shares of common stock reserved for issuance under our 2006 Equity Incentive Plan; and

 

   

                 shares of common stock reserved for issuance under our 2015 Equity Incentive Plan, which will become effective prior to the closing of this offering as well as shares of our common stock that become available pursuant to provisions in our 2015 Equity Incentive Plan that automatically increase the share reserve under the 2015 Equity Incentive Plan on January 1 of each calendar year as described in “Executive Compensation.”

Unless otherwise noted, the information in this prospectus reflects and assumes the following:

 

   

the conversion of all outstanding shares of our convertible preferred stock into an aggregate of              shares of common stock upon the closing of this offering;

 

   

no exercise of options outstanding as of December 31, 2014;

 

   

the effectiveness of our amended and restated certificate of incorporation upon the closing of this offering and adoption of our amended and restated bylaws;

 

   

no exercise by the underwriters of their option to purchase additional shares from us; and

 

   

a 1-for-              reverse stock split of our common stock, which will become effective prior to the closing of this offering.

 

 

 

 

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SUMMARY FINANCIAL AND OTHER DATA

The following tables set forth our summary financial data as of and for the dates indicated. The summary financial data as of and for the years ended December 31, 2014 and 2013 have been derived from our audited financial statements, which are included elsewhere in this prospectus.

Historical results are not indicative of the results to be expected in the future. The as adjusted summary financial data is not necessarily indicative of what our financial position or results of operations would have been if this offering had been completed as of the date indicated, nor is such data necessarily indicative of our financial position for any future date.

The following summary and as adjusted financial data should be read in conjunction with, and are qualified in their entirety by reference to, “Use of Proceeds,” “Capitalization,” “Selected Financial Data,” “Management’s Discussion and Analysis of Financial Condition and Results of Operations” and our financial statements and the related notes included elsewhere in this prospectus.

 

     Year ended December 31,  
     2014     2013  

Statement of Operations Data:

    

Revenues

   $ —        $ —     
  

 

 

   

 

 

 

Operating expenses:

    

Research and development

     1,168,938        651,660   

General and administrative

     1,140,953        911,757   
  

 

 

   

 

 

 

Total operating expenses

     2,309,891        1,563,417   
  

 

 

   

 

 

 

Loss from operations

     (2,309,891     (1,563,417
  

 

 

   

 

 

 

Other income (expense):

    

Interest income

     1,147        575   

Interest expense

     (397,064     (631,065
  

 

 

   

 

 

 

Total other expense, net

     (395,917     (630,490
  

 

 

   

 

 

 

Net loss before income tax expense

     (2,705,808     (2,193,907
  

 

 

   

 

 

 

Income tax expense

     247,500        —     
  

 

 

   

 

 

 

Net loss

     (2,953,308     (2,193,907
  

 

 

   

 

 

 

Comprehensive loss

   $ (2,953,308   $ (2,193,907
  

 

 

   

 

 

 

Net loss per share:

    

Basic and diluted

   $ (0.51   $ (0.53
  

 

 

   

 

 

 

Weighted average shares outstanding:

    

Basic and diluted

     5,735,392        4,132,114   

Pro forma net loss per share:

    

Basic and diluted(1)

   $       

Pro forma weighted average shares outstanding:

    

Basic and diluted

    

 

 

 

 

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     As of December 31, 2014  
     Actual     Pro  forma(2)      Pro forma as
adjusted(3)
 
           (unaudited)  

Balance Sheet Data:

       

Cash and cash equivalents

   $ 204,362      $                    $                

Working capital(4)

     (354,488     

Total assets

     293,253        

Convertible preferred stock

     50,278,871        

Total stockholders’ deficit

     1,788,301        

 

(1) 

The unaudited pro forma basic and diluted weighted average shares and pro forma basic and diluted net loss per common share data for the year ended December 31, 2014 give effect to the conversion of all outstanding shares of our convertible preferred stock to              shares of our common stock upon the closing of this offering, including the conversion of all outstanding shares of our Series C convertible preferred stock issued in January 2015. Unaudited pro forma net loss per share attributable to common stockholders is computed using the weighted average number of common shares outstanding after giving effect to the conversion of shares of all outstanding convertible preferred stock into              shares of our common stock as if such conversion had occurred at the beginning of the period presented.

(2) 

The pro forma balance sheet data give effect to the sale by us of              shares of Series C convertible preferred stock in January 2015 for gross proceeds of $36.9 million and the conversion of our $200,000 notes payable and the conversion of all outstanding shares of our convertible preferred stock into an aggregate of              shares of common stock upon the closing of this offering, including the              shares of our Series C convertible preferred stock issued in January 2015.

(3) 

The pro forma as adjusted balance sheet data give further effect to our issuance and sale of              shares of common stock in this offering at an assumed initial public offering price of $         per share, which is the midpoint of the price range set forth on the cover page of this prospectus, after deducting the estimated underwriting discounts and commissions and estimated offering expenses payable by us. A $1.00 increase (decrease) in the assumed initial public offering price of $         per share, which is the midpoint of the range set forth on the cover page of this prospectus, would increase (decrease) the pro forma as adjusted amount of each of cash and cash equivalents, working capital, total assets and total stockholders’ deficit by approximately $         million, assuming that the number of shares offered by us, as set forth on the cover page of this prospectus, remains the same and after deducting the estimated underwriting discounts and commissions and estimated offering expenses payable by us.

(4) 

Working capital is defined as current assets minus current liabilities.

 

 

 

 

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RISK FACTORS

An investment in our common stock involves a high degree of risk. You should carefully consider the following risk factors and all the other information in this prospectus before you decide to buy our common stock. If any of the following risks related to our business actually occurs, our business, financial condition, operating results, and prospects would be adversely affected. The market price of our common stock could decline due to any of these risks and uncertainties related to our business, or related to an investment in our common stock, and you may lose part or all of your investment.

Risks Related to Our Financial Condition

We are highly dependent on the success of lasmiditan, which is still in clinical development, and we may not obtain FDA approval for lasmiditan or successfully commercialize lasmiditan or any other product candidates.

We currently do not have any product candidates that have gained marketing approval for sale in the United States or any other country, and we cannot guarantee that we will ever have marketable products. To date, we have invested substantially all of our efforts and financial resources in the research and development and commercial planning for our current product candidates. In particular, we have completed a Phase 2b clinical trial for lasmiditan and a Phase 2 clinical trial for IV lasmiditan. Our near-term prospects, including our ability to finance our company and generate revenue, as well as our future growth, will depend heavily on the successful development, marketing approval and commercialization of our product candidates. The clinical and commercial success of product candidates will depend on a number of factors, including the following:

 

   

initiating and obtaining favorable results from our planned Phase 3 clinical program for our product candidates, which may be slower or cost more than we currently anticipate;

 

   

even if our trials are successful, there can be no assurance that the FDA will agree that we have satisfactorily demonstrated safety or efficacy or that the FDA will not raise new issues regarding the design of our clinical trials;

 

   

our ability to demonstrate the safety our product candidates to the satisfaction of the FDA and other applicable foreign regulatory authorities;

 

   

our ability to demonstrate efficacy of our product candidates to the satisfaction of the FDA and other applicable foreign regulatory authorities, including our ability to utilize FDA-acceptable endpoint tools for measuring efficacy of lasmiditan in our clinical trials;

 

   

whether we are required by the FDA or comparable foreign regulators to conduct additional clinical trials to support the approval of our product candidates;

 

   

the acceptance by the FDA, or comparable foreign regulators, of our proposed parameters for regulatory approval, including our proposed indication, endpoints and endpoint measurement tools relating to our product candidates;

 

   

the incidence, duration and severity of adverse side effects;

 

   

the timely receipt of necessary marketing approvals from the FDA and comparable foreign regulators around the world;

 

   

achieving and maintaining compliance with all regulatory requirements applicable to our product candidates;

 

   

the availability, perceived advantages, relative cost, relative safety and relative efficacy of alternative and competing treatments;

 

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the effectiveness of our and our potential collaborators’ marketing, sales and distribution strategy and operations in the United States and other markets around the world;

 

   

whether we are able to secure collaborations for the development and commercialization of IV lasmiditan in the United States, if approved;

 

   

whether we are able to secure collaborations for the development and, if approved, commercialization of lasmiditan and IV lasmiditan outside of the United States and whether such collaborators will be required to conduct additional studies for the approval of our product candidates in such markets in a timely manner;

 

   

our success in educating physicians and patients about the benefits, administration and use of lasmiditan;

 

   

the ability of our third-party manufacturers and potential collaborators to manufacture clinical trial and commercial supplies of lasmiditan to remain in good standing with regulatory bodies, and to develop, validate and maintain commercially viable manufacturing processes that are compliant with current Good Manufacturing Practices, or cGMP, regulations;

 

   

our ability to successfully commercialize our product candidates in the United States, if approved for marketing;

 

   

our potential collaborators’ ability to successfully commercialize our product candidates in other markets outside of the United States;

 

   

our ability to enforce our intellectual property rights in and to lasmiditan;

 

   

our ability to avoid third-party patent interference or patent infringement claims;

 

   

acceptance of our product candidates as safe and effective by patients and the medical community; and

 

   

a continued acceptable safety profile of our product candidates following approval.

Many of these factors are beyond our control. Accordingly, we cannot assure you that we will ever be able to generate revenue through the sale of our product candidates. Any one of these factors or other factors discussed in this prospectus could affect our ability to successfully commercialize product candidates, which could impact our ability to earn sufficient revenues to transition from a developmental stage company and continue our business. If we are not successful in obtaining marketing approval of and commercializing our product candidates, or are significantly delayed in doing so, our business will be materially harmed.

We have a limited operating history and have incurred significant losses since our inception, and we anticipate that we will continue to incur losses for the foreseeable future and may never achieve or maintain profitability. We have one lead product candidate and no commercial sales, which, together with our limited operating history, make it difficult to assess our future viability.

We are a Phase 3 clinical-stage biopharmaceutical company with a limited operating history. Pharmaceutical product development is a highly speculative undertaking and involves a substantial degree of risk. To date, we have focused principally on developing our lead product candidate, lasmiditan. We are not profitable and have incurred losses in each year since our inception in 2005. We have only a limited operating history upon which you can evaluate our business and prospects. In addition, we have limited experience and have not yet demonstrated an ability to successfully overcome many of the risks and uncertainties frequently encountered by companies in new and rapidly evolving fields, particularly in the specialty pharmaceutical industry. We have not generated any revenue to date. We continue to incur significant research and development and other expenses related to our ongoing operations. Our net loss for the year ended December 31, 2014 was approximately $3.0 million. As of

 

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December 31, 2014, we had an accumulated deficit of $54.5 million. We expect to continue to incur losses for the foreseeable future, as we continue our development of, and seek marketing approvals for our product candidates assuming we obtain marketing approval, begin to commercialize lasmiditan and IV lasmiditan. Even if we achieve profitability in the future, we may not be able to sustain profitability in subsequent periods. Our prior losses, combined with expected future losses, have had and will continue to have an adverse effect on our stockholders’ equity and working capital.

We currently have no source of product sales revenue.

We have not generated any revenues from commercial sales of our product candidates. Our ability to generate product revenue depends upon our ability to successfully commercialize products, including any of our current product candidates or other product candidates that we may develop, in-license or acquire in the future. We do not anticipate generating revenue from the sale of products for the foreseeable future. Our ability to generate future product revenue from our current or future product candidates also depends on a number of additional factors, including our ability to:

 

   

successfully complete research and clinical development of current and future product candidates;

 

   

establish and maintain supply and manufacturing relationships with third parties, and ensure adequate and legally compliant manufacturing of bulk drug substances and drug products to maintain that supply;

 

   

obtain regulatory approval from relevant regulatory authorities in jurisdictions where we intend to market our product candidates;

 

   

launch and commercialize future product candidates for which we obtain marketing approval, if any, and if launched independently, successfully establish a sales force, marketing and distribution infrastructure;

 

   

obtain coverage and adequate product reimbursement from third-party payors, including government payors;

 

   

achieve market acceptance for our products, if any;

 

   

establish, maintain and protect our intellectual property rights; and

 

   

attract, hire and retain qualified personnel.

In addition, because of the numerous risks and uncertainties associated with clinical product development, including that our product candidates may not advance through development or achieve the endpoints of applicable clinical trials, we are unable to predict the timing or amount of any potential future product sales revenues. Our expenses also could increase beyond expectations if we decide to or are required by the FDA, or comparable foreign regulatory authorities, to perform studies or trials in addition to those that we currently anticipate. Even if we complete the development and regulatory processes described above, we anticipate incurring significant costs associated with launching and commercializing these products.

We will require substantial additional financing to obtain marketing approval of our product candidates and commercialize our product candidates, and a failure to obtain this necessary capital when needed on acceptable terms, or at all, could force us to delay, limit, reduce or terminate our product development, other operations or commercialization efforts.

Since our inception, substantially all of our resources have been dedicated to the preclinical and clinical development of our lead product candidate, lasmiditan. As of December 31, 2014, we had an accumulated deficit of $54.5 million, working capital of $(354,000) and cash and cash equivalents of $204,000. We believe that we will continue to expend substantial resources for the foreseeable future on

 

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the completion of clinical development and regulatory preparedness of our product candidates, preparations for a commercial launch of our product candidates, if approved, and development of any other current or future product candidates we may choose to further develop. These expenditures will include costs associated with research and development, conducting preclinical studies and clinical trials, obtaining marketing approvals, and manufacturing and supply as well as marketing and selling any products approved for sale. In addition, other unanticipated costs may arise. Because the outcome of any drug development process is highly uncertain, we cannot reasonably estimate the actual amounts necessary to successfully complete the development and commercialization of our current product candidates, if approved, or future product candidates, if any.

We estimate that our net proceeds from this offering will be approximately $        , or approximately $         if the underwriters exercise their option to purchase additional shares from us in full. This estimate is based on the assumed initial public offering price of $         per share, which is the midpoint of the price range set forth on the cover page of this prospectus, after deducting the estimated underwriting discounts and commissions and estimated offering expenses payable by us. We believe that such proceeds together with our existing cash and cash equivalents, will be sufficient to fund our operations through             . In particular, we expect that the net proceeds from this offering, along with our existing cash and cash equivalents, will be sufficient to fund our two planned pivotal Phase 3 clinical trials of lasmiditan, the submission of an NDA if our Phase 3 clinical trials are completed successfully, and the initiation of our long-term, open label study of lasmiditan. However, our operating plan may change as a result of factors currently unknown to us, and we may need to seek additional funds sooner than planned, through public or private equity or debt financings or other sources, such as strategic collaborations. Such financing may result in dilution to stockholders, imposition of debt covenants and repayment obligations, or other restrictions that may adversely affect our business. In addition, we may seek additional capital due to favorable market conditions or strategic considerations even if we believe we have sufficient funds for our current or future operating plans.

Our future capital requirements depend on many factors, including:

 

   

the scope, progress, results and costs of researching and developing our current product candidates, future product candidates and conducting preclinical and clinical trials;

 

   

the cost of commercialization activities if our current product candidates and future product candidates are approved for sale, including marketing, sales and distribution costs and preparedness of our corporate infrastructure;

 

   

the cost of manufacturing our current product candidates and future product candidates that we obtain approval for and successfully commercialize;

 

   

our ability to establish and maintain strategic collaborations, licensing or other arrangements and the financial terms of such agreements;

 

   

the number and characteristics of any additional product candidates we may develop or acquire;

 

   

any product liability or other lawsuits related to our products or commenced against us;

 

   

the expenses needed to attract and retain skilled personnel;

 

   

the costs associated with being a public company;

 

   

the costs involved in preparing, filing, prosecuting, maintaining, defending and enforcing patent claims, including litigation costs and the outcome of such litigation; and

 

   

the timing, receipt and amount of sales of, or royalties on, any future approved products, if any.

 

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Additional funds may not be available when we need them, on terms that are acceptable to us, or at all. If adequate funds are not available to us on a timely basis, we may be required to:

 

   

delay, limit, reduce or terminate preclinical studies, clinical trials or other development activities for our current product candidates or future product candidates, if any;

 

   

delay, limit, reduce or terminate our research and development activities; or

 

   

delay, limit, reduce or terminate our establishment of sales and marketing capabilities or other activities that may be necessary to commercialize o or future product candidates.

Raising additional capital may cause dilution to our existing stockholders, restrict our operations or require us to relinquish rights to our technologies or product candidates.

We may seek additional capital through a combination of public and private equity offerings, debt financings, strategic collaborations and alliances and licensing arrangements. To the extent that we raise additional capital through the sale of equity or convertible debt securities, your ownership interest will be diluted, and the terms may include liquidation or other preferences that adversely affect your rights as a stockholder. The incurrence of indebtedness would result in increased fixed payment obligations and could involve certain restrictive covenants, such as limitations on our ability to incur additional debt, limitations on our ability to acquire or license intellectual property rights and other operating restrictions that could adversely impact our ability to conduct our business. If we raise additional funds through strategic collaborations and alliances and licensing arrangements with third parties, we may have to relinquish valuable rights to our technologies or product candidate, or grant licenses on terms unfavorable to us.

Our ability to use our net operating loss carryforwards and certain other tax attributes to offset future taxable income may be subject to certain limitations.

As of December 31, 2014, we had U.S. federal and state net operating loss carryforwards, or NOLs, of approximately $43.3 million and $43.8 million, respectively, which begin to expire in 2025 and 2021, respectively, unless previously utilized. Under Sections 382 and 383 of Internal Revenue Code of 1986, as amended, or the Code, if a corporation undergoes an “ownership change,” the corporation’s ability to use its pre-change NOLs and other pre-change tax attributes, such as research tax credits, to offset its future post-change income and taxes may be limited. In general, an “ownership change” occurs if there is a cumulative change in our ownership by “5% stockholders” that exceeds 50 percentage points over a rolling three-year period. Similar rules may apply under state tax laws. In the event that it is determined that we have in the past experienced additional ownership changes, or if we experience one or more ownership changes as a result of this offering or future transactions in our stock, then we may be further limited in our ability to use our NOLs and other tax assets to reduce taxes owed on the net taxable income that we earn in the event that we attain profitability. Any such limitations on the ability to use our NOLs and other tax assets could adversely impact our business, financial condition and operating results in the event that we attain profitability.

Risks Related to the Clinical Development and Marketing Approval of Our Product Candidates

The marketing approval processes of the FDA and comparable foreign authorities are lengthy, time consuming and inherently unpredictable, and if we are ultimately unable to obtain marketing approval for our product candidates, our business will be substantially harmed.

We currently do not have any product candidates that have gained marketing approval for sale in the United States or any other country, and we cannot guarantee that we will ever have marketable products. Our business is substantially dependent on our ability to complete the development of, obtain marketing approval for and successfully commercialize our product candidates in a timely manner. We cannot

 

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commercialize our product candidates in the United States without first obtaining marketing approval to market each product candidate from the FDA. Similarly, we cannot commercialize our product candidates outside of the United States without obtaining regulatory approval from comparable foreign regulatory authorities. Our product candidates could fail to receive marketing approval for many reasons, including the following:

 

   

the FDA or comparable foreign regulatory authorities may disagree with the design or implementation of our clinical trials;

 

   

we may be unable to demonstrate to the satisfaction of the FDA or comparable foreign regulatory authorities that a product candidate is safe and effective for its proposed indication;

 

   

the results of clinical trials may not meet the level of statistical significance required by the FDA or comparable foreign regulatory authorities for approval;

 

   

we may be unable to demonstrate that a product candidate’s clinical and other benefits outweigh its safety risks;

 

   

the FDA or comparable foreign regulatory authorities may disagree with our interpretation of data from preclinical studies or clinical trials;

 

   

the data collected from clinical trials of our product candidates may not be sufficient to support the submission of an NDA or other submission or to obtain marketing approval in the United States or elsewhere;

 

   

the FDA or comparable foreign regulatory authorities may fail to find adequate the manufacturing processes or facilities of third-party manufacturers with which we contract for clinical and commercial supplies; and

 

   

the approval policies or regulations of the FDA or comparable foreign regulatory authorities may significantly change in a manner that would delay marketing approval.

Before obtaining marketing approvals for the commercial sale of any product candidate for a target indication, we must demonstrate in preclinical studies and well-controlled clinical trials and, with respect to approval in the United States, to the satisfaction of the FDA, that the product candidate is safe and effective for use for that target indication and that the manufacturing facilities, processes and controls are adequate. In the United States, it is necessary to submit and obtain approval of an NDA from the FDA. An NDA must include extensive preclinical and clinical data and supporting information to establish the product candidate’s safety and efficacy for each desired indication. The NDA must also include significant information regarding the chemistry, manufacturing and controls for the product. The manufacturing facilities used to manufacture a product candidate must be approved by the FDA pursuant to inspections that will be conducted after we submit an NDA to the FDA to ensure that the facilities are in compliance with the applicable regulatory requirements. The FDA and other regulatory authorities may also inspect our clinical trial sites to ensure that our studies are properly conducted in accordance with good clinical practices, or GCP, which are regulations and guidelines enforced by the FDA, the Competent Authorities of the Member States of the European Economic Area, or EEA, and comparable foreign regulatory authorities for products in clinical development. Obtaining approval of an NDA is a lengthy, expensive and uncertain process, and approval may not be obtained. Upon submission of an NDA, the FDA must make an initial determination that the application is sufficiently complete to accept the submission for filing. We cannot be certain that any submissions will be accepted for filing and reviewed by the FDA, or ultimately be approved. If the application is not accepted for review or approval, the FDA may require that we conduct additional clinical or preclinical trials, or take other actions before it will reconsider our application. If the FDA requires additional studies or data, we would incur increased costs and delays in the marketing approval process, which may require us to expend more resources than we have available. In addition, the FDA may not consider any additional

 

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information to be complete or sufficient to support approval. Regulatory authorities outside of the United States, such as in Europe and Japan and in emerging markets, also have requirements for approval of drugs for commercial sale with which we must comply prior to marketing in those areas. Regulatory requirements can vary widely from country to country and could delay or prevent the introduction of our product candidates. Clinical trials conducted in one country may not be accepted by regulatory authorities in other countries, and obtaining regulatory approval in one country does not mean that regulatory approval will be obtained in any other country. However, the failure to obtain regulatory approval in one jurisdiction could have a negative impact on our ability to obtain approval in a different jurisdiction. Approval processes vary among countries and can involve additional product candidate testing and validation and additional administrative review periods. Seeking foreign regulatory approval could require additional non-clinical studies or clinical trials, which could be costly and time consuming. Foreign regulatory approval may include all of the risks associated with obtaining FDA approval. For all of these reasons, we may not obtain foreign regulatory approvals on a timely basis, if at all.

The process to develop, obtain marketing approval for and commercialize product candidates is long, complex and costly both inside and outside of the United States, and approval is never guaranteed. The time required to obtain approval by the FDA and comparable foreign authorities is unpredictable but typically takes many years following the commencement of clinical trials and depends upon numerous factors, including the substantial discretion of the regulatory authorities. In addition, approval policies, regulations, or the type and amount of clinical data necessary to gain approval may change during the course of a product candidate’s clinical development and may vary among jurisdictions. Even if our product candidates were to successfully obtain approval from regulatory authorities, any such approval might significantly limit the approved indications for use, including more limited patient populations, require that precautions, warnings or contraindications be included on the product labeling, including black box warnings, require expensive and time-consuming post-approval clinical studies, risk evaluation and mitigation strategies or surveillance as conditions of approval, or, through the product label, the approval may limit the claims that we may make, which may impede the successful commercialization of our product candidates. Following any approval for commercial sale of our product candidates, certain changes to the product, such as changes in manufacturing processes and additional labeling claims, as well as new safety information, may require new studies and will be subject to additional FDA notification, or review and approval. Also, marketing approval for any of our product candidates may be withdrawn. If we are unable to obtain marketing approval for our product candidates in one or more jurisdictions, or any approval contains significant limitations, our ability to market to our full target market will be reduced and our ability to realize the full market potential of our product candidates will be harmed. Furthermore, we may not be able to obtain sufficient funding or generate sufficient revenue and cash flows to continue or complete the development of any of our current or future product candidates.

Clinical drug development involves a lengthy and expensive process with an uncertain outcome, and results of earlier studies and trials may not be predictive of future trial results.

Clinical testing is expensive, and can take many years to complete, and its outcome is inherently uncertain. The FDA and comparable foreign regulatory authorities have substantial discretion in the approval process, and determining when or whether marketing approval will be obtained for our current product candidates. Even if we believe the data collected from clinical trials of our current product candidates are promising, such data may not be sufficient to support approval by the FDA or comparable foreign authorities. Our future clinical trial results may not be successful.

It is impossible to predict the extent to which the clinical trial process may be affected by legislative and regulatory developments. Due to these and other factors, our current product candidates or future product candidates could take a significantly longer time to gain marketing approval than expected or

 

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may never gain marketing approval. This could delay or eliminate any potential product revenue by delaying or terminating the potential commercialization of our current product candidates.

Preclinical trials must also be conducted in accordance with FDA and comparable foreign authorities’ legal requirements, regulations or guidelines, including Good Laboratory Practice, or GLP, an international standard meant to harmonize the conduct and quality of nonclinical studies and the archiving and reporting of findings. Preclinical studies including long-term toxicity studies and carcinogenicity studies in experimental animals may result in findings which may require further evaluation, which could affect the risk-benefit evaluation of clinical development, or which may even lead the regulatory agencies to delay, prohibit the initiation of or halt clinical trials or delay or deny marketing authorization applications. Failure to adhere to the applicable GLP standards or misconduct during the course of the study may invalidate the study requiring repeat of the study.

Clinical trials must also be conducted in accordance with FDA and comparable foreign authorities’ legal requirements, regulations or guidelines, including GCP. Clinical trials are further subject to oversight by these governmental agencies and institutional review boards, or IRBs, at the medical institutions where the clinical trials are conducted. In addition, clinical trials must be conducted with supplies of our current product candidates produced under cGMP, and other requirements. Our clinical trials are conducted at multiple sites, including some sites in countries outside the United States and the European Union, which may subject us to further delays and expenses as a result of increased shipment costs, additional regulatory requirements and the engagement of foreign and non-EU clinical research organizations, as well as expose us to risks associated with clinical investigators who are unknown to the FDA or the European regulatory authorities, and with different standards of diagnosis, screening and medical care.

To date, we have not completed all clinical trials required for the approval of our current product candidates. The commencement and completion of clinical trials for our current product candidates may be delayed, suspended or terminated as a result of many factors, including but not limited to:

 

   

the delay or refusal of regulators or IRBs to authorize us to commence a clinical trial at a prospective trial site and changes in regulatory requirements, policies and guidelines;

 

   

the FDA or comparable foreign regulatory authorities disagreeing as to the design or implementation of our clinical trials;

 

   

failure to reach agreement on acceptable terms with prospective contract research organizations, or CROs, and clinical trial sites, the terms of which can be subject to extensive negotiation and may vary significantly among different CROs and trial sites;

 

   

delays in patient enrollment and variability in the number and types of patients available for clinical trials;

 

   

the inability to enroll a sufficient number of patients in trials to ensure adequate statistical power to detect statistically significant treatment effects;

 

   

lower than anticipated retention rates of patients and volunteers in clinical trials;

 

   

clinical sites deviating from trial protocol or dropping out of a trial;

 

   

adding new clinical trial sites;

 

   

negative or inconclusive results, which may require us to conduct additional preclinical or clinical trials or to abandon projects that we expect to be promising;

 

   

safety or tolerability concerns could cause us to suspend or terminate a trial if we find that the participants are being exposed to unacceptable health risks;

 

   

regulators or IRBs requiring that we or our investigators suspend or terminate clinical research for various reasons, including noncompliance with regulatory requirements;

 

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our third-party research and manufacturing contractors failing to comply with regulatory requirements or meet their contractual obligations to us in a timely manner, or at all;

 

   

difficulty in maintaining contact with patients after treatment, resulting in incomplete data;

 

   

delays in establishing the appropriate dosage levels;

 

   

the quality or stability of our current product candidates falling below acceptable standards;

 

   

the inability to produce or obtain sufficient quantities of our current product candidates to complete clinical trials; and

 

   

exceeding budgeted costs due to difficulty in predicting accurately costs associated with clinical trials.

Patient enrollment is a significant factor in the timing of clinical trials and is affected by many factors, including the size and nature of the patient population, the proximity of patients to clinical sites, the eligibility criteria for the trial, the design of the clinical trial, competing clinical trials and clinicians’ and patients’ perceptions as to the potential advantages of the drug being studied in relation to other available therapies, including any new drugs or treatments that may be approved for the indications we are investigating.

We could encounter delays if a clinical trial is suspended or terminated by us, by the IRBs of the institutions in which such trials are being conducted, by the data safety monitoring board, or DSMB, for such trial or by the FDA or comparable foreign regulatory authorities. We or such authorities may impose a suspension or termination due to a number of factors, including failure to conduct the clinical trial in accordance with regulatory requirements or our clinical protocols, inspection of the clinical trial operations or trial site by the FDA or comparable foreign regulatory authorities resulting in the imposition of a clinical hold, safety issues or adverse side effects, failure to demonstrate a benefit from using the drug, changes in governmental regulations or administrative actions or lack of adequate funding to continue the clinical trial. If we experience delays in the completion of, or termination of, any clinical trial of our current product candidates, the commercial prospects of our current product candidates will be harmed, and our ability to generate product revenues from our product candidates will be delayed. In addition, any delays in completing our clinical trials will increase our costs, slow our development and approval process and jeopardize our ability to commence product sales and generate revenues. Many of the factors that cause, or lead to, a delay in the commencement or completion of clinical trials may also ultimately lead to the denial of marketing approval of our product candidates.

Moreover, principal investigators for our clinical trials may serve as scientific advisors or consultants to us from time to time and receive compensation in connection with such services. Under certain circumstances, we may be required to report some of these relationships to the FDA. The FDA may conclude that a financial relationship between us and a principal investigator has created a conflict of interest or otherwise affected interpretation of the study. FDA may therefore question the integrity of the data generated at the applicable clinical trial site and the utility of the clinical trial itself may be jeopardized. This could result in a delay in approval, or rejection, of our marketing applications by the FDA and may ultimately lead to the denial of marketing approval of one or more of our product candidates.

Any of these occurrences could materially adversely affect our business, financial condition, results of operations, and prospects. In addition, many of the factors that cause, or lead to, a delay in the commencement or completion of clinical trials may also ultimately lead to the denial of marketing approval of our current product candidates. Significant clinical trial delays could also allow our competitors to bring products to market before we do or shorten any periods during which we have the exclusive right to commercialize our current product candidates and impair our ability to commercialize our current product candidates, which may harm our business, financial condition, results of operations, and prospects.

 

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Clinical failure can occur at any stage of clinical development. Because the results of earlier clinical trials are not necessarily predictive of future results, any product candidate we advance through clinical trials may not have favorable results in later clinical trials or receive marketing approval.

Clinical failure can occur at any stage of our clinical development. The results of preclinical studies and early clinical trials of our product candidates may not be predictive of the results of later-stage clinical trials. For example, the positive results generated to date in clinical trials for lasmiditan and IV lasmiditan do not ensure that later clinical trials, including our planned Phase 3 studies, will demonstrate similar results. Product candidates in later stages of clinical trials may fail to show the desired safety and efficacy traits despite having progressed through preclinical studies and initial clinical trials. A number of companies in the biopharmaceutical industry have suffered significant setbacks in advanced clinical trials due to lack of efficacy or adverse safety profiles, notwithstanding promising results in earlier trials. Clinical trials may produce negative or inconclusive results, and we may decide, or regulators may require us, to conduct additional clinical or preclinical testing. Data obtained from tests are susceptible to varying interpretations, and regulators may not interpret our data as favorably as we do, which may delay, limit or prevent marketing approval. In addition, the design of a clinical trial can determine whether its results will support approval of a product, or approval of a product for desired indications, and flaws or shortcomings in the design of a clinical trial may not become apparent until the clinical trial is well advanced. We have limited experience in designing clinical trials and may be unable to design and execute a clinical trial to support marketing approval for our desired indications. Further, clinical trials of potential products often reveal that it is not practical or feasible to continue development efforts. If one of our product candidates is found to be unsafe or lack efficacy, we will not be able to obtain marketing approval for it and our business would be harmed. For example, if the results of our planned Phase 3 clinical trials of our product candidates do not achieve pre-specified endpoints or we are unable to provide primary or secondary endpoint measurements deemed acceptable by the FDA or comparable foreign regulators of if we are unable to demonstrate an acceptable level of safety relative to the efficacy associated with our proposed indications, the prospects for approval of our product candidates would be materially and adversely affected. A number of companies in the pharmaceutical industry, including those with greater resources and experience than us, have suffered significant setbacks in Phase 2 and Phase 3 clinical trials, even after seeing promising results in earlier clinical trials.

In some instances, there can be significant variability in safety and/or efficacy results between different trials of the same product candidate due to numerous factors, including differences in trial protocols and design, the size and type of the patient populations, adherence to the dosing regimen and the rate of dropout among clinical trial participants. We do not know whether any Phase 3 or other clinical trials we may conduct will demonstrate consistent and/or adequate efficacy and safety to obtain marketing approval to market our product candidates.

While we have negotiated an SPA agreement with the FDA relating to SAMURAI, this agreement does not guarantee approval of lasmiditan or any other particular outcome with respect to regulatory review of the study or the product candidate.

In May 2014, we announced that we reached an SPA agreement with the FDA for SAMURAI. The FDA’s SPA process is designed to facilitate the FDA’s review and approval of drugs by allowing the FDA to evaluate the proposed design and size of Phase 3 clinical trials that are intended to form the primary basis for determining a drug product’s efficacy. Upon specific request by a clinical trial sponsor, the FDA will evaluate the protocol and respond to a sponsor’s questions regarding, among other things, primary efficacy endpoints, trial conduct and data analysis, within 45 days of receipt of the request. The FDA ultimately assesses whether the protocol design and planned analysis of the trial are acceptable to support regulatory submission for the product candidate with respect to the indication studied. All agreements and disagreements between the FDA and the sponsor regarding an SPA must be clearly documented in an SPA letter or the minutes of a meeting between the sponsor and the FDA. However, an SPA agreement does not guarantee approval of a product candidate, and even if the FDA agrees to the

 

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design, execution, and analysis proposed in protocols reviewed under the SPA process, the FDA may revoke or alter its agreement in certain circumstances. In particular, an SPA agreement is not binding on the FDA if public health concerns emerge that were unrecognized at the time of the SPA agreement, other new scientific concerns regarding product safety or efficacy arise, the sponsor fails to comply with the agreed upon trial protocols, or the relevant data, assumptions or information provided by the sponsor in a request for the SPA change or are found to be false or omit relevant facts. After an SPA agreement is finalized, the SPA agreement may be modified, and such modification will be deemed binding on the FDA review division, except under the circumstances described above, if the FDA and the sponsor agree in writing to modify the protocol and such modification is intended to improve the study. The FDA retains significant latitude and discretion in interpreting the terms of the SPA agreement and the data and results from any study that is the subject of the SPA agreement.

We cannot assure you that our planned Phase 3 clinical trial under an SPA will succeed, will be deemed acceptable to the FDA under our SPA agreement, or will result in any FDA approval for lasmiditan. The trial is expected to administer lasmiditan treatment to approximately 1,483 patients with a history of migraine with or without aura from approximately 70 general practice and neurology study centers, but we cannot assure you that our desired number of patients will enroll within our anticipated timeline, which could result in delays. We expect to begin enrolling patients in the first half of 2015 and expect enrollment completion and top-line data in mid-2016. We expect that the FDA will review our compliance with the protocol under our SPA agreement and that it will conduct inspections of some of the approximately 70 sites we expect to have in the United States where the clinical trials will be conducted. We cannot assure you that the clinical trial sites will pass such FDA inspections, and negative inspection results could significantly delay or prevent any potential approval for lasmiditan. If the FDA revokes or alters its agreement under the SPA, or interprets the data collected from the clinical trial, or the manner in which the study was conducted, as not consistent with the terms of our SPA, the FDA may not deem the data sufficient to support an application for marketing approval, which could materially adversely affect our business, financial condition and results of operations.

As an organization, we have never completed a Phase 3 clinical trial before and may be unable to do so efficiently or at all for our current product candidates or any product candidate we are developing.

We intend to conduct Phase 3 clinical trials of our product candidates. The conduct of Phase 3 clinical trials and the submission of a successful NDA is a complicated process. As an organization, we have not completed a Phase 3 clinical trial before, and we have limited experience in preparing and submitting regulatory filings. Consequently, we may be unable to successfully and efficiently execute and complete necessary clinical trials in a way that leads to NDA submission and approval of our current product candidates or for any other product candidate we develop. We may require more time and incur greater costs than anticipated and may not succeed in obtaining marketing approvals of the product candidates we develop. Failure to commence or complete, or delays in, our planned clinical trials would prevent us from or delay us in commercializing our current product candidates or any other product candidate we are developing.

 

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Marketing approval may be substantially delayed or may not be obtained for one or all of our product candidates if regulatory authorities require additional or more time-consuming studies to assess the safety and efficacy of our product candidates.

We may be unable to initiate or complete development of our product candidates on schedule, if at all. The timing for the completion of the studies for our product candidates will require funding beyond the proceeds of this offering. In addition, if regulatory authorities require additional or more time-consuming studies to assess the safety or efficacy of our product candidates, we may not have or be able to obtain adequate funding to complete the necessary steps for approval for any or all of our product candidates. Additional delays may result if the FDA, an FDA Advisory Committee, if one is convened to review our NDA, or other regulatory authority indicates that the product candidate should not be approved or there should be restrictions on approval, such as the requirement for a Risk Evaluation and Mitigation Strategy, or REMS, to ensure safe use of the drug. Delays in marketing approvals or rejections of applications for marketing approval in the United States or other markets may result from many factors, including:

 

   

the FDA’s or comparable foreign regulatory authorities’ disagreement with the design or implementation of our clinical trials;

 

   

regulatory requests for additional analyses, reports, data, non-clinical and preclinical studies and clinical trials;

 

   

regulatory questions or disagreement by the FDA or comparable regulatory authorities regarding interpretations of data and results and the emergence of new information regarding our current or future product candidates or the field of research;

 

   

unfavorable or inconclusive results of clinical trials and supportive non-clinical studies, including unfavorable results regarding safety or efficacy of our product candidates during clinical trials;

 

   

failure to meet the level of statistical significance required for approval;

 

   

inability to demonstrate that a product candidate’s clinical and other benefits outweigh its safety risks;

 

   

lack of adequate funding to commence or continue our clinical trials due to unforeseen costs or other business decisions;

 

   

regulatory authorities may find inadequate the manufacturing processes or facilities of the third-party manufacturers with whom we contract for clinical and commercial supplies;

 

   

we may have insufficient funds to pay the significant user fees required by the FDA upon the filing of an NDA; and

 

   

the approval policies or regulations of the FDA or comparable foreign regulatory authorities may significantly change in a manner that would delay marketing approval.

The lengthy and unpredictable approval process, as well as the unpredictability of future clinical trial results, may result in our failure to obtain marketing approval to market our other product candidates, which would significantly harm our business, results of operations and prospects.

Our product candidates may cause undesirable adverse effects or have other properties that could delay or prevent their marketing approval, limit the commercial profile of an approved label, or result in significant negative consequences following marketing approval, if any.

Undesirable side effects caused by our product candidates could cause us or regulatory authorities to interrupt, delay or halt clinical trials and could result in a more restrictive label or the delay or denial of marketing approval by the FDA or other comparable foreign authorities. If our current product

 

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candidates or any other product candidate we develop is associated with serious adverse, undesirable or unacceptable side effects, we may need to abandon such candidate’s development or limit development to certain uses or sub-populations in which such side effects are less prevalent, less severe or more acceptable from a risk-benefit perspective. Many compounds that initially showed promise in early-stage or clinical testing have later been found to cause side effects that prevented further development of the compound. Results of our trials could reveal a high and unacceptable prevalence of these or other side effects. In such an event, our trials could be suspended or terminated and the FDA or comparable foreign regulatory authorities could order us to cease further development of or deny approval of our product candidates for any or all targeted indications. The drug-related side effects could affect patient recruitment or the ability of enrolled patients to complete the trial or result in potential product liability claims. To date, the most common side effects observed in clinical studies of our product candidates include dizziness, fatigue and paresthesia (tingling sensation). Because our product candidates have been tested in relatively small patient populations and for limited durations, additional side effects may be observed as development of our product candidates progresses.

If our product candidates receive marketing approval, and we or others later identify undesirable side effects caused by such products, a number of potentially significant negative consequences could result, including:

 

   

regulatory authorities may withdraw approvals of such product;

 

   

we may be required to recall a product or change the way such product is administered to patients;

 

   

additional restrictions may be imposed on the marketing of the particular product or the manufacturing process for the product or any component thereof;

 

   

regulatory authorities may require the addition of labeling statements, such as a precaution, “black box” warning or other warnings or a contraindication;

 

   

we or our collaborators may be required to implement a REMS or create a medication guide outlining the risks of such side effect for distribution to patients;

 

   

we or our collaborators could be sued and held liable for harm caused to patients;

 

   

the product may become less competitive; and

 

   

our reputation may suffer.

Any of these events could prevent us from achieving or maintaining market acceptance of our product candidates, if approved, and could materially adversely affect our business, financial condition, results of operations and prospects.

Even if we receive marketing approval for our product candidates, such approved products will be subject to ongoing obligations and continued regulatory review, which may result in significant additional expense. Additionally, our product candidates, if approved, could be subject to labeling and other restrictions, and we may be subject to penalties and legal sanctions if we fail to comply with regulatory requirements or experience unanticipated problems with our approved products.

If the FDA approves any of our product candidates, the manufacturing processes, labeling, packaging, distribution, adverse event reporting, storage, advertising, promotion and recordkeeping for the product will be subject to extensive and ongoing regulatory requirements. These requirements include submissions of safety and other post-marketing information and reports, registration, as well as continued compliance with cGMP, and GCP for any clinical trials that we conduct post-approval. Any marketing approvals that we receive for our product candidates may also be subject to limitations on the approved indicated uses for which the product may be marketed or to conditions of approval, or contain

 

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requirements for potentially costly post-marketing testing, including Phase 4 clinical trials, and surveillance to monitor safety and efficacy.

Later discovery of previously unknown problems with an approved product, including adverse events of unanticipated severity or frequency, or with manufacturing operations or processes, or failure to comply with regulatory requirements, may result in, among other things:

 

   

restrictions on the marketing or manufacturing of the product, withdrawal of the product from the market, or voluntary or mandatory product recalls;

 

   

fines, warning letters, or holds on clinical trials;

 

   

refusal by the FDA to approve pending applications or supplements to approved applications filed by us, or suspension or revocation of product license approvals;

 

   

product seizure or detention, or refusal to permit the import or export of products; and

 

   

injunctions or the imposition of civil or criminal penalties.

The FDA’s policies may change and additional government regulations may be enacted that could prevent, limit or delay marketing approval, manufacturing or commercialization of our product candidates. We cannot predict the likelihood, nature or extent of government regulation that may arise from future legislation or administrative action, either in the United States or abroad. If we are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or not able to maintain regulatory compliance, we may lose any marketing approval that may have been obtained and we may not achieve or sustain profitability, which would adversely affect our business.

If we fail to obtain regulatory approval in jurisdictions outside the United States, we will not be able to market our products in those jurisdictions.

We intend to market our product candidates, if approved, in international markets, or in conjunction with collaborators. Such marketing will require separate regulatory approvals in each market and compliance with numerous and varying regulatory requirements. The approval procedures vary from country-to-country and may require testing in addition to what is required for a marketing application in the United States. Moreover, the time required to obtain approval may differ from that required to obtain FDA approval. In addition, in many countries outside the United States, a product candidate must be approved for reimbursement before it can be approved for sale in that country. Approval by the FDA does not ensure approval by regulatory authorities in other countries or jurisdictions, and approval by one foreign regulatory authority does not ensure approval by regulatory authorities in other foreign countries or by the FDA. The failure to obtain approval in one jurisdiction may negatively impact our ability to obtain approval in another jurisdiction. The foreign regulatory approval process may include all of the risks associated with obtaining FDA approval and additional or different risks. We may not be able to file for regulatory approvals and may not receive necessary approvals to commercialize our products in any market.

Agencies like the FDA and national competition regulators in European countries regulate the promotion and uses of drugs not consistent with approved product labeling requirements. If we are found to have improperly promoted our current product candidates for uses beyond those that are approved, we may become subject to significant liability.

Regulatory authorities like the FDA and national competition laws in Europe strictly regulate the promotional claims that may be made about prescription products, such as lasmiditan and IV lasmiditan, if approved. In particular, a product may not be promoted for uses that are not approved by the FDA or comparable foreign regulatory authorities as reflected in the product’s approved labeling, known as “off-label” use, nor may it be promoted prior to obtaining marketing approval. If we receive marketing approval for our product candidates for our proposed indications, physicians may nevertheless use our products for their patients in a manner that is inconsistent with the approved label, if the physicians

 

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personally believe in their professional medical judgment it could be used in such manner. Although physicians may prescribe legally available drugs for off-label uses, manufacturers may not market or promote such off-label uses.

In addition, the FDA requires that promotional claims not be “false or misleading” as such terms are defined in the FDA’s regulations. For example, the FDA requires substantial evidence, which generally consists of two adequate and well-controlled head-to-head clinical trials, for a company to make a claim that its product is superior to another product in terms of safety or effectiveness. Generally, unless we perform clinical trials meeting that standard comparing our product candidates to competitive products and these claims are approved in our product labeling, we will not be able promote our current product candidates as superior to other products. If we are found to have made such claims we may become subject to significant liability. In the United States, the federal government has levied large civil and criminal fines against companies for alleged improper promotion and has enjoined several companies from engaging in improper promotion. The FDA has also requested that companies enter into consent decrees or corporate integrity agreements, or could seek permanent injunctions under which specified promotional conduct is monitored, changed or curtailed.

Our current and future relationships with healthcare professionals, investigators, consultants, collaborators, actual customers, potential customers and third-party payors in the United States and elsewhere may be subject, directly or indirectly, to applicable anti-kickback, fraud and abuse, false claims, physician payment transparency, health information privacy and security and other healthcare laws and regulations, which could expose us to sanctions.

Healthcare providers, physicians and third-party payors in the United States and elsewhere will play a primary role in the recommendation and prescription of any drug candidates for which we obtain marketing approval. Our current and future arrangements with healthcare professionals, investigators, consultants, collaborators, actual customers, potential customers and third-party payors may expose us to broadly applicable fraud and abuse and other healthcare laws, including, without limitation, the federal Anti-Kickback Statute and the federal False Claims Act, that may constrain the business or financial arrangements and relationships through which we sell, market and distribute any drug candidates for which we obtain marketing approval. In addition, we may be subject to physician payment transparency laws and patient privacy and security regulation by the federal government and by the U.S. states and foreign jurisdictions in which we conduct our business. The applicable federal, state and foreign healthcare laws that may affect our ability to operate include the following:

 

   

the federal Anti-Kickback Statute, which prohibits, among other things, persons from knowingly and willfully soliciting, offering, receiving or providing remuneration, directly or indirectly, in cash or in kind, to induce or reward, or in return for, either the referral of an individual for, or the purchase, lease, order or recommendation of, any good, facility, item or service, for which payment may be made, in whole or in part, under federal and state healthcare programs such as Medicare and Medicaid;

 

   

federal civil and criminal false claims laws and civil monetary penalty laws, including the federal False Claims Act, which impose criminal and civil penalties, including civil whistleblower or qui tam actions, against individuals or entities for, among other things, knowingly presenting, or causing to be presented, to the federal government, including the Medicare and Medicaid programs, claims for payment that are false or fraudulent or making a false statement to avoid, decrease or conceal an obligation to pay money to the federal government;

 

   

the civil monetary penalties statute, which imposes penalties against any person or entity who, among other things, is determined to have presented or caused to be presented a claim to a federal health program that the person knows or should know is for an item or service that was not provided as claimed or is false or fraudulent;

 

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the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which created new federal criminal statutes that prohibit knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program or obtain, by means of false or fraudulent pretenses, representations or promises, any of the money or property owned by, or under the custody or control of, any healthcare benefit program, regardless of the payor (e.g., public or private), knowingly and willfully embezzling or stealing from a health care benefit program, willfully obstructing a criminal investigation of a healthcare offense and knowingly and willfully falsifying, concealing or covering up by any trick or device a material fact or making any materially false statements in connection with the delivery of, or payment for, healthcare benefits, items or services relating to healthcare matters;

 

   

HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, or HITECH, and their respective implementing regulations, which impose obligations on covered entities, including healthcare providers, health plans, and healthcare clearinghouses, as well as their respective business associates that create, receive, maintain or transmit individually identifiable health information for or on behalf of a covered entity, with respect to safeguarding the privacy, security and transmission of individually identifiable health information;

 

   

the federal Open Payments program, created under Section 6002 of the Affordable Care Act and its implementing regulations, which imposed new annual reporting requirements for manufacturers of drugs, devices, biologicals and medical supplies for certain payments and “transfers of value” provided to physicians and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members. Failure to submit timely, accurately and completely the required information for all covered payments, transfers of value and ownership or investment interests may result in civil monetary penalties; and

 

   

analogous state and foreign laws, such as state anti-kickback and false claims laws, which may apply to sales or marketing arrangements and claims involving healthcare items or services reimbursed by non-governmental third-party payors, including private insurers; state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government or otherwise restrict payments that may be made to healthcare providers; state and foreign laws that require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers or marketing expenditures; and state and foreign laws governing the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts.

Further, the Affordable Care Act, among other things, amended the intent requirement of the federal Anti-Kickback Statute and certain criminal statutes governing healthcare fraud. A person or entity no longer needs to have actual knowledge of the statute or specific intent to violate it. In addition, the Affordable Care Act provided that the government may assert that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the False Claims Act.

Efforts to ensure that our future business arrangements with third parties will comply with applicable healthcare laws and regulations may involve substantial costs. It is possible that governmental authorities will conclude that our business practices may not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws. If our operations are found to be

 

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in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant civil, criminal and administrative penalties, including, without limitation, damages, fines, imprisonment, exclusion from participation in government healthcare programs, such as Medicare and Medicaid, and the curtailment or restructuring of our operations, which could significantly harm our business. If any of the physicians or other healthcare providers or entities with whom we expect to do business, including our current and future collaborators, if any, is found not to be in compliance with applicable laws, those persons or entities may be subject to criminal, civil or administrative sanctions, including exclusions from participation in government healthcare programs, which could also affect our business.

The impact of recent healthcare reform legislation and other changes in the healthcare industry and healthcare spending on us is currently unknown, and may adversely affect our business model.

In the United States and some foreign jurisdictions, legislative and regulatory changes and proposed changes regarding the healthcare system could prevent or delay marketing approval of our drug candidates, restrict or regulate post-approval activities and affect our ability to profitably sell any drug candidates for which we obtain marketing approval.

Our revenue prospects could be affected by changes in healthcare spending and policy in the United States and abroad. We operate in a highly regulated industry and new laws, judicial decisions, or new interpretations of existing laws, or decisions, related to healthcare availability, the method of delivery or payment for healthcare products and services could negatively impact our business, financial condition, results of operations, and prospects. There is significant interest in promoting health care reform, as evidenced by the enactment in the United States of the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or the Affordable Care Act. Among other things, the Affordable Care Act contains provisions that may reduce the profitability of drug products, including, for example, revising the methodology by which rebates owed by manufacturers for covered outpatient drugs under the Medicaid Drug Rebate Program are calculated, extending the Medicaid Drug Rebate Program to utilization of prescriptions of individuals enrolled in Medicaid managed care plans, imposing mandatory discounts for certain Medicare Part D beneficiaries, and subjecting drug manufacturers to payment of an annual fee.

In addition, other legislative changes have been proposed and adopted in the United States since the Affordable Care Act was enacted. On August 2, 2011, the Budget Control Act of 2011 among other things, created measures for spending reductions by Congress. A Joint Select Committee on Deficit Reduction, tasked with recommending a targeted deficit reduction of at least $1.2 trillion for the years 2013 through 2021, was unable to reach required goals, thereby triggering the legislation’s automatic reduction to several government programs. This includes aggregate reductions to Medicare payments to providers of 2% per fiscal year, which started in April 2013, and, due to subsequent legislative amendments, will remain in effect through 2024 unless additional Congressional action is taken. On January 2, 2013, the American Taxpayer Relief Act of 2012 was signed into law, which, among other things, also reduced Medicare payments to several providers, including hospitals, imaging centers and cancer treatment centers.

We expect that the Affordable Care Act, as well as other healthcare reform measures that may be adopted in the future, may result in more rigorous coverage criteria and in additional downward pressure on the price that we receive for any approved product. Any reduction in reimbursement from Medicare or other government programs may result in a similar reduction in payments from private payors. The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue or commercialize our drugs.

 

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It is likely that federal and state legislatures within the United States and foreign governments will continue to consider changes to existing healthcare legislation. We cannot predict the reform initiatives that may be adopted in the future or whether initiatives that have been adopted will be repealed or modified. The continuing efforts of the government, insurance companies, managed care organizations and other payors of healthcare services to contain or reduce costs of healthcare may adversely affect:

 

   

the demand for any drug products for which we may obtain marketing approval;

 

   

our ability to set a price that we believe is fair for our products;

 

   

our ability to obtain coverage and reimbursement approval for a product;

 

   

our ability to generate revenues and achieve or maintain profitability; and

 

   

the level of taxes that we are required to pay.

Risks Related to Our Business

Due to our limited resources and access to capital, we must decide to prioritize development of our current product candidates for certain indications and at certain doses. These decisions may prove to have been wrong and may materially adversely affect our business, financial condition, results of operations and prospects.

Because we have limited resources and access to capital to fund our operations, we must decide which dosages and indications to pursue for the clinical development of our current product candidates and the amount of resources to allocate to each. Our decisions concerning the allocation of research, collaboration, management and financial resources toward dosages or therapeutic areas may not lead to the development of viable commercial products and may divert resources away from better opportunities. If we make incorrect determinations regarding the market potential of our current product candidates or misread trends in the pharmaceutical industry, our business, financial condition, results of operations and prospects could be materially adversely affected.

We may not be able to win government, academic institution or non-profit contracts or grants.

From time to time, we may apply for contracts or grants from government agencies, non-profit entities and academic institutions. Such contracts or grants can be highly attractive because they provide capital to fund the on-going development of our product candidates without diluting our stockholders. However, there is often significant competition for these contracts or grants. Entities offering contracts or grants may have requirements to apply for or to otherwise be eligible for certain contracts or grants that our competitors may be able to satisfy that we cannot. In addition, such entities may make arbitrary decisions as to whether to offer contracts or make grants, to whom the contracts or grants may will be awarded and the size of the contracts or grants to each awardee. Even if we are able to satisfy the award requirements, there is no guarantee that we will be a successful awardee. Therefore, we may not be able to win any contracts or grants in a timely manner, if at all.

If we fail to attract and retain key management and scientific personnel, we may be unable to successfully develop or commercialize our product candidates.

Our success as a biopharmaceutical company depends on our continued ability to attract, retain and motivate highly qualified management and scientific and clinical personnel. The loss of the services of any of our senior management could delay or prevent obtaining marketing approval or commercialization of our product candidates.

We may not be able to attract or retain qualified management and scientific personnel in the future due to the intense competition for a limited number of qualified personnel among biopharmaceutical, biotechnology, pharmaceutical and other businesses. Our failure to attract, hire, integrate and retain qualified personnel could impair our ability to achieve our business objectives.

 

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If a successful product liability claim or series of claims is brought against us for uninsured liabilities or in excess of insured liabilities, we could be forced to pay substantial damage awards.

The use of any of our product candidates in clinical trials, and the sale of any approved products, may expose us to product liability claims. We currently maintain $5 million of product liability insurance coverage, which is an amount we believe is adequate for our clinical trials currently in progress and those recently completed. We monitor the amount of coverage we maintain as the size and design of our clinical trials evolve and intend to adjust the amount of coverage we maintain accordingly. However, we cannot assure you that such insurance coverage will fully protect us against some or all of the claims to which we might become subject. We might not be able to maintain adequate insurance coverage at a reasonable cost or in sufficient amounts or scope to protect us against potential losses. In the event a claim is brought against us, we might be required to pay legal and other expenses to defend the claim, as well as uncovered damages awards resulting from a claim brought successfully against us. Furthermore, whether or not we are ultimately successful in defending any such claims, we might be required to direct financial and managerial resources to such defense and adverse publicity could result, all of which could harm our business.

Our employees, independent contractors, investigators, contract research organizations, consultants, collaborators and vendors may engage in misconduct or other improper activities, including noncompliance with regulatory standards and requirements and insider trading.

We are exposed to the risk that our employees and other third parties may engage in fraudulent conduct or other illegal activity. Misconduct by employees and other third parties could include intentional, reckless and/or negligent conduct or disclosure of unauthorized activities to us that violate FDA regulations, including those laws requiring the reporting of true, complete and accurate information to the FDA, manufacturing standards, federal and state healthcare fraud and abuse laws and regulations, or laws that require the reporting of financial information or data accurately. In particular, sales, marketing and business arrangements in the healthcare industry are subject to extensive laws intended to prevent fraud, kickbacks, self-dealing and other abusive practices. These laws and regulations may restrict or prohibit a wide range of pricing, discounting, marketing and promotion, sales commission, customer incentive programs and other business arrangements. Activities subject to these laws also involve the improper use of information obtained in the course of clinical trials, which could result in regulatory sanctions and serious harm to our reputation. It is not always possible to identify and deter employee and other third-party misconduct, and the precautions we take to detect and prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to be in compliance with such laws. If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business, including the imposition of significant civil, criminal and administrative penalties, damages, monetary fines, disgorgement, possible exclusion from participation in Medicare, Medicaid and other federal healthcare programs, contractual damages, reputational harm, diminished profits and future earnings and curtailment or restructuring of our operations, any of which could adversely affect our ability to operate.

As we evolve from a company primarily involved in clinical development to a company also involved in commercialization, if we obtain approval of our product candidates, we may encounter difficulties in managing our growth and expanding our operations successfully.

As we advance our product candidates through clinical trials, we will need to expand our development, regulatory, manufacturing, marketing and sales capabilities or contract with third parties to provide these capabilities for us. As our operations expand, we expect that we will need to manage additional relationships with such third parties, as well as additional collaborators and suppliers.

 

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Maintaining these relationships and managing our future growth will impose significant added responsibilities on members of our management and other personnel. We must be able to: manage our development efforts effectively; manage our clinical trials effectively; hire, train and integrate additional management, development, administrative and sales and marketing personnel; improve our managerial, development, operational and finance systems; and expand our facilities, all of which may impose a strain on our administrative and operational infrastructure.

Our internal computer systems, or those of our development collaborators, third-party clinical research organizations or other contractors or consultants, may fail or suffer security breaches, which could result in a material disruption of our product development programs.

Despite the implementation of security measures, our internal computer systems and those of our current and any future contract research organizations and other contractors, consultants and collaborators are vulnerable to damage from computer viruses, unauthorized access, natural disasters, terrorism, war and telecommunication and electrical failures. While we have not experienced any such material system failure, accident or security breach to date, if such an event were to occur and cause interruptions in our operations, it could result in a material disruption of our development programs and our business operations. For example, the loss of clinical trial data from completed or future clinical trials could result in delays in our marketing approval efforts and significantly increase our costs to recover or reproduce the data. Likewise, we rely on third parties to manufacture our product candidates and conduct clinical trials, and similar events relating to their computer systems could also have a material adverse effect on our business. To the extent that any disruption or security breach were to result in a loss of, or damage to, our data or applications, or inappropriate disclosure of confidential or proprietary information, we could incur liability and the further development and commercialization of our product candidates could be delayed.

Risks Related to Commercialization of Our Product Candidates

Even if we obtain the required regulatory approvals in the United States and other territories, the commercial success of our product candidates will depend on market awareness and acceptance of our product candidates.

Even if we obtain marketing approval for our current product candidates or any other product candidates that we may develop or acquire in the future, the product may not gain market acceptance among physicians, key opinion leaders, healthcare payors, patients and the medical community. Market acceptance of any approved products depends on a number of factors, including:

 

   

the timing of market introduction;

 

   

the efficacy and safety of the product, as demonstrated in clinical trials;

 

   

the clinical indications for which the product is approved and the label approved by regulatory authorities for use with the product, including any precautions, warnings or contraindications that may be required on the label;

 

   

acceptance by physicians, key opinion leaders and patients of the product as a safe and effective treatment;

 

   

the cost, safety and efficacy of treatment in relation to alternative treatments;

 

   

the availability of coverage and adequate reimbursement and pricing by third-party payors and government authorities;

 

   

the number and clinical profile of competing products;

 

   

the growth of drug markets in our various indications;

 

   

relative convenience and ease of administration;

 

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marketing and distribution support;

 

   

the prevalence and severity of adverse side effects; and

 

   

the effectiveness of our sales and marketing efforts.

Market acceptance is critical to our ability to generate revenue. Any product candidate, if approved and commercialized, may be accepted in only limited capacities or not at all. If any approved products are not accepted by the market to the extent that we expect, we may not be able to generate revenue and our business would suffer.

We have never commercialized a product candidate, and we currently have no marketing and sales organization. To the extent our product candidates are approved for marketing, if we are unable to establish marketing and sales capabilities or enter into agreements with third parties to market and sell our product candidates, we may not be able to effectively market and sell our product candidates or generate product revenue.

We have never commercialized a product candidate, and we currently do not have marketing, sales or distribution capabilities for our product candidates. In order to commercialize any of our products that receive marketing approval, we would have to build marketing, sales, distribution, managerial and other non-technical capabilities or make arrangements with third parties to perform these services, and we may not be successful in doing so. In the event of successful development of our product candidates, if we elect to build a targeted specialty sales force, such an effort would be expensive and time consuming. Any failure or delay in the development of our internal sales, marketing and distribution capabilities would adversely impact the commercialization of these products. We may choose to collaborate with third parties that have their own sales forces and established distribution systems, in lieu of or to augment any sales force and distribution systems we may create. If we are unable to enter into collaborations with third parties for the commercialization of approved products, if any, on acceptable terms or at all, or if any such collaborator does not devote sufficient resources to the commercialization of our product or otherwise fails in commercialization efforts, we may not be able to successfully commercialize our product candidates if it receives marketing approval. If we are not successful in commercializing our product candidates, either on our own or through collaborations with one or more third parties, our future revenue will be materially and adversely impacted.

If we fail to enter into strategic relationships or collaborations, our business, financial condition, commercialization prospects and results of operations may be materially adversely affected.

Our product development programs and the potential commercialization of our current product candidates will require substantial additional cash to fund expenses. Therefore, in addition to financing the developments of our product candidates through additional equity financings or through debt financings, we may decide to enter into collaborations with pharmaceutical or biopharmaceutical companies for the development and potential commercialization of our product candidates.

We face significant competition in seeking appropriate collaborators. Collaborations are complex and time-consuming to negotiate and document. We may also be restricted under existing and future collaboration agreements from entering into agreements on certain terms with other potential collaborators. We may not be able to negotiate collaborations on acceptable terms, or at all. If that were to occur, we may have to curtail the development of a particular product, reduce or delay its development program or one or more of our other development programs, delay its potential commercialization or reduce the scope of our sales or marketing activities, or increase our expenditures and undertake development or commercialization activities at our own expense. If we elect to increase our expenditures to fund development or commercialization activities on our own, we may need to obtain additional capital, which may not be available to us on acceptable terms or at all. If we do not have sufficient funds, we will not be able to bring our product candidates to market and generate

 

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product revenue. If we do enter into a new collaboration agreement, we could be subject to the following risks, each of which may materially harm our business, commercialization prospects and financial condition:

 

   

we may not be able to control the amount and timing of resources that the collaborator devotes to the product development program;

 

   

the collaborator may experience financial difficulties and thus not commit sufficient financial resources to the product development program;

 

   

we may be required to relinquish important rights such as marketing, distribution and intellectual property rights;

 

   

a collaborator could move forward with a competing product developed either independently or in collaboration with third parties, including our competitors; or

 

   

business combinations or significant changes in a collaborator’s business strategy may adversely affect our willingness to complete our obligations under any arrangement.

Our strategy for the development and commercialization of IV lasmiditan depends on securing a collaboration prior to commencing a pivotal Phase 3 clinical trial, and if we fail to secure such a collaboration on acceptable terms, it could delay or limit our ability to successfully develop and commercialize IV lasmiditan.

We plan to commence a pivotal Phase 3 clinical trial for IV lasmiditan after securing a collaboration for the development and commercialization of IV lasmiditan. Given the unique call point of emergency rooms and other urgent care settings, which will be outside of our specialty sales force, a sales force with expertise in such settings would be best positioned for commercialization of IV lasmiditan. We expect to face significant challenges in securing a collaboration with a party that has the appropriate expertise to successfully develop and commercialize IV lasmiditan. Even if we are able to identify an appropriate collaborator, we may be unable to negotiate such collaboration on acceptable terms, or at all. If we are unable to secure such a collaboration, it could delay or limit our ability to develop and commercialize IV lasmiditan as we continue to seek an appropriate collaboration or expend additional capital to hire additional personnel with the necessary expertise to develop and commercialize IV lasmiditan.

Our product candidates utilize a novel mechanism of action, which may result in greater research and development expenses, regulatory issues that could delay or prevent approval, or discovery of unknown or unanticipated adverse effects.

Lasmiditan is a new chemical entity designed to treat migraine using a novel mechanism by acting as an agonist at the 5-HT1F receptor. In contrast to triptans, which act peripherally, lasmiditan is designed to penetrate the CNS and to block the pathway that contributes to headache pain. There can be no assurance that problems related to the development of this novel mechanism will not arise in the future, which may cause significant delays or we may not be able to resolve.

Regulatory approval of novel product candidates such as ours can be more expensive and take longer than for other, more well-known or extensively studied pharmaceutical or biopharmaceutical product candidates due to our and regulatory agencies’ lack of experience with them. The novelty of our mechanism of action may lengthen the regulatory review process, require us to conduct additional studies or clinical trials, increase our development costs, lead to changes in regulatory positions and interpretations, delay or prevent approval and commercialization of our product candidates or lead to significant post-approval limitations or restrictions. The novel mechanism of action of lasmiditan and IV lasmitidan also means that fewer people are trained in or experienced with product candidates of this type, which may make it more difficult to find, hire and retain personnel for research, development and manufacturing positions. Because lasmiditan utilizes a novel mechanism of action that has not been the subject of extensive study compared to more well-known product candidates, there is also an increased

 

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risk that we may discover previously unknown or unanticipated adverse effects during our pivotal Phase 3 clinical trials and beyond. Any such events could adversely impact our business prospects, financial condition and results of operations.

Coverage and reimbursement may be limited or unavailable in certain market segments for our product candidates, which could make it difficult for us to sell our products profitably.

There is significant uncertainty related to third-party coverage and reimbursement of newly approved pharmaceuticals. Market acceptance and sales of any approved product candidates will depend significantly on the availability of coverage and adequate reimbursement from third-party payors and may be affected by existing and future healthcare reform measures. Government authorities and third-party payors, such as private health insurers and health maintenance organizations, decide which drugs they will pay for and establish reimbursement levels. Increasingly, third-party payors are requiring that drug companies provide them with predetermined discounts from list prices and are challenging the prices charged for drugs and products. Coverage and reimbursement may not be available for any product that we commercialize and, even if these are available, the level of reimbursement may not be satisfactory. Inadequate reimbursement levels may adversely affect the demand for, or the price of, any drug candidate for which we obtain marketing approval.

Reimbursement by a third-party payor may depend upon a number of factors, including the third-party payor’s determination that use of a product is, among other things:

 

   

a covered benefit under its health plan;

 

   

safe, effective and medically necessary;

 

   

appropriate for the specific patient;

 

   

cost-effective; and

 

   

neither experimental nor investigational.

Obtaining coverage and adequate reimbursement approval for a product from a government or other third-party payor is a time consuming and costly process that could require us to provide supporting scientific, clinical and cost-effectiveness data for the use of our products to the payor. We may not be able to provide data sufficient to gain acceptance with respect to coverage and adequate reimbursement. In addition to examining the medical necessity and cost-effectiveness of new products, there may be limited coverage to specific drug products on an approved list, or formulary, which might not include all of the FDA-approved drug products for a particular indication. There may also be formulary placements that result in lower reimbursement levels and higher cost-sharing borne by patients, any of which could have an adverse effect on our revenues and profits. Moreover, a third-party payor’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved. Adequate third-party reimbursement may not be available to enable us to maintain price levels sufficient to realize an appropriate return on our investment in product development. Additionally, coverage and reimbursement for drug products can differ significantly from payor to payor. One third-party payor’s decision to cover a particular drug product does not ensure that other payors will also provide coverage for the drug product, or even if coverage is available, establish an adequate reimbursement rate.

Patients who are prescribed treatments for their conditions and providers performing the prescribed services generally rely on third-party payors to reimburse all or part of the associated healthcare costs. Patients are unlikely to use our product candidates, once approved, unless coverage is provided and reimbursement is adequate to cover a significant portion of the cost of our products. Sales of our product candidates will, therefore, depend substantially on the extent to which the costs of our product candidates will be paid by third-party payors.

 

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We cannot be sure that coverage or adequate reimbursement will be available for any of our product candidates. Also, we cannot be sure that reimbursement amounts will not reduce the demand for, or the price of, our products. If reimbursement is not available or is available only to limited levels, we may not be able to commercialize certain of our products. In addition in the United States, third-party payors are increasingly attempting to contain healthcare costs by limiting both coverage and the level of reimbursement of new drugs. As a result, significant uncertainty exists as to whether and how much third-party payors will reimburse patients for their use of newly approved drugs, which in turn will put pressure on the pricing of drugs.

Outside of the United States, government programs that reimburse at typically predetermined fixed rates may decrease or otherwise limit amounts available through reimbursement. For example, in the European Union, member states impose controls on whether products are reimbursable by national or regional health service providers and on the prices at which medicines and medical devices are reimbursed under state-run healthcare schemes. Some member states operate reference pricing systems in which they set national reimbursement prices by reference to those in other member states. Other governmental funding restrictions, legislative proposals and interpretations of policy may negatively impact amounts available through reimbursement, including by restricting payment increases to hospitals and other providers through reimbursement systems. We are not able to predict whether changes will be made in the rates prescribed by these governmental programs or, if they are made, what effect they could have on our business. However, governmental rate changes and other similar developments could negatively affect our ability to sell our products, if approved.

We face substantial competition, which may result in others discovering, developing or commercializing products before, or more successfully, than we do.

The life sciences industry is highly competitive, and we face significant competition from many pharmaceutical, biopharmaceutical and biotechnology companies that are researching and marketing products designed to treat migraine and headache pain. Such competition may include large pharmaceutical and biotechnology companies, specialty pharmaceutical and generic companies and medical technology companies. Our future success depends on our ability to demonstrate and maintain a competitive advantage with respect to the design, development and commercialization of our product candidates. Our objective is to design, develop and commercialize new products with superior efficacy, convenience, tolerability and safety. In many cases, the product candidates that we intend to commercialize with our strategic collaborators or on our own will compete with existing, market-leading products.

If our product candidates are approved, they will compete with currently marketed drugs and devices and potentially with product candidates currently in development to treat migraine. Many of our potential competitors have significantly greater financial, manufacturing, marketing, development, technical and human resources than we do. Large pharmaceutical and biotechnology companies, in particular, have extensive experience in clinical testing, obtaining regulatory approvals, recruiting patients and in manufacturing clinical products. These companies also have significantly greater research and marketing capabilities than we do and may also have products that have been approved or are in late stages of development, and have collaborative arrangements in our target markets with leading companies and research institutions. Established companies may also invest heavily to accelerate discovery and development of compounds that could make the product candidates that we develop obsolete. As a result of all of these factors, the highly competitive nature of and rapid technological changes in the industry could render our product candidates or our technology obsolete or non-competitive. Our competitors may, among other things:

 

   

have greater name and brand recognition, financial and human resources;

 

   

develop and commercialize products that are safer, more effective, less expensive, or more convenient or easier to administer;

 

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obtain quicker marketing approval;

 

   

establish superior proprietary positions;

 

   

have access to more manufacturing capacity;

 

   

implement more effective approaches to sales and marketing; or

 

   

form more advantageous strategic alliances.

Should any of these factors occur, our business, financial condition, results of operations, and prospects could be materially adversely affected. If we are not able to compete effectively against potential competitors, our business will not grow and our financial condition and operations will suffer.

We believe that our ability to successfully compete will depend on, among other things:

 

   

our ability to design and successfully execute appropriate clinical trials;

 

   

our ability to recruit and enroll patients for our clinical trials;

 

   

the results of our clinical trials and the efficacy and safety of our product candidates;

 

   

the speed at which we develop our product candidates;

 

   

achieving and maintaining compliance with regulatory requirements applicable to our business;

 

   

the timing and scope of regulatory approvals, including labeling;

 

   

adequate levels of reimbursement under private and governmental health insurance plans, including Medicare;

 

   

our ability to protect intellectual property rights related to our product candidates;

 

   

our ability to commercialize and market any of our product candidates that may receive marketing approval;

 

   

our ability to manufacture and sell commercial quantities of any approved product candidates to the market;

 

   

acceptance of our product candidates by physicians, other healthcare providers and patients; and

 

   

the cost of treatment in relation to alternative therapies.

Price controls may be imposed in foreign markets, which may adversely affect our future profitability.

In some countries, particularly member states of the European Union, the pricing of prescription drugs is subject to governmental control. In these countries, pricing negotiations with governmental authorities can take considerable time after receipt of marketing approval for a product. In addition, there can be considerable pressure by governments and other stakeholders on prices and reimbursement levels, including as part of cost containment measures. Political, economic and regulatory developments may further complicate pricing negotiations, and pricing negotiations may continue after reimbursement has been obtained. Reference pricing used by various European Union member states and parallel distribution, or arbitrage between low-priced and high-priced member states, can further reduce prices. In some countries, we may be required to conduct a clinical trial or other studies that compare the cost-effectiveness of our product candidates to other available therapies in order to obtain or maintain reimbursement or pricing approval. Publication of discounts by third-party payors or authorities may lead to further pressure on the prices or reimbursement levels within the country of publication and other countries. If reimbursement of our products is unavailable or limited in scope or amount, or if pricing is set at unsatisfactory levels, our business could be adversely affected.

 

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Risks Related to Third Parties

We currently rely on third-party suppliers and other third parties for production of our product candidates and our dependence on these third parties may impair the advancement of our research and development programs and the development of our product candidates.

We do not currently own or operate manufacturing facilities for clinical or commercial production of our product candidates. We lack the resources and the capability to manufacture any of our product candidates on a clinical or commercial scale. Instead, we currently rely on, and expect to continue to rely on, only one third party for the supply of raw materials and manufacture of drug supplies necessary to conduct our preclinical studies and clinical trials. Our current reliance on one third party may expose us to more risk than if we were to manufacture our current product candidates or other products ourselves, or if we were to have relationships with multiple or back-up third parties. Delays in production by this third party could delay our clinical trials or have an adverse impact on any commercial activities. In addition, the fact that we are dependent on this third party for the manufacture of and formulation of our product candidates means that we are subject to the risk that the products may have manufacturing defects that we have limited ability to prevent or control. Although we oversee these activities to ensure compliance with our quality standards, budgets and timelines, we have had and will continue to have less control over the manufacturing of our product candidates than potentially would be the case if we were to manufacture our product candidates, or have alternative manufacturers to turn to in instances where batches of our product candidates did not meet required standards. Further, the third party we deal with could have staffing difficulties, might undergo changes in priorities or may become financially distressed, which would adversely affect the manufacturing and production of our lasmiditan oral tablets and IV formulation. In addition, they could be acquired by, or enter into an exclusive arrangement with, one of our competitors, which would adversely affect our ability to access the formulations we require. In the event that we need to transition to alternate sources of raw materials supply or finished goods manufacturing to satisfy our requirements, we cannot be certain that such sources exist or that there would not be significant delay or material additional costs associated with such a transition.

The facilities used by our current contract manufacturer and any future manufacturers to manufacture our product candidates must be inspected by the FDA after we submit our NDA to the FDA. We do not control the manufacturing process of, and are completely dependent on, our contract manufacturers for compliance with the regulatory requirements, known as cGMPs, for manufacture of both active drug substances and finished drug products. If our contract manufacturers cannot successfully manufacture material that conforms to our specifications and the strict regulatory requirements of the FDA or others, FDA may refuse to approve our NDA. If the FDA or a comparable foreign regulatory authority does not approve our NDA because of concerns about the manufacture of our product candidates or if significant manufacturing issues arise in the future, we may need to find alternative manufacturing facilities, which would significantly impact our ability to develop, obtain marketing approval of our NDA or to continue to market our product candidates, if approved. Although we are ultimately responsible for ensuring compliance with these regulatory requirements, we do not have day-to-day control over a contract manufacturing organization, or CMO, or other third-party manufacturer’s compliance with applicable laws and regulations, including cGMPs and other laws and regulations, such as those related to environmental health and safety matters. Any failure to achieve and maintain compliance with these laws, regulations and standards could subject us to the risk that we may have to suspend the manufacturing of our product candidates or that obtained approvals could be revoked, which would adversely affect our business and reputation. In addition, third-party contractors, such as our CMOs, may elect not to continue to work with us due to factors beyond our control. They may also refuse to work with us because of their own financial difficulties, business priorities or other reasons, at a time that is costly or otherwise inconvenient for us. If we were unable to find adequate replacement or another acceptable solution in time, our clinical trials could be delayed or our commercial activities could be harmed.

 

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Problems with the quality of the work of third parties, may lead us to seek to terminate our working relationships and use alternative service providers. However, making this change may be costly and may delay the trials. In addition, it may be very challenging, and in some cases impossible, to find replacement service providers that can develop and manufacture the lasmiditan in an acceptable manner and at an acceptable cost and on a timely basis. The sale of products containing any defects or any delays in the supply of necessary services could adversely affect our business, financial condition, results of operations, and prospects.

Growth in the costs and expenses of components or raw materials may also adversely affect our business, financial condition, results of operations, and prospects. Supply sources could be interrupted from time to time and, if interrupted, supplies may not be resumed (whether in part or in whole) within a reasonable timeframe and at an acceptable cost or at all.

We currently rely on one CRO to conduct clinical trials for our product candidates and plan to rely on third parties to conduct future clinical trials. If these third parties do not successfully carry out their contractual duties or meet expected deadlines, it may cause delays in commencing and completing clinical trials of our product candidates or we may be unable to obtain marketing approval for or commercialize our product candidates.

Clinical trials must meet applicable FDA and foreign regulatory requirements. We do not have the ability to independently conduct Phase 2 or Phase 3 clinical trials for any of our product candidates. We currently rely and expect to continue to rely on third parties, such as contract research organizations, medical institutions, clinical investigators and contract laboratories, to conduct all of our clinical trials of our product candidates; however, we remain responsible for ensuring that each of our clinical trials is conducted in accordance with its investigational plan and protocol. Moreover, the FDA and other foreign regulatory authorities require us to comply with regulations and standards, commonly referred to as GCPs for conducting, monitoring, recording and reporting the results of clinical trials to ensure that the data and results are scientifically credible and accurate and that the trial subjects are adequately informed of the potential risks of participating in clinical trials. Our reliance on third parties does not relieve us of these responsibilities and requirements. Regulatory authorities enforce these GCPs through periodic inspections of trial sponsors, principal investigators and trial sites. If we or any of our third-party contractors fail to comply with applicable GCPs, the clinical data generated in our clinical trials may be deemed unreliable and the FDA or comparable foreign regulatory authorities may require us to perform additional clinical trials before approving our marketing applications. We cannot assure you that upon inspection by a given regulatory authority, such regulatory authority will determine that any of our clinical trials comply with cGCP regulations. In addition, our clinical trials must be conducted with product produced under cGMP regulations. Our failure to comply with these regulations may require us to repeat clinical trials, which would delay the marketing approval process.

We or the third parties we rely on may encounter problems in clinical trials that may cause us or the FDA or foreign regulatory agencies to delay, suspend or terminate our clinical trials at any phase. These problems could include the possibility that we may not be able to manufacture sufficient quantities of materials for use in our clinical trials, conduct clinical trials at our preferred sites, enroll a sufficient number of patients for our clinical trials at one or more sites, or begin or successfully complete clinical trials in a timely fashion, if at all. Furthermore, we, the FDA or foreign regulatory agencies may suspend clinical trials of our product candidates at any time if we or they believe the subjects participating in the trials are being exposed to unacceptable health risks, whether as a result of adverse events occurring in our trials or otherwise, or if we or they find deficiencies in the clinical trial process or conduct of the investigation.

The FDA and foreign regulatory agencies could also require additional clinical trials before or after granting of marketing approval for any products, which would result in increased costs and significant delays in the development and commercialization of such products and could result in the withdrawal of

 

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such products from the market after obtaining marketing approval. Our failure to adequately demonstrate the safety and efficacy of a product candidate in clinical development could delay or prevent obtaining marketing approval of the product candidate and, after obtaining marketing approval, data from post-approval studies could result in the product being withdrawn from the market, either of which would likely have a material adverse effect on our business.

If our contractors fail to comply with continuing regulations, we or they may be subject to enforcement action that could adversely affect us.

If any of our contractors fail to comply with the requirements of the FDA and other applicable U.S. or foreign governmental or regulatory authorities or previously unknown problems with our products, manufacturers or manufacturing processes are discovered, we or the contractor could be subject to administrative or judicially imposed sanctions, including: restrictions on the products, the manufacturers or manufacturing processes we use, warning letters, civil or criminal penalties, fines, injunctions, product seizures or detentions, import bans, voluntary or mandatory product recalls and publicity requirements, suspension or withdrawal of regulatory approvals, total or partial suspension of production, and refusal to approve pending applications for marketing approval of new products to approved applications.

If we fail to retain accounting and finance staff with appropriate experience, our ability to maintain the financial controls required of a public company may adversely affect our business.

We currently rely on third-party accounting professionals to assist us with our financial accounting and compliance obligations. We are seeking financial professionals with appropriate experience to maintain our financial control and reporting obligations as a public company. If we are unable to identify and retain such qualified and experienced personnel, our business may be adversely impacted.

 

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Risks Related to Our Intellectual Property

Our proprietary rights may not adequately protect our technologies and product candidates.

Our commercial success will depend in part on our ability to obtain additional patents and protect our existing patent position as well as our ability to maintain adequate protection of other intellectual property for our technologies, product candidates, and any future products in the United States and other countries. If we do not adequately protect our intellectual property, competitors may be able to use our technologies and erode or negate any competitive advantage we may have, which could harm our business and ability to achieve profitability. The laws of some foreign countries do not protect our proprietary rights to the same extent or in the same manner as U.S. laws, and we may encounter significant problems in protecting and defending our proprietary rights in these countries. We will be able to protect our proprietary rights from unauthorized use by third parties only to the extent that our proprietary technologies, product candidates and any future products are covered by valid and enforceable patents or are effectively maintained as trade secrets.

We apply for patents covering both our technologies and product candidates, as we deem appropriate. However, we may fail to apply for patents on important technologies or product candidates in a timely fashion, or at all. Our existing patents and any future patents we obtain may not be sufficiently broad to prevent others from practicing our technologies or from developing competing products and technologies. We cannot be certain that our patent applications will be approved or that any patents issued will adequately protect our intellectual property.

While we are responsible for and have control over the filing and prosecuting of patent applications and maintaining patents which cover making, using or selling lasmiditan we may lose such rights if we decide to allow any licensed patent to lapse. If we fail to appropriately prosecute and maintain patent protection for any of our product candidates, our ability to develop and commercialize those product candidates may be adversely affected and we may not be able to prevent competitors from making, using and selling competing products.

Moreover, the patent positions of pharmaceutical companies are highly uncertain and involve complex legal and factual questions for which important legal principles are often evolving and remain unresolved. As a result, the validity and enforceability of patents cannot be predicted with certainty. In addition, we do not know whether:

 

   

we or our licensors were the first to make the inventions covered by each of our issued patents and pending patent applications;

 

   

we or our licensors were the first to file patent applications for these inventions;

 

   

any of our product candidates will be Orange Book eligible;

 

   

others will independently develop similar or alternative technologies or duplicate any of our technologies;

 

   

any of our or our licensors’ pending patent applications will result in issued patents;

 

   

any of our or our licensors’ patents will be valid or enforceable;

 

   

any patents issued to us or our licensors and collaborators will provide us with any competitive advantages, or will be challenged by third parties;

 

   

we will develop additional proprietary technologies that are patentable;

 

   

the U.S. government will exercise any of its statutory rights to our intellectual property that was developed with government funding; or

 

   

our business may infringe the patents or other proprietary rights of others.

 

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The actual protection afforded by a patent varies based on products or processes, from country to country and depends upon many factors, including the type of patent, the scope of its coverage, the availability of regulatory related extensions, the availability of legal remedies in a particular country, the validity and enforceability of the patents and our financial ability to enforce our patents and other intellectual property. Our ability to maintain and solidify our proprietary position for our products will depend on our success in obtaining effective claims and enforcing those claims once granted. Our issued patents and those that may issue in the future, or those licensed to us, may be challenged, narrowed, invalidated or circumvented, and the rights granted under any issued patents may not provide us with proprietary protection or competitive advantages against competitors with similar products. Due to the extensive amount of time required for the development, testing and regulatory review of a potential product, it is possible that, before any of our product candidates can be commercialized, any related patent may expire or remain in force for only a short period following commercialization, thereby reducing any advantage of the patent.

We may also rely on trade secrets to protect some of our technology, especially where we do not believe patent protection is appropriate or obtainable. However, trade secrets are difficult to maintain. While we use reasonable efforts to protect our trade secrets, our or any of our collaborators’ employees, consultants, contractors or scientific and other advisors may unintentionally or willfully disclose our proprietary information to competitors and we may not have adequate remedies in respect of that disclosure. Enforcement of claims that a third party has illegally obtained and is using trade secrets is expensive, time consuming and uncertain. In addition, foreign courts are sometimes less willing than U.S. courts to protect trade secrets. If our competitors independently develop equivalent knowledge, methods and know-how, we would not be able to assert our trade secrets against them and our business could be harmed.

We are a party to a license agreement with Eli Lilly under which we license the intellectual property and receive commercialization rights to lasmiditan; any termination of such agreement would adversely affect our business.

In 2005, we entered into an agreement with Eli Lilly pursuant to which we obtained an exclusive, worldwide license from Eli Lilly to develop and commercialize lasmiditan. Pursuant to our agreement with Eli Lilly, we have been granted an exclusive worldwide license, with the right to grant sublicenses, under certain patents and know-how owned or controlled by Eli Lilly relating to lasmiditan. Under this license agreement, we are subject to commercialization and development, diligence obligations, royalty payments and other obligations. If we fail to comply with any of these obligations or otherwise breach this license agreement, Eli Lilly may have the right to terminate the license in whole or in part or to terminate the exclusive nature of the license. Generally, the loss of the licenses granted to us under our agreement with Eli Lilly or the rights provided therein could materially harm our business, financial condition, results of operations, and prospects. See “Business—Strategic Relationships—Eli Lilly and Company” for a description of the material terms of this agreement.

We may not be able to protect our intellectual property rights throughout the world.

Filing, prosecuting and defending patents on product candidates in all countries throughout the world would be prohibitively expensive, and our intellectual property rights in some countries outside the United States can be less extensive than those in the United States. In addition, the laws of some foreign countries do not protect intellectual property rights to the same extent as federal and state laws in the United States. For example, many foreign countries have compulsory licensing laws under which a patent owner must grant licenses to third parties. Consequently, we may not be able to prevent third parties from practicing our inventions in all countries outside the United States, or from selling or importing products made using our inventions in and into the United States or other jurisdictions. Competitors may use our technologies in jurisdictions where we have not obtained patent protection to develop their own products and further, may export otherwise infringing products to territories where we have patent

 

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protection, but enforcement rights are not as strong as those in the United States. These products may compete with our product candidates in jurisdictions where we do not have any issued patents and our patent claims or other intellectual rights may not be effective or sufficient to prevent them from so competing.

Many companies have encountered significant problems in protecting and defending intellectual property rights in foreign jurisdictions. The legal systems of certain countries do not favor the enforcement of patents and other intellectual property protection, which could make it difficult for us to stop the infringement of our patents generally. Proceedings to enforce our patent rights in foreign jurisdictions could result in substantial costs and divert our efforts and attention from other aspects of our business, could put our patents at risk of being invalidated or interpreted narrowly and our patent applications at risk of not issuing and could provoke third parties to assert claims against us. We may not prevail in any lawsuits that we initiate and the damages or other remedies awarded, if any, may not be commercially meaningful. Accordingly, our efforts to enforce our intellectual property rights around the world may be inadequate to obtain a significant commercial advantage from the intellectual property that we develop or license.

If we do not obtain patent term extension in the United States under the Hatch-Waxman Act and in foreign countries under similar legislation, thereby potentially extending the term of marketing exclusivity for our product candidates, our business may be materially harmed.

Depending on the timing, duration and specifics of FDA marketing approval of our product candidates, if any, one of the U.S. patents covering each of such approved product(s) or the use thereof may be eligible for up to five years of patent term restoration under the Hatch-Waxman Act. The Hatch-Waxman Act allows a maximum of one patent to be extended per FDA approved product. Patent term extension also may be available in certain foreign countries upon regulatory approval of our product candidates. Nevertheless, we may not be granted patent term extension either in the United States or in any foreign country because of, for example, failing to apply within applicable deadlines, failing to apply prior to expiration of relevant patents or otherwise failing to satisfy applicable requirements. Moreover, the term of extension, as well as the scope of patent protection during any such extension, afforded by the governmental authority could be less than we request.

If we are unable to obtain patent term extension or restoration, or the term of any such extension is less than we or our collaborators request, the period during which we will have the right to exclusively market our product will be shortened and our competitors may obtain approval of competing products following our patent expiration, and our revenue could be reduced, possibly materially.

We may not identify relevant patents or may incorrectly interpret the relevance, scope or expiration of a patent, which may adversely affect our ability to develop and market our product candidates.

We cannot guarantee that any of our patent searches or analyses, including but not limited to the identification of relevant patents, the scope of patent claims or the expiration of relevant patents, are complete or thorough, nor can we be certain that we have identified each and every patent and pending application in the United States and abroad that is relevant to or necessary for the commercialization of our product candidates in any jurisdiction.

The scope of a patent claim is determined by an interpretation of the law, the written disclosure in a patent and the patent’s prosecution history. Our interpretation of the relevance or the scope of a patent or a pending application may be incorrect, which may negatively impact our ability to market our product candidates. We may incorrectly determine that our product candidates are not covered by a third-party patent.

 

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Many patents may cover a marketed product, including but not limited to patents covering the composition, methods of use, formulations, production processes and purification processes of or for the product. The identification of all patents and their expiration dates relevant to the production and sale of a therapeutic product is extraordinarily complex and requires sophisticated legal knowledge in the relevant jurisdiction. It may be impossible to identify all patents in all jurisdictions relevant to a marketed product. Our determination of the expiration date of any patent in the United States or abroad that we consider relevant may be incorrect, which may negatively impact our ability to develop and market our product candidates.

Obtaining and maintaining our patent protection depends on compliance with various procedural, documentary, fee payment and other requirements imposed by governmental patent agencies, and our patent protection could be reduced or eliminated for non-compliance with these requirements.

The United States Patent and Trademark Office, or USPTO, and various foreign governmental patent agencies require compliance with a number of procedural, documentary, fee payment and other similar provisions during the patent prosecution process. Periodic maintenance fees, renewal fees, annuity fees and various other governmental fees on any issued patent and/or pending patent applications are due to be paid to the USPTO and foreign patent agencies in several stages over the lifetime of a patent or patent application. We have systems in place to remind us to pay these fees, and we employ an outside firm and rely on our outside counsel to pay these fees. While an inadvertent lapse may sometimes be cured by payment of a late fee or by other means in accordance with the applicable rules, there are many situations in which noncompliance can result in abandonment or lapse of the patent or patent application, resulting in partial or complete loss of patent rights in the relevant jurisdiction. If we fail to maintain the patents and patent applications directed to our product candidates, our competitors might be able to enter the market earlier than should otherwise have been the case, which would have a material adverse effect on our business.

The patent protection for our product candidates may expire before we are able to maximize their commercial value, which may subject us to increased competition and reduce or eliminate our opportunity to generate product revenue.

The patents for our product candidates have varying expiration dates and, if these patents expire, we may be subject to increased competition and we may not be able to recover our development costs or market any of our approved products profitably. In some of the larger potential market territories, such as the United States and Europe, patent term extension or restoration may be available to compensate for time taken during aspects of the product’s development and regulatory review. However, we cannot be certain that such an extension will be granted, or if granted, what the applicable time period or the scope of patent protection afforded during any extension period will be. In addition, even though some regulatory authorities may provide some other exclusivity for a product under their own laws and regulations, we may not be able to qualify the product or obtain the exclusive time period. If we are unable to obtain patent term extension/restoration or some other exclusivity, we could be subject to increased competition and our opportunity to establish or maintain product revenue could be substantially reduced or eliminated. Furthermore, we may not have sufficient time to recover our development costs prior to the expiration of our U.S. and foreign patents.

We may become involved in lawsuits to protect our patents or other intellectual property rights, which could be expensive, time-consuming and ultimately unsuccessful.

Competitors may infringe our patents or other intellectual property rights. To counter infringement or unauthorized use, we may be required to file infringement claims, which can be expensive and time consuming. In addition, in an infringement proceeding, a court may decide that a patent of ours is not valid or is unenforceable, or may refuse to stop the other party from using the technology at issue on the grounds that our patents do not cover the technology in question. An adverse result in any litigation or

 

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defense proceedings could put one or more of our patents at risk of being invalidated or interpreted narrowly and could put our patent applications at risk of not issuing.

Interference proceedings brought by the USPTO may be necessary to determine the priority of inventions with respect to our patents and patent applications or those of our current or future collaborators. An unfavorable outcome could require us to cease using the technology or to attempt to license rights to it from the prevailing party. Our business could be harmed if a prevailing party does not offer us a license on terms that are acceptable to us. Litigation or interference proceedings may fail and, even if successful, may result in substantial costs and distraction of our management and other employees. We may not be able to prevent, alone or with our collaborators, misappropriation of our proprietary rights, particularly in countries where the laws may not protect those rights as fully as in the United States.

Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of our confidential and proprietary information could be compromised by disclosure during this type of litigation. In addition, there could be public announcements of the results of hearings, motions or other interim proceedings or developments. If securities analysts or investors perceive these results to be negative, it could have a substantial adverse effect on the price of our common stock.

Third-party claims of intellectual property infringement or misappropriation may adversely affect our business and could prevent us from developing or commercializing our product candidates.

Our commercial success depends in part on us not infringing the patents and proprietary rights of third parties. There is a substantial amount of litigation, both within and outside the United States, involving patent and other intellectual property rights in the biotechnology and pharmaceutical industries, including patent infringement lawsuits, interferences, oppositions, ex-parte review and inter partes reexamination and post-grant review proceedings before the USPTO and corresponding foreign patent offices. Numerous U.S. and foreign issued patents and pending patent applications owned by third parties exist in the fields in which we are developing and may develop our product candidates. As the biotechnology and pharmaceutical industries expand and more patents are issued, the risk increases that our product candidates may be subject to claims of infringement of the patent rights of third parties. If a third party claims that we infringe on their products or technology, we could face a number of issues, including:

 

   

infringement and other intellectual property claims which, with or without merit, can be expensive and time-consuming to litigate and can divert management’s attention from our core business;

 

   

substantial damages for past infringement, which we may have to pay if a court decides that our product infringes on a competitor’s patent;

 

   

a court prohibiting us from selling or licensing our product unless the patent holder licenses the patent to us, which the collaborator would not be required to do;

 

   

if a license is available from a patent holder, we may have to pay substantial royalties or grant cross licenses to our patents; and

 

   

redesigning our processes so they do not infringe, which may not be possible or could require substantial funds and time.

Third parties may assert that we are employing their proprietary technology without authorization. There may be third-party patents or patent applications with claims to materials, formulations, methods of manufacture or methods for treatment related to the use or manufacture of our product candidates, that we failed to identify. For example, applications filed before November 29, 2000 and certain applications filed after that date that will not be filed outside the United States remain confidential until

 

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issued as patents. Except for the preceding exceptions, patent applications in the United States and elsewhere are generally published only after a waiting period of approximately 18 months after the earliest filing. Therefore, patent applications covering our platform technology or our product candidates could have been filed by others without our knowledge. Additionally, pending patent applications which have been published can, subject to certain limitations, be later amended in a manner that could cover our platform technologies, our product candidates or the use or manufacture of our product candidates. We may also face a claim of misappropriation if a third party believes that we inappropriately obtained and used trade secrets of such third party. If we are found to have misappropriated a third party’s trade secrets, we may be prevented from further using such trade secrets, limiting our ability to develop our product candidates, and we may be required to pay damages.

If any third-party patents were held by a court of competent jurisdiction to cover aspects of our materials, formulations, methods of manufacture or methods for treatment, the holders of any such patents would be able to block our ability to develop and commercialize the applicable product candidate until such patent expired or unless we obtain a license. These licenses may not be available on acceptable terms, if at all. Even if we were able to obtain a license, the rights may be nonexclusive, which could result in our competitors gaining access to the same intellectual property. Ultimately, we could be prevented from commercializing a product, or be forced to cease some aspect of our business operations, if, as a result of actual or threatened patent infringement claims, we are unable to enter into licenses on acceptable terms. In addition, during the course of any patent or other intellectual property litigation, there could be public announcements of the results of hearings, rulings on motions, and other interim proceedings in the litigation. If securities analysts or investors regard these announcements as negative, the perceived value of our product candidates, programs, or intellectual property could be diminished. Accordingly, the market price of our common stock may decline.

Parties making claims against us may obtain injunctive or other equitable relief, which could effectively block our ability to further develop and commercialize one or more of our product candidates. Defending against claims of patent infringement or misappropriation of trade secrets could be costly and time-consuming, regardless of the outcome. Thus, even if we were to ultimately prevail, or to settle at an early stage, such litigation could burden us with substantial unanticipated costs. In addition, litigation or threatened litigation could result in significant demands on the time and attention of our management team, distracting them from the pursuit of other company business. In the event of a successful claim of infringement against us, we may have to pay substantial damages, including treble damages and attorneys’ fees for willful infringement, pay royalties, redesign our infringing products or obtain one or more licenses from third parties, which may be impossible or require substantial time and monetary expenditure. In addition, the uncertainties associated with litigation could have a material adverse effect on our ability to raise the funds necessary to continue our clinical trials, continue our research programs, license necessary technology from third parties, or enter into development collaborations that would help us bring our product candidates to market.

Changes in U.S. patent law could diminish the value of patents in general, thereby impairing our ability to protect our product candidates.

As is the case with other pharmaceutical companies, our success is heavily dependent on intellectual property, particularly on obtaining and enforcing patents. Obtaining and enforcing patents in the specialty pharmaceutical industry involves both technological and legal complexity, and therefore, is costly, time-consuming and inherently uncertain. In addition, the United States has recently enacted and is currently implementing wide-ranging patent reform legislation. Further, several recent U.S. Supreme Court rulings have either narrowed the scope of patent protection available in certain circumstances or weakened the rights of patent owners in certain situations. In addition to increasing uncertainty with regard to our ability to obtain patents in the future, this combination of events has created uncertainty with respect to the value of patents, once obtained.

 

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For our U.S. patent applications containing a claim not entitled to priority before March 16, 2013, there is a greater level of uncertainty in the patent law. In September 2011, the Leahy-Smith America Invents Act, or the American Invents Act, or AIA, was signed into law. The AIA includes a number of significant changes to U.S. patent law, including provisions that affect the way patent applications will be prosecuted, reviewed after issuance, and may also affect patent litigation. The USPTO is currently developing regulations and procedures to govern administration of the AIA, and many of the substantive changes to patent law associated with the AIA. It is not clear what other, if any, impact the AIA will have on the operation of our business. Moreover, the AIA and its implementation could increase the uncertainties and costs surrounding the prosecution of our patent applications and the enforcement or defense of our issued patents, all of which could have a material adverse effect on our business and financial condition.

An important change introduced by the AIA is that, as of March 16, 2013, the United States transitioned to a “first-inventor-to-file” system for deciding which party should be granted a patent when two or more patent applications are filed by different parties claiming the same invention. A third party that files a patent application in the USPTO after that date but before us could therefore be awarded a patent covering an invention of ours even if we had made the invention before it was made by the third party. This will require us to be cognizant going forward of the time from invention to filing of a patent application. Furthermore, our ability to obtain and maintain valid and enforceable patents depends on whether the differences between our technology and the prior art allow our technology to be patentable over the prior art. Since patent applications in the United States and most other countries are confidential for a period of time after filing, we cannot be certain that we were the first to either (a) file any patent application related to our product candidates or (b) invent any of the inventions claimed in our patents or patent applications.

Among some of the other changes introduced by the AIA are changes that limit where a patentee may file a patent infringement suit and providing opportunities for third parties to challenge any issued patent in the USPTO. This applies to all of our U.S. patents, even those issued before March 16, 2013. Because of a lower evidentiary standard in USPTO proceedings compared to the evidentiary standard in United States federal court necessary to invalidate a patent claim, a third party could potentially provide evidence in a USPTO proceeding sufficient for the USPTO to hold a claim invalid as unpatentable even though the same evidence may be insufficient to invalidate the claim if first presented in a district court action. Accordingly, a third party may attempt to use the USPTO procedures to invalidate our patent claims that would not have been invalidated if first challenged by the third party as a defendant in a district court action.

Depending on decisions by the U.S. Congress, the federal courts, and the USPTO, the laws and regulations governing patents could change in unpredictable ways that would weaken our ability to obtain new patents or to enforce our existing patents and patents that we might obtain in the future.

Because of the expense and uncertainty of litigation, we may not be in a position to enforce our intellectual property rights against third parties.

Because of the expense and uncertainty of litigation, we may conclude that even if a third party is infringing our patents or other intellectual property rights, the risk-adjusted cost of bringing and enforcing such a claim or action may be too high or not in the best interest of our company or our stockholders. In such cases, we may decide that the more prudent course of action is to simply monitor the situation or initiate or seek some other non-litigious action or solution.

 

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Intellectual property rights do not address all potential threats to our competitive advantage.

The degree of future protection afforded by our intellectual property rights is uncertain because intellectual property rights have limitations, and may not adequately protect our business, or permit us to maintain our competitive advantage. The following examples are illustrative:

 

   

Others may be able to make products that are similar to our product candidates but that are not covered by the claims of the patents that we own or license from others.

 

   

Others may independently develop similar or alternative technologies or otherwise circumvent any of our technologies without infringing our intellectual property rights.

 

   

We or any of our collaborators might not have been the first to conceive and reduce to practice the inventions covered by the patents or patent applications that we own, license or will own or license.

 

   

We or any of our collaborators might not have been the first to file patent applications covering certain of the patents or patent applications that we or they own or have obtained a license, or will own or will have obtained a license.

 

   

It is possible that our pending patent applications will not lead to issued patents.

 

   

Issued patents that we own may not provide us with any competitive advantage, or may be held invalid or unenforceable, as a result of legal challenges by our competitors.

 

   

Our competitors might conduct research and development activities in countries where we do not have patent rights, or in countries where research and development safe harbor laws exist, and then use the information learned from such activities to develop competitive products for sale in our major commercial markets.

 

   

Ownership of our patents or patent applications may be challenged by third parties.

 

   

The patents of third parties or pending or future applications of third parties, if issued, may have an adverse effect on our business.

Confidentiality agreements with employees and others may not adequately prevent disclosure of trade secrets and protect other proprietary information.

We consider proprietary trade secrets and/or confidential know-how and unpatented know-how to be important to our business. We may rely on trade secrets and/or confidential know-how to protect our technology, especially where patent protection is believed by us to be of limited value. However, trade secrets and/or confidential know-how can be difficult to maintain as confidential.

To protect this type of information against disclosure or appropriation by competitors, our policy is to require our employees, consultants, contractors and advisors to enter into confidentiality agreements with us. However, current or former employees, consultants, contractors and advisers may unintentionally or willfully disclose our confidential information to competitors, and confidentiality agreements may not provide an adequate remedy in the event of unauthorized disclosure of confidential information. Enforcing a claim that a third party obtained illegally and is using trade secrets and/or confidential know-how is expensive, time consuming and unpredictable. The enforceability of confidentiality agreements may vary from jurisdiction to jurisdiction.

Failure to obtain or maintain trade secrets and/or confidential know-how trade protection could adversely affect our competitive position. Moreover, our competitors may independently develop substantially equivalent proprietary information and may even apply for patent protection in respect of the same. If successful in obtaining such patent protection, our competitors could limit our use of our trade secrets and/or confidential know-how.

 

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We may need to license certain intellectual property from third parties, and such licenses may not be available or may not be available on commercially reasonable terms.

A third party may hold intellectual property, including patent rights that are important or necessary to the development or commercialization of our product candidates. It may be necessary for us to use the patented or proprietary technology of third parties to commercialize our product candidates, in which case we would be required to obtain a license from these third parties. Such a license may not be available on commercially reasonable terms or at all, which could materially harm our business.

We may be subject to claims that our employees, consultants or independent contractors have wrongfully used or disclosed confidential information of third parties.

We have received confidential and proprietary information from third parties. In addition, we employ individuals who were previously employed at other biotechnology or pharmaceutical companies. We may be subject to claims that we or our employees, consultants or independent contractors have inadvertently or otherwise improperly used or disclosed confidential information of these third parties or our employees’ former employers. Further, we may be subject to ownership disputes in the future arising, for example, from conflicting obligations of consultants or others who are involved in developing our product candidates. We may also be subject to claims that former employees, consultants, independent contractors, collaborators or other third parties have an ownership interest in our patents or other intellectual property. Litigation may be necessary to defend against these and other claims challenging our right to and use of confidential and proprietary information. If we fail in defending any such claims, in addition to paying monetary damages, we may lose our rights therein. Such an outcome could have a material adverse effect on our business. Even if we are successful in defending against these claims, litigation could result in substantial cost and be a distraction to our management and employees.

We may be subject to claims challenging the inventorship or ownership of our patents and other intellectual property.

We may also be subject to claims that former employees, collaborators or other third parties have an ownership interest in our patents or other intellectual property. We may be subject to ownership disputes in the future arising, for example, from conflicting obligations of consultants or others who are involved in developing our product candidates. Litigation may be necessary to defend against these and other claims challenging inventorship or ownership. If we fail in defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights, such as exclusive ownership of, or right to use, valuable intellectual property. Such an outcome could have a material adverse effect on our business. Even if we are successful in defending against such claims, litigation could result in substantial costs and be a distraction to management and other employees.

Our reliance on third parties requires us to share our trade secrets, which increases the possibility that a competitor will discover them or that our trade secrets will be misappropriated or disclosed.

Because we rely on third parties to assist with the research and develop and to manufacture our product candidates, we must, at times, share trade secrets with them. We seek to protect our proprietary technology in part by entering into confidentiality agreements and, if applicable, material transfer agreements, consulting agreements or other similar agreements with our advisors, employees, third-party contractors and consultants prior to beginning research or disclosing proprietary information. These agreements typically limit the rights of the third parties to use or disclose our confidential information, including our trade secrets. Despite the contractual provisions employed when working with third parties, the need to share trade secrets and other confidential information increases the risk that such trade secrets become known by our competitors, are inadvertently incorporated into the technology of others, or are disclosed or used in violation of these agreements. Given that our proprietary position is based, in part, on our know-how and trade secrets, a competitor’s discovery of our trade secrets or other

 

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unauthorized use or disclosure would impair our competitive position and may have a material adverse effect on our business.

In addition, these agreements typically restrict the ability of our advisors, employees, third-party contractors and consultants to publish data potentially relating to our trade secrets, although our agreements may contain certain limited publication rights. For example, any academic institution that we may collaborate with in the future will usually expect to be granted rights to publish data arising out of such collaboration, provided that we are notified in advance and given the opportunity to delay publication for a limited time period in order for us to secure patent protection of intellectual property rights arising from the collaboration, in addition to the opportunity to remove confidential or trade secret information from any such publication. In the future we may also conduct joint research and development programs that may require us to share trade secrets under the terms of our research and development or similar agreements. Despite our efforts to protect our trade secrets, our competitors may discover our trade secrets, either through breach of our agreements with third parties, independent development or publication of information by any of our third-party collaborators. A competitor’s discovery of our trade secrets would impair our competitive position and have an adverse impact on our business.

If our trademarks and trade names are not adequately protected, then we may not be able to build name recognition in our markets of interest and our business may be adversely affected.

If our trademarks and trade names are not adequately protected, than we may not be able to build name recognition in our markets of interest and our business may be adversely affected. We currently do not have any registered trademarks. Our unregistered trademarks or trade names may be challenged, infringed, circumvented or declared generic or determined to be infringing on other marks. We may not be able to protect our rights to these trademarks and trade names, which we need to build name recognition among potential collaborators or customers in our markets of interest. At times, competitors may adopt trade names or trademarks similar to ours, thereby impeding our ability to build brand identity and possibly leading to market confusion. In addition, there could be potential trade name or trademark infringement claims brought by owners of other registered trademarks or trademarks that incorporate variations of our unregistered trademarks or trade names. Over the long term, if we are unable to successfully register our trademarks and trade names and establish name recognition based on our trademarks and trade names, then we may not be able to compete effectively and our business may be adversely affected. Our efforts to enforce or protect our proprietary rights related to trademarks, trade secrets, domain names, copyrights or other intellectual property may be ineffective and could result in substantial costs and diversion of resources and could adversely impact our financial condition or results of operations.

Risks Related to This Offering and Ownership of Our Common Stock

An active trading market for our common stock may not develop.

Prior to this offering, there has been no public market for our common stock. Although we expect our common stock to be approved for listing on The NASDAQ Global Market, an active trading market for our shares may never develop or be sustained following this offering. If the market does not develop or is not sustained, it may be difficult for you to sell your shares of common stock at a price that is attractive to you or at all. In addition, an inactive market may impair our ability to raise capital by selling shares and may impair our ability to acquire other companies or technologies by using our shares as consideration, which, in turn, could materially adversely affect our business.

 

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The trading price of the shares of our common stock could be highly volatile, and purchasers of our common stock may not be able to resell the shares of our common stock at or above the initial public offering price and could incur substantial losses.

Our stock price is likely to be volatile. The stock market in general has experienced extreme volatility that has often been unrelated to the operating performance of particular companies. As a result of this volatility, investors may not be able to sell their common stock at or above the initial public offering price. The market price for our common stock may be influenced by many factors, including:

 

   

our ability to enroll patients in planned clinical trials;

 

   

results of the clinical trials, and the results of trials of our competitors or those of other companies in our market sector, and the timing of the release of those results;

 

   

the passage of legislation or other regulatory developments in the United States and foreign countries;

 

   

actual or anticipated variations in our financial results or those of companies that are perceived to be similar to us;

 

   

changes in the structure of healthcare payment systems, especially in light of current reforms to the U.S. healthcare system;

 

   

our ability to discover and develop additional product candidates;

 

   

announcements by us or our competitors of significant acquisitions, strategic collaborations, joint ventures or capital commitments;

 

   

our ability to enter into strategic collaborations for the development of our product candidates;

 

   

market conditions in the pharmaceutical and biotechnology sectors and issuance of securities analysts’ research reports or recommendations;

 

   

sales of our stock by us, our insiders and our other stockholders;

 

   

trading volume of our common stock;

 

   

speculation in the press or investment community;

 

   

general economic, industry and market conditions other events or factors, many of which are beyond our control;

 

   

additions or departures of key personnel; and

 

   

intellectual property, product liability or other litigation against us.

In addition, the stock market has recently experienced significant volatility with respect to pharmaceutical, biotechnology and other life sciences company stocks. The volatility of pharmaceutical, biotechnology and other life sciences company stocks often does not relate to the operating performance of the companies represented by the stock. As we operate in a single industry, we are especially vulnerable to these factors to the extent that they affect our industry or our product candidates, or to a lesser extent our markets.

We are an “emerging growth company,” and the reduced disclosure requirements applicable to emerging growth companies may make our common stock less attractive to investors.

We are an “emerging growth company,” as defined in the JOBS Act, and may remain an emerging growth company for up to five years. For so long as we remain an emerging growth company, we are

 

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permitted and intend to rely on exemptions from certain disclosure requirements that are applicable to other public companies that are not emerging growth companies. These exemptions include:

 

   

being permitted to provide only two years of audited financial statements, in addition to any required unaudited interim financial statements, with correspondingly reduced “Management’s Discussion and Analysis of Financial Condition and Results of Operations” in this prospectus;

 

   

not being required to comply with the auditor attestation requirements in the assessment of our internal control over financial reporting;

 

   

not being required to comply with any requirement that may be adopted by the Public Company Accounting Oversight Board regarding mandatory audit firm rotation or a supplement to the auditor’s report providing additional information about the audit and the financial statements;

 

   

reduced disclosure obligations regarding executive compensation; and

 

   

exemptions from the requirements of holding a nonbinding advisory vote on executive compensation and stockholder approval of any golden parachute payments not previously approved.

We have taken advantage of reduced reporting burdens in this prospectus. In particular, in this prospectus, we have provided only two years of audited financial statements and have not included all of the executive compensation related information that would be required if we were not an emerging growth company. We cannot predict whether investors will find our common stock less attractive if we rely on these exemptions. If some investors find our common stock less attractive as a result, there may be a less active trading market for our common stock and our stock price may be reduced or more volatile. In addition, the JOBS Act provides that an emerging growth company can take advantage of an extended transition period for complying with new or revised accounting standards. This allows an emerging growth company to delay the adoption of these accounting standards until they would otherwise apply to private companies. We have irrevocably elected not to avail ourselves of this exemption and, therefore, we will be subject to the same new or revised accounting standards as other public companies that are not emerging growth companies.

Sales of a substantial number of shares of our common stock by our existing stockholders in the public market could cause our stock price to fall.

Sales of a substantial number of shares of our common stock in the public market or the perception that these sales might occur, could significantly reduce the market price of our common stock and impair our ability to raise adequate capital through the sale of additional equity securities.

Based on shares of common stock outstanding as of                     , 2015, upon the closing of this offering and the conversion of our convertible preferred stock into              shares of our common stock, we will have outstanding a total of              shares of common stock after this offering, assuming no exercise of the underwriters’ option to purchase additional shares and no exercise of outstanding options and warrants. Of these shares, only the shares of common stock sold in this offering by us, plus any shares sold upon exercise of the underwriters’ option to purchase additional shares, will be freely tradable without restriction in the public market immediately following this offering, unless they are purchased by one of our affiliates.

We and our executive officers, directors, stockholders and optionholders have agreed, subject to certain exceptions, not to engage in sales or dispositions of, or other transactions relating to, our common stock or securities convertible into or exercisable or exchangeable for our common stock or warrants or other rights to acquire shares of our common stock. These “lock-up” restrictions end 180 days after the date of

 

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this prospectus. However, Piper Jaffray & Co. and Stifel, Nicolaus & Company, Incorporated, in their sole discretion, may permit persons who are subject to these lock-up agreements to sell shares prior to the expiration of the lock-up agreements.

After the lock-up agreements expire, up to an additional              shares of common stock will be eligible for sale in the public market of which              shares are held by directors, executive officers and other affiliates and will be subject to volume limitations under Rule 144 under the Securities Act of 1933, as amended, or the Securities Act. In addition, shares of common stock that are either subject to outstanding options or reserved for future issuance under our employee benefit plans will become eligible for sale in the public market to the extent permitted by the provisions of various vesting schedules, the lock-up agreements and Rule 144 and Rule 701 under the Securities Act. If these additional shares of common stock are sold, or if it is perceived that they will be sold, in the public market, the trading price of our common stock could decline.

Following completion of this offering, the holders of              shares of our outstanding common stock, or approximately         % of our total outstanding common stock, will be entitled to rights with respect to the registration of their shares under the Securities Act, subject to the 180-day lock-up agreements described above. See “Description of Capital Stock—Registration Rights.” Registration of these shares under the Securities Act would result in the shares becoming freely tradable without restriction under the Securities Act, except for shares held by affiliates, as defined in Rule 144 under the Securities Act. Any sales of securities by these stockholders could have a material adverse effect on the trading price of our common stock.

Our operating results may fluctuate significantly.

We expect our operating results to be subject to fluctuations due to the unpredictability of our expenses. Our net loss and other operating results will be affected by numerous factors, including:

 

   

variations in the level of expenses related to our clinical trial and development programs;

 

   

addition or termination of clinical trials;

 

   

regulatory developments affecting our current or future product candidates;

 

   

our execution of any collaborative, licensing or similar arrangements and the timing of payments we may make or receive under these arrangements; and

 

   

nature and terms of stock-based compensation grants and any intellectual property infringement lawsuit in which we may become involved.

Fluctuations in our operating results may cause the price of our stock to fluctuate substantially.

We may use the net proceeds from this offering in ways that you and other stockholders may not approve.

Our management will have broad discretion in the application of the net proceeds from this offering, including for any of the purposes described in the section entitled “Use of Proceeds,” and you will not have the opportunity as part of your investment decision to assess whether the net proceeds are being used appropriately. Because of the number and variability of factors that will determine our use of the net proceeds from this offering, their ultimate use may vary substantially from their currently intended use. Our management might not apply our net proceeds in ways that ultimately increase the value of your investment. We intend to use the net proceeds from this offering, together with our existing cash resources, to fund our clinical trials and the continued development of our product candidates, for working capital and general corporate purposes. The failure by our management to apply the net proceeds from this offering effectively could harm our business. Pending their use, we may invest the net

 

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proceeds from this offering in a variety of capital preservation investments, including short-term, interest-bearing, investment-grade instruments and U.S. government securities. These investments may not yield a favorable return to our stockholders.

You will suffer immediate and substantial dilution in the net tangible book value of the common stock you purchase.

The initial public offering price of our common stock is substantially higher than the pro forma as adjusted net tangible book value per share of our outstanding common stock immediately after the closing of this offering. Purchasers of common stock in this offering will experience immediate dilution of approximately $         per share, based on the assumed initial public offering price of $         per share, which is the midpoint of the price range set forth on the cover page of this prospectus. In the past, we issued options and warrants to acquire common stock at prices significantly below the assumed initial public offering price. To the extent these outstanding options and warrants are ultimately exercised, investors purchasing common stock in this offering will sustain further dilution. For a further description of the dilution that you will experience immediately after this offering, see “Dilution.”

We do not intend to pay dividends on our common stock, and, consequently, your ability to achieve a return on your investment will depend on appreciation, if any, in the price of our common stock.

We have never declared or paid any cash dividend on our common stock and do not currently intend to do so for the foreseeable future. We currently anticipate that we will retain future earnings for the development, operation and expansion of our business. In addition, any future debt financing arrangement may contain terms prohibiting or limiting the amount of dividends that may be declared or paid on our common stock. Any return to stockholders will therefore be limited to the appreciation of their stock. Therefore, the success of an investment in shares of our common stock will depend upon any future appreciation in their value. There is no guarantee that shares of our common stock will appreciate in value or even maintain the price at which our stockholders have purchased their shares.

We will incur significant increased costs as a result of operating as a public company, and our management will be required to devote substantial time to new compliance initiatives.

As a public company, we will incur significant legal, accounting and other expenses that we did not incur as a private company. We will be subject to the reporting requirements of the Securities Exchange Act of 1934, as amended, or the Exchange Act, which will require, among other things, that we file with the Securities and Exchange Commission, or the SEC, annual, quarterly and current reports with respect to our business and financial condition. In addition, the Sarbanes-Oxley Act, as well as rules subsequently adopted by the SEC, and the NASDAQ stock market to implement provisions of the Sarbanes-Oxley Act, imposes significant requirements on public companies, including requiring establishment and maintenance of effective disclosure and financial controls and changes in corporate governance practices. Further, pursuant to the Dodd-Frank Wall Street Reform and Consumer Protection Act of 2010, the SEC has adopted additional rules and regulations in these areas, such as mandatory “say on pay” voting requirements that will apply to us when we cease to be an emerging growth company. Stockholder activism, the current political environment and the current high level of government intervention and regulatory reform may lead to substantial new regulations and disclosure obligations, which may lead to additional compliance costs and may impact the manner in which we operate our business in ways we cannot currently anticipate.

We expect the rules and regulations applicable to public companies to substantially increase our legal and financial compliance costs and to make some activities more time-consuming and costly. If these requirements divert the attention of our management and personnel from other business concerns, they could have a material adverse effect on our business, financial condition, results of operations, and prospects. The increased costs will decrease our net income or increase our net loss, and may require us

 

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to reduce costs in other areas of our business or increase the prices of our products or services. For example, we expect these rules and regulations to make it more difficult and more expensive for us to obtain director and officer liability insurance, and we may be required to incur substantial costs to maintain the same or similar coverage. We are evaluating these rules and regulations, and cannot predict or estimate the amount of additional costs we may incur or the timing of such costs. These rules and regulations are often subject to varying interpretations, in many cases due to their lack of specificity, and, as a result, their application in practice may evolve over time as new guidance is provided by regulatory and governing bodies. This could result in continuing uncertainty regarding compliance matters and higher costs necessitated by ongoing revisions to disclosure and governance practices. The impact of these requirements could also make it more difficult for us to attract and retain qualified persons to serve on our board of directors, our board committees or as executive officers.

If we fail to maintain proper and effective internal control over financial reporting in the future, our ability to produce accurate and timely financial statements could be impaired, which could harm our operating results, investors’ views of us and, as a result, the value of our common stock.

Pursuant to Section 404 of the Sarbanes-Oxley Act, our management will be required to report upon the effectiveness of our internal control over financial reporting beginning with the annual report for our fiscal year ending December 31, 2015. When and if we are a “large accelerated filer” or an “accelerated filer” and are no longer an “emerging growth company,” each as defined in the Exchange Act, our independent registered public accounting firm will be required to attest to the effectiveness of our internal control over financial reporting. However, for so long as we remain an emerging growth company, we intend to take advantage of an exemption available to emerging growth companies from these auditor attestation requirements. We could be an “emerging growth company” for up to five years. The rules governing the standards that must be met for management to assess our internal control over financial reporting are complex and require significant documentation, testing, and possible remediation. To comply with the requirements of being a reporting company under the Exchange Act, we will need to upgrade our systems including information technology; implement additional financial and management controls, reporting systems, and procedures; and hire additional accounting and finance staff.

Any failure to implement required new or improved controls, or difficulties encountered in their implementation could cause us to fail to meet our reporting obligations. In addition, any testing by us conducted in connection with Section 404 of the Sarbanes-Oxley Act of 2002, or any subsequent testing by our independent registered public accounting firm, may reveal deficiencies in our internal control over financial reporting that are deemed to be material weaknesses or that may require prospective or retroactive changes to our financial statements or identify other areas for further attention or improvement. Inferior internal controls could also cause investors to lose confidence in our reported financial information, which could have a negative effect on the trading price of our common stock.

In addition, we may encounter problems or delays in implementing any changes necessary to make a favorable assessment of our internal control over financial reporting. Further, once we are no longer an emerging growth company, we may encounter problems or delays in completing the implementation of any requested improvements and receiving a favorable attestation in connection with the attestation provided by our independent registered public accounting firm. If we cannot favorably assess the effectiveness of our internal control over financial reporting, or if our independent registered public accounting firm is unable to provide an unqualified attestation report on our internal controls, investors could lose confidence in our financial information and the trading price of our common stock could decline.

In connection with our future evaluation of our internal controls over financial reporting, we may need to upgrade our systems or create new systems, implement additional financial and management controls, update our reporting systems and procedures, create or outsource an internal audit function, and hire

 

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additional accounting and finance staff. If we are unable to accomplish these objectives in a timely and effective fashion, our ability to comply with the financial reporting requirements and other rules that apply to reporting companies could be impaired. Any failure to maintain effective internal control over financial reporting could have a material adverse effect on our business, financial condition and results of operations and the trading price of our common stock.

Anti-takeover provisions in our charter documents and under Delaware law could make an acquisition of us, which may be beneficial to our stockholders, more difficult and may prevent attempts by our stockholders to replace or remove our current management.

Provisions in our amended and restated certificate of incorporation and amended and restated bylaws that will become effective upon the closing of this offering, as well as provisions of Delaware law, may delay or prevent an acquisition of us or a change in our management. These provisions include:

 

   

authorizing the issuance of “blank check” preferred stock, the terms of which may be established and shares of which may be issued without stockholder approval;

 

   

limiting the removal of directors by the stockholders;

 

   

creating a staggered board of directors;

 

   

prohibiting cumulative voting in the election of directors, which would otherwise allow for less than a plurality of stockholders to elect director candidates;

 

   

prohibiting stockholder action by written consent, thereby requiring all stockholder actions to be taken at a meeting of our stockholders;

 

   

eliminating the ability of stockholders to call a special meeting of stockholders;

 

   

establishing advance notice requirements for nominations for election to the board of directors or for proposing matters that can be acted upon at stockholder meetings; and

 

   

requiring that any amendment or repeal of our amended and restated bylaws by our stockholders be approved by a vote of the holders of at least two-thirds of the votes that all our stockholders would be entitled to cast in an election of directors.

These provisions may frustrate or prevent any attempts by our stockholders to replace or remove our current management by making it more difficult for stockholders to replace members of our board of directors, who are responsible for appointing the members of our management. In addition, because we are incorporated in Delaware, we are governed by the provisions of Section 203 of the Delaware General Corporation Law, which limits the ability of stockholders owning in excess of 15% of our outstanding voting stock to merge or combine with us. These provisions would apply even if an offer rejected by our board were considered beneficial by some stockholders. Any provision of our amended and restated certificate of incorporation or amended and restated bylaws or Delaware law that has the effect of delaying or deterring a change of control could limit the opportunity for our stockholders to receive a premium for their shares of our common stock, and could also affect the price that some investors are willing to pay for our common stock.

Our amended and restated bylaws provide that any current or former stockholder bringing an unsuccessful action against us or our officers, directors or other employees may be obligated to reimburse us for any costs we have incurred in connection with such unsuccessful action.

Our amended and restated bylaws, which will become effective upon the closing of this offering, provide that under certain circumstances the fees, costs, and expenses that we incur in connection with actions or proceedings brought by any person or entity, which we refer to as claiming parties, may be shifted to such person or entity. If a claiming party asserts any claim, initiates any proceeding, or joins, offers substantial assistance to, or has a direct financial interest in any claim or proceeding against us or any of

 

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our directors, officers or other employees (including any proceeding purportedly filed on behalf of us or any stockholder), and such claiming party (or the third party that received substantial assistance from a claiming party or in whose claim or proceeding such claiming party has a direct financial interest) is unsuccessful in obtaining a judgment on the merits that substantially achieves, in substance and amount, the full remedy sought, then such claiming party may be obligated to reimburse us and our directors, officers or other employees for all fees, costs and expenses of every kind and description, including but not limited to all reasonable attorneys’ fees and other litigation expenses, that we or our directors, officers or other employees may incur in connection with such claim, suit, action, or proceeding.

Fee-shifting bylaws are relatively new and untested. The case law and potential legislative action on fee shifting bylaws are evolving and there exists considerable uncertainty regarding the validity of, and potential judicial and legislative responses to, such bylaws. For example, it is unclear whether our ability to invoke our fee-shifting bylaw in connection with claims under the federal securities laws, including claims related to this offering, would be pre-empted by federal law. Similarly, it is unclear how courts might apply the standard that a claiming party must obtain a judgment that substantially achieves, in substance and amount, the full remedy sought. The application of our fee shifting bylaw in connection with such claims, if any, will depend in part on future developments of the law. We cannot assure you that we will or will not invoke our fee-shifting bylaw in any particular dispute, including any claims related to this offering. In addition, given the unsettled state of the law related to fee-shifting bylaws, such as ours, we may incur significant additional costs associated with resolving disputes with respect to such bylaw, which could adversely affect our business and financial condition.

If a stockholder that brings any such claim, suit, action or proceeding is unable to obtain the required judgment, the attorneys’ fees and other litigation expenses that might be shifted to a claiming party are potentially significant. This fee-shifting bylaw, therefore, may dissuade or discourage current or former stockholders (and their attorneys) from initiating lawsuits or claims against us or our directors, officers and other employees. In addition, it may impact the fees, contingency or otherwise, required by potential plaintiffs’ attorneys to represent our stockholders or otherwise discourage plaintiffs’ attorneys from representing our stockholders at all. As a result, this bylaw may limit the ability of stockholders to affect the management and direction of our company, particularly through litigation or the threat of litigation.

After this offering, our executive officers, directors and principal stockholders will maintain the ability to control all matters submitted to stockholders for approval.

Assuming the sale by us of             shares of common stock in this offering (or             shares if the underwriters exercise their option to purchase additional shares in full), our executive officers, directors and stockholders who owned more than 5% of our outstanding common stock before this offering will, in the aggregate, beneficially own shares representing approximately     % of our capital stock (or     % if the underwriters exercise their option to purchase additional shares in full). As a result, if these stockholders were to act together, they would be able to control all matters submitted to our stockholders for approval, as well as our management and affairs. For example, these persons, if they act together, would control the election of directors and approval of any merger, consolidation or sale of all or substantially all of our assets. This concentration of voting power could delay or prevent an acquisition of our company on terms that other stockholders may desire or result in management of our company that our public stockholders disagree with.

If securities or industry analysts do not publish research, or publish inaccurate or unfavorable research, about our business, the price of our common stock and our trading volume could decline.

The trading market for our common stock will depend in part on the research and reports that securities or industry analysts publish about us or our business. Securities and industry analysts do not currently, and may never, publish research on our company. If no or too few securities or industry analysts commence coverage of our company, the trading price for our ordinary shares would likely be negatively

 

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affected. In the event securities or industry analysts initiate coverage, if one or more of the analysts who cover us downgrade our ordinary shares or publish inaccurate or unfavorable research about our business, the price of our ordinary shares would likely decline. If one or more of these analysts cease coverage of our company or fail to publish reports on us regularly, demand for our common stock could decrease, which might cause the price of our shares and trading volume to decline.

Claims for indemnification by our directors and officers may reduce our available funds to satisfy successful third-party claims against us and may reduce the amount of money available to us.

Our amended and restated certificate of incorporation and amended and restated bylaws that will become effective upon the closing of this offering provide that we will indemnify our directors and officers, in each case to the fullest extent permitted by Delaware law.

In addition, as permitted by Section 145 of the Delaware General Corporation Law, our amended and restated certificate of incorporation, our amended and restated bylaws, indemnification agreements that we have entered into with our directors and indemnification agreements that we intend to enter into with our executive officers provide that:

 

   

We will indemnify our directors and officers for serving us in those capacities or for serving other business enterprises at our request, to the fullest extent permitted by Delaware law. Delaware law provides that a corporation may indemnify such person if such person acted in good faith and in a manner such person reasonably believed to be in or not opposed to the best interests of the registrant and, with respect to any criminal proceeding, had no reasonable cause to believe such person’s conduct was unlawful.

 

   

We may, in our discretion, indemnify employees and agents in those circumstances where indemnification is permitted by applicable law.

 

   

We are required to advance expenses, as incurred, to our directors and officers in connection with defending a proceeding, except that such directors or officers shall undertake to repay such advances if it is ultimately determined that such person is not entitled to indemnification.

 

   

We will not be obligated pursuant to our amended and restated bylaws to indemnify a person with respect to proceedings initiated by that person against us or our other indemnitees, except with respect to proceedings authorized by our board of directors or brought to enforce a right to indemnification.

 

   

The rights conferred in our amended and restated bylaws are not exclusive, and we are authorized to enter into indemnification agreements with our directors, officers, employees and agents and to obtain insurance to indemnify such persons.

 

   

No repeal or modification of the indemnification provisions in our amended and restated certificate of incorporation and our amended and restated bylaws will diminish or adversely affect the rights of any director, officer, employee or agent under those provisions in respect of any occurrence or matter arising prior to any such repeal or modification.

Our amended and restated certificate of incorporation designates the state or federal courts located in the State of Delaware as the sole and exclusive forum for certain types of actions and proceedings that may be initiated by our stockholders, which could limit our stockholders’ ability to obtain a favorable judicial forum for disputes with us or our directors, officers or employees.

Our amended and restated certificate of incorporation that will become effective upon the closing of this offering provides that, subject to certain exceptions, the state and federal courts located in the State of Delaware will be the sole and exclusive forum for any or all intracorporate claims, which shall include claims, including claims in the right of the company, (i) that are based upon a violation of a duty by a current or former director or officer or stockholder in such capacity, or (ii) as to which Title 8 of the Delaware General Corporation Law confers jurisdiction upon the Delaware Court of Chancery.

 

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This choice of forum provision may limit a stockholder’s ability to bring a claim in a judicial forum that it finds favorable for disputes with us or our directors, officers or other employees, which may discourage such lawsuits against us and our directors, officers and employees. Alternatively, if a court were to find these provisions of our amended and restated certificate of incorporation inapplicable to, or unenforceable in respect of, one or more of the specified types of actions or proceedings, we may incur additional costs associated with resolving such matters in other jurisdictions, which could adversely affect our business, financial condition, results of operations and prospects.

 

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INFORMATION REGARDING FORWARD-LOOKING STATEMENTS

This prospectus contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this prospectus, including statements regarding our business, operations and financial performance and condition, as well as our plans, objectives and expectations for our business operations and financial performance and condition, are forward-looking statements. In some cases, you can identify forward-looking statements by the following words: “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “might,” “target,” “ongoing,” “plan,” “potential,” “predict,” “project,” “should,” “will,” “would,” or the negative of these terms or other comparable terminology, although not all forward-looking statements contain these words. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause our results, levels of activity, performance or achievements to be materially different from the information expressed or implied by the forward-looking statements in this prospectus. The forward-looking statements in this prospectus include, among other things, statements relating to:

 

   

the initiation, timing, progress and results of ongoing and future preclinical studies and clinical trials, and our research and development programs;

 

   

our expectations regarding timing of results in our two pivotal Phase 3 clinical trials of lasmiditan;

 

   

our expectations regarding the timing of our submission of an NDA for approval of lasmiditan with the FDA and the likelihood and timing of approval of such NDA;

 

   

the potential for commercialization and market acceptance of our product candidates;

 

   

our expectations regarding the potential market size and opportunity for our product candidates, if approved for commercial use;

 

   

our plans to commercialize our product candidates and our ability to develop and maintain sales and marketing capabilities;

 

   

estimates of our expenses, future revenue, capital requirements and our needs for additional financing;

 

   

the implementation of our business model, strategic plans for our business, product candidates and technology;

 

   

the scope of protection we are able to establish and maintain for intellectual property rights covering our product candidates and technology and our ability to operate our business without infringing on the intellectual property rights of others;

 

   

regulatory developments in the United States and foreign countries;

 

   

the success of competing procedures that are or become available;

 

   

our ability to maintain and establish collaborations or obtain additional funding;

 

   

our expectations regarding the time during which we will be an emerging growth company under the JOBS Act;

 

   

our use of proceeds from this offering;

 

   

our financial performance; and

 

   

developments and projections relating to our competitors and our industry.

You should read the matters described in “Risk Factors” and the other cautionary statements made in this prospectus as being applicable to all related forward-looking statements wherever they appear in this

 

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prospectus. We cannot assure you that the forward-looking statements in this prospectus will prove to be accurate and therefore prospective investors are encouraged not to place undue reliance on forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements we make. You should read this prospectus, the documents that we reference in this prospectus and the documents that we have filed as exhibits to the registration statement, of which this prospectus is a part, completely. Other than as required by law, we undertake no obligation to update or revise these forward-looking statements, even though our situation may change in the future. Our forward-looking statements do not reflect the potential impact of any future acquisitions, mergers, dispositions, joint ventures or investments that we may make.

 

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USE OF PROCEEDS

We estimate that the net proceeds from our sale of shares of common stock in this offering will be approximately $         million, or approximately $         million if the underwriters exercise their option to purchase additional shares from us in full. This estimate is based upon an assumed initial public offering price of $         per share, which is the midpoint of the price range set forth on the cover page of this prospectus, less the estimated underwriting discounts and commissions and estimated offering expenses payable by us.

A $1.00 increase (decrease) in the assumed initial public offering price of $         per share would increase (decrease) the net proceeds to us from this offering by approximately $         million, assuming the number of shares offered by us, as set forth on the cover page of this prospectus, remains the same and after deducting the estimated underwriting discounts and commissions and estimated offering expenses payable by us.

We intend to use the net proceeds from this offering as follows:

 

   

approximately $         million to fund our clinical trials of lasmiditan and to fund development of lasmiditan; and

 

   

the remainder for working capital, general and administrative expenses and other general corporate purposes.

This expected use of net proceeds from this offering represents our intentions based upon our current plans and business conditions, which could change in the future as our plans and business conditions evolve. The amounts and timing of our actual expenditures may vary significantly depending on numerous factors, including the progress of our development, the status of, and results from, clinical trials, the potential need to conduct additional clinical trials to obtain approval of our product candidates for all intended indications, as well as any additional collaborations that we may enter into with third parties for our product candidates and any unforeseen cash needs. As a result, our management will retain broad discretion over the allocation of the net proceeds from this offering.

We estimate that the net proceeds from this offering, together with our existing cash and cash equivalents, will be sufficient to enable us to complete our two planned pivotal Phase 3 clinical trials of lasmiditan, submit an NDA if our Phase 3 clinical trials are completed successfully, and initiate our long-term open label study of lasmiditan, as well as fund our operating expenses and capital expenditure requirements through             . We do not currently anticipate that any of the net proceeds from this offering will be used to fund the development of IV lasmiditan. We have based this estimate on assumptions that may prove to be wrong, and we could use our available capital resources sooner than we currently expect.

Pending the uses described above, we intend to invest the net proceeds of this offering in short- to medium-term, investment-grade, interest-bearing securities.

 

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DIVIDEND POLICY

We have never declared or paid any cash dividends on our common stock. Following the closing of this offering, we intend to retain our future earnings, if any, to finance the operation and expansion of our business. We do not expect to pay cash dividends on our common stock in the foreseeable future.

Payment of future cash dividends, if any, will be at the discretion of our board of directors after taking into account various factors, including our financial condition, operating results, current and anticipated cash needs, outstanding indebtedness and restrictions imposed by lenders, if any.

 

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CAPITALIZATION

The following table sets forth our cash and cash equivalents and capitalization as of December 31, 2014:

 

   

on an actual basis;

 

   

on a pro forma basis to give effect to the completion of our Series C financing in January 2015 for gross proceeds of $36.9 million, the conversion of our $200,000 notes payable into              shares of Series C convertible preferred stock and the conversion of all outstanding convertible preferred stock into an aggregate of              shares of our common stock upon the closing of this offering; and

 

   

on a pro forma as adjusted basis to give additional effect to the sale of              shares in this offering at an assumed initial public offering price of $         per share, which is the midpoint of the price range set forth on the cover page of this prospectus, after deducting the estimated underwriting discounts and commissions and estimated offering expenses, and the application of the net proceeds from our sale of common stock in this offering.

Our capitalization following the closing of this offering will be adjusted based on the actual initial public offering price and other terms of the offering determined at pricing. You should read this information in conjunction with “Selected Financial Data,” “Management’s Discussion and Analysis of Financial Condition and Results of Operations” and our financial statements and the related notes appearing elsewhere in this prospectus.

 

     As of December 31, 2014  
     Actual      Pro
Forma
     Pro Forma
As Adjusted
 
            (unaudited)  

Cash and cash equivalents

   $                    $                    $                
  

 

 

    

 

 

    

 

 

 

Notes payable

   $         $         $     
  

 

 

    

 

 

    

 

 

 

Stockholders’ equity:

        

Series C convertible preferred stock, $0.001 par value per share, 180,000,000 shares authorized,              shares issued and outstanding, actual, and no shares authorized, issued or outstanding, pro forma and pro forma as adjusted

        

Series B convertible preferred stock, $0.001 par value per share, 136,000,000 shares authorized,              shares issued and outstanding, actual, and no shares authorized, issued or outstanding, pro forma and pro forma as adjusted

        

Series A convertible preferred stock, $0.001 par value per share, 74,000,000 shares authorized,              shares issued and outstanding, actual, and no shares authorized, issued or outstanding, pro forma and pro forma as adjusted

        

Preferred stock, $0.001 par value per share, no shares authorized, issued or outstanding, actual,              shares authorized, no shares issued or outstanding pro forma and pro forma as adjusted

        

 

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     As of December 31, 2014  
     Actual      Pro
Forma
     Pro Forma
As Adjusted
 
            (unaudited)  

Common stock $0.001 par value per share, 600,000,000 shares authorized,              shares issued and outstanding, actual; authorized, pro forma and pro forma as adjusted;              shares issued and outstanding pro forma;              shares issued and outstanding pro forma as adjusted

        

Additional paid-in capital

        

Accumulated deficit

        
  

 

 

    

 

 

    

 

 

 

Total stockholders’ deficit

        
  

 

 

    

 

 

    

 

 

 

Total capitalization

   $         $         $     
  

 

 

    

 

 

    

 

 

 

A $1.00 increase (decrease) in the assumed initial public offering price of $         per share, which is the midpoint of the range listed on the cover page of this prospectus, would increase (decrease) the pro forma as adjusted amount of each of cash and cash equivalents, additional paid-in capital, total stockholders’ deficit and total capitalization by approximately $         million, assuming that the number of shares offered by us, as set forth on the cover page of this prospectus, remains the same and after deducting the estimated underwriting discounts and commissions and estimated offering expenses payable by us.

The table and calculations above are based on the number of shares of common stock outstanding as of December 31, 2014, and excludes:

 

   

             shares issuable upon the exercise of then outstanding options at a weighted average exercise price of $         per share;

 

   

             shares that will be available for future issuance under our 2015 Employee Stock Purchase Plan as of the effectiveness of the registration statement for this offering;

 

   

             shares then available for future issuance under our 2006 Equity Incentive Plan;

 

   

             shares that will be available for future issuance under our 2015 Equity Incentive Plan as of the effectiveness of the registration statement for this offering; and

 

   

             shares of common stock subject to the underwriters’ option to purchase additional shares from us.

 

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DILUTION

If you invest in our common stock, your ownership interest will be diluted to the extent of the difference between the initial public offering price per share of our common stock and the pro forma as adjusted net tangible book value per share of our common stock immediately after completion of this offering.

Our net tangible book value represents total tangible assets less total liabilities. Our net tangible book value (deficit) per share is our net tangible book value divided by the number of shares of common stock outstanding as of a historical date. The net tangible book value (deficit) of our common stock as of December 31, 2014 was approximately $         million, or approximately $         per share.

Our pro forma net tangible book value (deficit) represents total tangible assets less total liabilities. Our pro forma net tangible book value (deficit) per share is our pro forma net tangible book value (deficit) divided by the number of shares of common stock outstanding as of a historical date, after giving effect to the Series C financing in January 2015 and the conversion of all of our outstanding convertible preferred stock into                 shares of our common stock upon the closing of this offering. The pro forma net tangible book value of our common stock as of December 31, 2014 was approximately $         million, or approximately $         per share.

After giving effect to our sale of shares at an assumed initial public offering price of $         per share, which is the midpoint of the price range set forth on the cover page of this prospectus, deducting the estimated underwriting discounts and commissions and estimated offering expenses, and applying the net proceeds from this sale, the pro forma as adjusted net tangible book value (deficit) of our common stock, as of December 31, 2014, would have been approximately $         million, or approximately $         per share. This amount represents an immediate increase in pro forma net tangible book value (deficit) to our existing stockholders of $         per share and an immediate dilution to new investors purchasing shares in this offering of $         per share. We determine dilution by subtracting the pro forma as adjusted net tangible book value (deficit) per share after this offering from the amount of cash that a new investor paid for a share of common stock. The following table illustrates this per share dilution:

 

Assumed initial public offering price per share

      $                

Pro forma net tangible book value (deficit) per share as of December 31, 2014

   $                   

Increase per share attributable to new investors

     
  

 

 

    

Pro forma as adjusted net tangible book value (deficit) per share after this offering

     
     

 

 

 

Dilution per share to new investors

      $     
     

 

 

 

A $1.00 increase (decrease) in the assumed initial public offering price of $             per share, which is the midpoint of the price range set forth on the cover page of this prospectus, would increase (decrease) the pro forma as adjusted net tangible book value (deficit) per share after this offering by approximately $            , and dilution in pro forma net tangible book value (deficit) per share to new investors by approximately $            , assuming that the number of shares offered by us, as set forth on the cover page of this prospectus, remains the same and after deducting the estimated underwriting discounts and commissions and estimated offering expenses payable by us.

If the underwriters exercise their option to purchase additional shares from us in full, there will be an increase in pro forma as adjusted net tangible book value (deficit) to existing stockholders of $             per share and an immediate dilution in pro forma as adjusted net tangible book value (deficit) to new investors of $             per share based on the assumed initial public offering price, which is the midpoint of the price range set forth on the cover page of this prospectus.

 

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The following table summarizes, as of December 31, 2014, on a pro forma as adjusted basis, the number of shares of common stock purchased from us, the total consideration paid to us and the average price per share paid by our existing stockholders and by new investors, based upon an assumed initial public offering price of $             per share, which is the midpoint of the price range set forth on the cover page of this prospectus, and before deducting the estimated underwriting discounts and commissions and estimated offering expenses payable by us.

 

     Shares Purchased      Total Consideration     Average Price  
     Number    Percent      Amount      Percent     Per Share  

Existing stockholders

                        $                                     $                

New investors

             
  

 

  

 

 

    

 

 

    

 

 

   

 

 

 

Total

        100    $           100   $     
  

 

  

 

 

    

 

 

    

 

 

   

A $1.00 increase (decrease) in the assumed initial public offering price of $         per share, which is the midpoint of the range listed on the cover page of this prospectus, would increase (decrease) the total consideration paid by new investors by $         million, and increase (decrease) the percentage of total consideration paid by new investors by approximately     %, assuming that the number of shares offered by us, as set forth on the cover page of this prospectus, remains the same and before deducting estimated underwriting discounts and commissions and estimated offering expenses payable by us.

The foregoing tables and calculations are based on the number of shares of our common stock outstanding as of December 31, 2014 after giving effect to our Series C financing in January 2015 and the conversion of all outstanding shares of our convertible preferred stock into              shares of our common stock upon the closing of this offering, and excludes:

 

   

                 shares of common stock issuable upon the exercise of then outstanding options at a weighted average exercise price of $         per share;

 

   

                 shares of common stock that will be available for future issuance under our 2015 Employee Stock Purchase Plan, which will become effective prior to the closing of this offering;

 

   

                 shares of common stock reserved for future issuance under our 2006 Equity Incentive Plan; and

 

   

                 shares of common stock reserved future issuance under our 2015 Equity Incentive Plan, which will become effective prior to the closing of this offering.

To the extent any of these outstanding options are exercised, there will be further dilution to new investors. To the extent all of such outstanding options had been exercised as of December 31, 2014, the pro forma as adjusted net tangible book value (deficit) per share after this offering would be $            , and total dilution per share to new investors would be $            .

If the underwriters exercise their option to purchase additional shares in full:

 

   

the percentage of shares of common stock held by existing stockholders will decrease to approximately     % of the total number of shares of our common stock outstanding after this offering; and

 

   

the number of shares held by new investors will increase to                 , or approximately     % of the total number of shares of our common stock outstanding after this offering.

Effective immediately upon closing of this offering, an aggregate of                 shares of our common stock will be reserved for issuance under our 2015 Equity Incentive Plan and                 shares of our common

 

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stock will be reserved for issuance under our 2015 Employee Stock Purchase Plan, and these share reserves will also be subject to automatic annual increases in accordance with the terms of the plans. Furthermore, we may choose to raise additional capital through the sale of equity or equity-linked securities due to market conditions or strategic considerations even if we believe we have sufficient funds for our current or future operating plans. To the extent that new equity awards are issued under our equity incentive plans or we issue additional shares of common stock or other equity or equity-linked securities in the future, there will be further dilution to investors participating in this offering.

 

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SELECTED FINANCIAL DATA

You should read the following selected financial data together with our financial statements and the related notes appearing at the end of this prospectus and “Management’s Discussion and Analysis of Financial Condition and Results of Operations,” which follows immediately after this section.

The following table sets forth our selected financial data as of and for the periods indicated. The selected financial data as of and for the year ended December 31, 2014 and 2013 have been derived from our audited financial statements, which are included elsewhere in this prospectus. Historical results are not indicative of the results to be expected in the future.

 

     Year ended December 31,  
     2014     2013  

Statement of Operations Data:

  

Revenues

   $ —        $ —     
  

 

 

   

 

 

 

Operating expenses:

    

Research and development

     1,168,938        651,660   

General and administrative

     1,140,953        911,757   
  

 

 

   

 

 

 

Total operating expenses

     2,309,891        1,563,417   
  

 

 

   

 

 

 

Loss from operations

     (2,309,891     (1,563,417
  

 

 

   

 

 

 

Other income (expense):

    

Interest income

     1,147        575   

Interest expense

     (397,064     (631,065
  

 

 

   

 

 

 

Total other expense, net

     (395,917     (630,490

Net loss before income tax expense

     (2,705,808     (2,193,907
  

 

 

   

 

 

 

Income tax expense

     247,500        —     
  

 

 

   

 

 

 

Net loss

     (2,953,308     (2,193,907
  

 

 

   

 

 

 

Comprehensive loss

   $ (2,953,308   $ (2,193,907
  

 

 

   

 

 

 

Net loss per share

    

Basic and diluted

   $ (0.51   $ (0.53

Weighted average shares outstanding

    

Basic and diluted

     5,735,392        4,132,114   
     As of December 31,  
     2014     2013  

Balance sheet data:

  

Cash and cash equivalents

   $ 204,362      $ 333,002   

Working capital(1)

     (354,488     (9,907,795

Total assets

     293,253        334,823   

Convertible preferred stock

     50,278,871        40,269,004   

Total stockholders’ deficit

     1,788,301        9,905,974   

 

(1)  

Working capital is defined as current assets minus current liabilities.

 

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MANAGEMENT’S DISCUSSION AND ANALYSIS OF

FINANCIAL CONDITION AND RESULTS OF OPERATIONS

The following discussion and analysis of our financial condition and results of operations should be read in conjunction with the Selected Financial Data and our financial statements and the accompanying notes appearing elsewhere in this prospectus. Our actual results could differ materially from those anticipated in the forward-looking statements included in this discussion as a result of certain factors, including, but not limited to, those discussed in “Risk Factors” and “Information Regarding Forward-Looking Statements” included elsewhere in this prospectus.

Overview

We are a Phase 3 clinical-stage biopharmaceutical company that is developing an innovative and proprietary small molecule for the acute treatment of migraine headaches. Our product candidates utilize the first new mechanism of action in the last twenty years, which we believe could address the unmet needs of migraine patients, including those with cardiovascular risk factors or stable cardiovascular disease and those who are dissatisfied with existing therapies. Lasmiditan, our lead product candidate, is an oral tablet for the acute treatment of migraine headaches in adults that does not have the clinical limitations associated with the most commonly used therapies. We are also developing intravenous lasmiditan, or IV lasmiditan, for the acute treatment of unspecified headache pain in adults in emergency room and other urgent care settings, another significant unmet medical need.

Since our inception in 2005, we have devoted substantially all of our resources to the development of our product candidates. We do not have regulatory approvals in any jurisdiction to sell any products and have not generated any revenue. Since our inception and through December 31, 2014, we have raised $50.6 million to fund our operations, substantially all of which was from the sale of capital stock. In January 2015, we issued and sold shares of our Series C convertible preferred stock in our Series C financing for gross proceeds of $36.9 million. Without accounting for any proceeds we may receive from this offering, we believe we have sufficient cash and cash equivalents to fund our operations for six months after the completion of SAMURAI, assuming it is completed in the third quarter of 2016.

We have never been profitable and have incurred net losses in each year since inception. Our net losses were $3.0 million and $2.2 million for the years ended December 31, 2014 and 2013, respectively, and as of December 31, 2014, our accumulated deficit accumulated was $54.5 million. These net losses resulted primarily from our research and development programs, including our preclinical development activities and clinical trials, and general and administrative costs associated with our operations. We expect to continue to incur significant expenses and increasing operating losses for at least the next several years. These net losses and negative operating cash flows have had, and will continue to have, an adverse effect on our stockholders’ equity and working capital. Because of the numerous risks and uncertainties associated with pharmaceutical product development, we are unable to accurately predict the timing or amount of increased expenses or when, or if, we will be able to achieve or maintain profitability.

We do not expect to generate revenue from product sales unless and until we obtain marketing approval from the FDA for our product candidates and successfully commercialize our product candidates. We expect that our expenses will increase substantially as we continue the research and development of our product candidates and maintain, expand and protect our intellectual property portfolio. If we obtain marketing authorization for our product candidates, we expect to incur significant commercialization expenses related to organizational growth, product sales, marketing, manufacturing and distribution. Accordingly, we will seek to fund our operations through public or private equity or debt financings or other sources, including potential commercial collaborations. However, we may be unable to raise additional funds or enter into such other arrangements when needed on favorable terms or at all. Our failure to raise capital or enter into such other arrangements as and when needed would have a negative impact on our financial condition and our ability to develop and commercialize our product candidates.

 

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License Agreement

On February 10, 2015, we entered into an amended and restated development and license agreement with Eli Lilly, which consolidated a number of amendments to our original development and license agreement with Eli Lilly dated December 16, 2005. Pursuant to such agreement, we hold a worldwide license, with the right to grant sublicenses, under certain patents and know-how owned or controlled by Eli Lilly for lasmiditan for all human health purposes. The license is exclusive except that Eli Lilly has retained the right to conduct research on lasmiditan and products containing lasmiditan for internal research purposes only. The term of the agreement will expire on a country-by-country basis upon expiration of our royalty obligations in such country, which occurs on the later of the tenth anniversary of the first commercial sale in such country or the expiration of the last-to-expire licensed patent in such country. Upon expiration of royalty payment provisions in a given country, we will have a fully paid up, perpetual, irrevocable know-how license in such country, unless the agreement is terminated earlier.

Eli Lilly may terminate the agreement for uncured material breach, in whole or on a country-by-country basis. Eli Lilly may also terminate the agreement upon a change of control of our company, unless the new owner agrees to be bound by the terms and conditions of the agreement. Either party may terminate the agreement upon written notice in the event of bankruptcy. We have the right to terminate in the case of material breach by Eli Lilly or if we believe it would be commercially unreasonable to continue to develop lasmiditan.

Under the agreement, we are also responsible for and have control over the filing and prosecuting of patent applications and maintaining patents which cover making, using or selling lasmiditan under the agreement. In the event we decide to allow any licensed patent to lapse, Eli Lilly may assume the responsibility for the patent and we will surrender our rights in the relevant affected countries. We have the first right (but not the obligation) to enforce these patent rights, and Eli Lilly has agreed to cooperate and assist us in matters regarding infringement as well as patent term extensions and certifications.

During the term of the agreement, we are required to use reasonable commercial efforts to develop and obtain regulatory approvals for selling products containing lasmiditan in all major markets, which include Japan, France, Germany, Italy, Spain, the United Kingdom and the United States. If we obtain regulatory approval for one of our product candidates containing lasmiditan, we are required to use reasonable commercial efforts to commercialize the product in that country. If we do not satisfy this obligation, Eli Lilly may terminate our agreement.

Upon execution of this agreement, we paid an upfront license fee to Eli Lilly in the amount of $1 million and issued to Eli Lilly shares of our common stock. Upon achievement of certain regulatory and/or sales milestones with respect to products containing lasmiditan, we will be obligated to make future payments to Eli Lilly of up to $32 million for the first indication and up to $3 million for each subsequent indication. In addition, we will be obligated to pay Eli Lilly royalties of between 8% and 11% (subject to downward adjustment in certain circumstances) on net sales of products containing lasmiditan. None of our upfront or milestone payments are creditable against our royalty obligations.

Financial Overview

Research and Development.    Research and development expenses consist of the costs associated with research and discovery activities, conducting preclinical studies and clinical trials, manufacturing development efforts and activities related to regulatory filings. Research and development expenses consist of:

 

   

employee salaries and related expenses for the personnel involved in our drug discovery and development activities;

 

   

external research and development expenses incurred under agreements with third-party contract research organizations and investigative sites;

 

 

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expenses incurred to manufacture clinical trial materials; and

 

   

license fees for and milestone payments related to in-licensed products and technologies.

We expense research and development costs as incurred. Conducting a significant amount of research and development is central to our business and strategy. Product candidates in late stages of clinical development generally have higher development costs than those in earlier stages of clinical development, primarily due to the increased size and duration of late-stage clinical trials. We plan to increase our research and development expenses for the foreseeable future as we seek to complete development of our product candidates.

General and Administrative Expenses.    Our general and administrative expenses consist primarily of salaries and related costs for personnel, including stock-based compensation and travel expenses for our employees and consultants. Other general and administrative expenses include professional fees for directors, accounting services, legal services, consultants and expenses associated with obtaining and maintaining patents.

We anticipate that our general and administrative expenses will increase in the future as we increase our headcount to support our continued research and development and the potential commercialization of our product candidates. We also anticipate increased expenses related to costs associated with being a public company, including audit, legal, regulatory and tax-related services associated with maintaining compliance with SEC rules and stock exchange listing rules, director and officer insurance premiums and investor relations costs. We anticipate that the additional costs for these services will increase our general and administrative expenses by approximately $2 million to $3 million on an annual basis. Additionally, prior to the potential regulatory approval of our product candidates, we anticipate an increase in payroll and related expenses as a result of our preparation for commercial operations.

Interest Expense.    We have interest expense related to our outstanding promissory notes. This expense is based on the interest rate and the maturity date at which the promissory notes were issued. We do not anticipate having interest expense in 2015 following the conversion of all outstanding promissory notes into shares of Series C convertible preferred stock.

Critical Accounting Policies and Estimates

Management’s discussion and analysis of our financial condition and results of operations is based on our financial statements, which have been prepared in accordance with U.S. generally accepted accounting principles. The preparation of these financial statements requires us to make estimates and judgments that affect the reporting amounts of assets, liabilities and expenses and the disclosure of contingent assets and liabilities in our financial statements. On an ongoing basis, we evaluate our estimates and judgments, including those related to accrued expenses and stock-based compensation. We base our estimates on historical experience, known trends and events and various other factors that we believe to be reasonable under the circumstances, the results of which form the basis for making judgments about the carrying value of assets and liabilities that are not readily apparent from other sources. Actual results may differ from these estimates under different assumptions or conditions.

While our significant accounting policies are described in more detail in the notes to our financial statements appearing elsewhere in this prospectus, we believe the following accounting policies to be the most critical to the judgments and estimates used in the preparation of our financial statements.

Accrued Expenses.    As part of the process of preparing our financial statements, we are required to estimate our accrued expenses. This process involves reviewing quotations and contracts, identifying services that have been performed on our behalf and estimating the level of service performed and the associated cost incurred for the service when we have not yet been invoiced or otherwise notified of the actual cost. The majority of our service providers invoice us monthly in arrears for services performed or when contractual milestones are met. We make estimates of our accrued expenses as of each balance

 

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sheet date in our financial statements based on facts and circumstances known to us at that time. We periodically confirm the accuracy of our estimates with the service providers and make adjustments if necessary. The significant estimates in our accrued research and development expenses include fees due in connection with research and development activities for which we have not yet been invoiced. Our accrued expenses primarily consist of accrued legal and development expenses.

Revenue Recognition and Deferred Revenue.    We have not generated any revenues. Our ability to generate revenue and become profitable depends upon our ability to successfully commercialize products upon obtaining regulatory approval, which we do not expect to occur for several years. If we fail to complete the development of our product candidates in a timely manner or obtain marketing approval for them, our ability to generate future revenue, and our results of operations and financial position, would be material adversely affected.

Redeemable Convertible Preferred Stock.    We classify our redeemable convertible preferred stock for which we do not control the redemption outside of permanent equity. We record redeemable convertible preferred stock at fair value upon issuance, net of any offering costs, and the carrying value is adjusted to the redemption value at the end of each reporting period. These adjustments are effected through charges against additional paid-in-capital and accumulated deficit.

Stock-Based Compensation.    We utilize the fair value method of accounting for stock-based compensation. The fair value method requires all such compensation, including the grant of employee stock options, to be recognized in our statement of operations based on its fair value at the measurement date, which his generally the grant date for grants made to our employees. For stock-based compensation granted to non-employees, the measurement is generally the date when all services have been rendered or the date that options have fully vested. The expense associated with stock-based compensation is recognized on a straight-line basis over the requisite service period of each award.

We compute the estimated fair values of stock options using the Black-Scholes option pricing model. Due to limited historical data, we estimate stock price volatility based on the actual volatility of comparable publicly traded companies over the expected life of the option. The expected term represents the average time options that vest are expected to be outstanding. We do not have sufficient history of exercise of stock options to estimate the expected term of employee stock options and thus continues to calculate expected life based on the mid-point between the vesting date and the contractual term in accordance with the simplified method allowed by the SEC’s Staff Accounting Bulletin 110. The expected term for stock-based compensation granted to non-employees is the contractual life. The risk-free rate is based on the U.S. Treasury yield curve during the expected life of the option.

Determining the appropriate fair value model and the related assumptions requires judgment. The fair value of each option modified is estimated using a Black-Scholes option-pricing model as follows:

 

     2014   2013

Estimated dividend yield

   0%   0%

Expected stock-price volatility

   70%   69%

Weighted average risk-free interest rate

   0.12%   0.12%

Expected life of options (in years)

   0.5   0.6

Due to the absence of an active market for our common stock, the fair value of common stock was determined by our board of directors based on a number of objective and subjective factors consistent with the methodologies outlined in the American Institute of Certified Public Accounts Practice Aid, Valuation of Privately-Held Company Equity Securities Issued as Compensation, including:

 

   

the prices at which we most recently sold preferred stock and the rights, preferences, and privileges of the preferred stock compared to those of our common stock, including the liquidation preferences of the preferred stock;

 

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the status of our research and development efforts, including the status of clinical trials and regulatory status and interactions with regulatory authorities; and

 

   

the likelihood of achieving a liquidity event for the holders of our common stock, such as an initial public offering or a strategic merger or sale of our company.

Income Taxes.    Deferred tax assets and liabilities are determined based on the temporary differences between the financial statement carrying amounts and the tax base of assets and liabilities using the enacted tax rates in effect in the years in which the differences are expected to reverse. We recognize the tax benefit from an uncertain tax position only if it is more likely than not that the tax position will be sustained on examination by the taxing authorizes based on the technical merits of the position.

Valuation allowances are established when we determine that it is more likely than not that some portion of a deferred tax asset will not be realized. We have incurred operating losses since inception and, therefore, have not recorded any income tax benefit associated with the corresponding tax asset because realization of these benefits could not be reasonably assured.

If necessary, we classify tax-related interest and penalties as a component of tax expense.

Results of Operations

The following table sets forth our results of operations for the years ended December 31, 2013 and 2014:

 

     Year ended December 31,  
     2014     2013  

Revenues

   $ —        $ —     

Operating expenses

    

Research and development

     1,168,938        651,660   

General and administrative

     1,140,953        911,757   
  

 

 

   

 

 

 

Total operating expenses

     2,309,891        1,563,417   
  

 

 

   

 

 

 

Loss from operations

     (2,309,891     (1,563,417

Other income (expense)

    

Interest income

     1,147        575   

Interest expense

     (397,064     (631,065
  

 

 

   

 

 

 

Total other expense, net

     (395,917     (630,490
  

 

 

   

 

 

 

Net loss before income tax expense

     (2,705,808     (2,193,907
  

 

 

   

 

 

 

Income tax expense

     247,500        —     
  

 

 

   

 

 

 

Net loss

     (2,953,308     (2,193,907
  

 

 

   

 

 

 

Comprehensive loss

   $ (2,953,308   $ (2,193,907
  

 

 

   

 

 

 

Revenues.    We did not recognize any revenue in 2014 or 2013. In 2014, we received a $1.5 million up-front payment in connection with the distribution and supply agreement with Ildong, which is reflected in deferred revenue and will be recognized as revenue after we commercialize lasmiditan. We do not expect to recognize revenue in 2015 as we continue development of our product candidates.

Research and Development Expenses.    Our research and development expenses increased by approximately $517,000 to $1.2 million in 2014, compared to $652,000 in 2013. The increase in our research and development expenses in 2014 was primarily due to increased costs relating to preparations for our first pivotal Phase 3 clinical trial of lasmiditan. All research and development expenses for such

 

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periods are attributable to lasmiditan and consisted primarily of clinical trial expenses, personnel-related costs, and external research and development expenses. We expect our research and development costs will significantly increase in 2015 due to additional expenses associated with our planned pivotal Phase 3 clinical trials of lasmiditan.

General and Administrative Expenses.    General and administrative expenses increased by approximately $229,000 to $1.1 million in 2014, compared to $912,000 in 2013. The increase in our general and administrative expenses in 2014 was primarily due to increased costs relating to our audit, consulting expenses and general legal fees related to our Series C convertible preferred stock. Our general and administrative expenses consist primarily of salaries and related costs for personnel, including stock-based compensation and travel expenses for our employees and consultants. Other general and administrative expenses include professional fees for directors, accounting services, legal services, consultants and expenses associated with obtaining and maintaining patents.

We anticipate that our general and administrative expenses will increase in the future as we increase our headcount to support our continued research and development and the potential commercialization of our product candidates. We also anticipate increased expenses related to costs associated with being a public company, including audit, legal, regulatory and tax-related services associated with maintaining compliance with SEC rules and stock exchange listing rules, director and officer insurance premiums and investor relations costs. We anticipate that the additional costs for these services will increase our general and administrative expenses by approximately $2 million to $3 million on an annual basis. Additionally, prior to the potential regulatory approval of our product candidates, we anticipate an increase in payroll and related expenses as a result of our preparation for commercial operations.

Interest Expense.    Interest expense decreased from $631,000 in 2013 to $397,000 in 2014. In 2014 and 2013, we had net interest expense due to interest payable on our outstanding promissory notes offset partially by earnings on our cash and cash equivalents. Interest expense consists of interest accrued on convertible debt. In 2014, our interest payable decreased due to the conversion and retirement of all then-outstanding promissory notes into shares of Series B preferred stock, which occurred in July 2014. We do not anticipate incurring any significant interest expense in 2015, as we have no commercial debt or outstanding promissory notes following the conversion of all then-outstanding promissory notes into shares of Series C preferred stock.

Income Taxes.    We paid $247,500 in income taxes in 2014 and no income tax in 2013. These taxes were paid to the Republic of South Korea in conjunction with our distribution and supply agreement with Ildong Pharmaceutical Co., Ltd.

Liquidity and Capital Resources

Cash Flows.    We have incurred losses and cumulative negative cash flows from operations since our inception in 2005, and as of December 31, 2014, we had a deficit accumulated of $54.5 million. We anticipate that we will continue to incur losses for at least the next several years. We expect that our research and development and general and administrative expenses will continue to increase and, as a result, we will need additional capital to fund our operations and to obtain regulatory approval for our product candidates, which we may raise through a combination of equity offerings, debt financings and other third-party funding.

We have funded our operations principally from the issuance of notes payable and preferred stock. Since our inception through December 31, 2014, we have raised aggregate proceeds of $50.6 million to fund our operations, of which $41.5 million was from the sale of preferred stock and $9.1 million was from our debt instruments. As of December 31, 2014, we had cash and cash equivalents of $204,000 and $200,000 of outstanding debt. In January 2015, we issued and sold Series C convertible preferred stock in our Series C financing with gross proceeds of $36.9 million. In this private placement, our $200,000 of outstanding debt was converted into Series C convertible preferred stock.

 

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The following table sets forth the primary sources and uses of cash and cash equivalents for each year set forth below:

 

     Year ended December 31,  
     2014     2013  

Net cash provided by (used in)

    

Operating activities

   $ (762,953   $ (1,505,599

Investing activities

     —          (2,049

Financing activities

     634,313        1,124,500   
  

 

 

   

 

 

 

Net increase (decrease) in cash and cash equivalents

   $ (128,640   $ (383,148
  

 

 

   

 

 

 

Net Cash Used in Operating Activities.    Net cash used in operating activities in 2014 consisted primarily of a net loss of $3.0 million, adjusted for interest on the convertible promissory notes of $397,000, as well as deferred revenue of $1.5 million, accounts payable of $251,000, accrued expenses of $62,000 and prepaid expenses of $23,000. Net cash used in operating activities in 2013 consisted primarily of a net loss of $2.2 million adjusted for interest on the convertible promissory notes of $631,000, as well as accounts payable of $38,000.

Net Cash Used in Investing Activities.    No cash was provided by or used in investing activities in 2014. Net cash used in investing activities in 2013 consisted of purchases of laboratory equipment for research and development.

Net Cash Provided by Financing Activities.    Net cash provided by financing activities in 2014 was $634,000, which consisted primarily of net proceeds of $701,000 from the issuance of notes payable, offset by $66,000 of financing costs. Net cash provided by financing activities in 2013 consisted entirely of proceeds from the issuance of notes payable.

Funding Requirements.    Our primary uses of capital are, and we expect will continue to be, salaries and personnel-related expenses, costs related to clinical trials, laboratory and related supplies, accounting expenses, legal expenses, other regulatory expenses and general overhead costs. We expect our expenses to significantly increase compared to prior periods in connection with our ongoing activities, particularly as we continue research and development, initiate large pivotal Phase 3 clinical trials and seek regulatory approvals for our product candidates. In anticipation of regulatory approval for our product candidates, we expect to incur significant pre-commercialization expenses related to product sales, marketing, distribution and manufacturing. Furthermore, as discussed above, upon the closing of this offering, we expect to incur additional costs associated with operating as a public company.

Without accounting for any proceeds we may receive from this offering, we believe we have sufficient cash and cash equivalents to fund our operations for six months after the completion of SAMURAI, assuming it is completed in the third quarter of 2016. Based on our planned use of the net proceeds from this offering and our existing cash and cash equivalents, we estimate that such funds will be sufficient to enable us to complete our two planned pivotal Phase 3 clinical trials, submit an NDA if our Phase 3 clinical trials are completed successfully, and initiate our long-term, open label study of lasmiditan. We also estimate that such funds will fund our operating expenses and capital expenditure requirements through                 . We have based this estimate on assumptions that may prove to be wrong, and we could use our available capital resources sooner than we currently expect. Additionally, the process of testing our product candidates in clinical trials is costly, and the timing of progress in these trials is uncertain. Because our product candidates have not received marketing authorization from the FDA and are in various stages of clinical development and the outcome of these efforts is uncertain, we cannot estimate the actual amounts necessary to successfully complete the development and commercialization of our product candidates or whether, or when, we may achieve profitability.

Until such time, if ever, as we can generate substantial product revenue, we expect to finance our cash needs through a combination of equity offerings, debt financings and revenue from potential research and development and other collaboration agreements. To the extent that we raise additional capital

 

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through the future sale of equity or debt, the ownership interest of our stockholders will be diluted, and the terms of these securities may include liquidation or other preferences that adversely affect the rights of our existing common stockholders. If we raise additional funds in the future, we may have to relinquish valuable rights to our technologies, future revenue streams or grant licenses on terms that may not be favorable to us. If we are unable to raise additional funds through equity or debt financings when needed, we may be required to delay, limit, reduce or terminate our product development or future commercialization efforts or grant licenses to develop and market products that we would otherwise prefer to develop and market ourselves.

Off-Balance Sheet Arrangements

We did not have during the periods presented, and we do not currently have, any off-balance sheet arrangements, as defined under the applicable regulations.

Contractual Obligations

As of December 31, 2014, other than $200,000 of convertible notes due in 2015, we did not have any long-term contractual obligations or commercial obligations. We enter into contracts in the normal course of business with clinical research organizations for clinical trials and clinical supply manufacturing and with vendors for preclinical research studies, research supplies and other services and products for operating purposes. These contracts generally provide for termination on notice, and therefore we believe that our non-cancelable obligations under these agreements are not material.

Net Operating Loss and Research and Development Tax Credit Carryforwards

As of December 31, 2014, we had federal and state net operating loss, or NOLs, carryforwards of $43.3 million and $43.8 million, respectively, which begin to expire in 2025 and 2021, respectively, unless previously utilized. As of December 31, 2014 and December 31, 2013, we also recognized federal research and development tax credit carryforwards of $1.2 million and $1.4 million, respectively. The federal research and development tax credit carryforwards will begin to expire in 2026. Utilization of the net operating losses and credits may be subject to a substantial annual limitation due to ownership change limitations provided by the Internal Revenue Code of 1986, as amended. The annual limitation may result in the expiration of our net operating losses and credits before we can use them.

Quantitative and Qualitative Disclosures about Market Risk

We are exposed to market risk from changes in interest rates, primarily related to our investment activities. The principal objectives of our investment activities are to preserve principal, provide liquidity and maximize income consistent with minimizing risk of material loss. The recorded carrying amounts of cash and cash equivalents approximate fair value due to their short maturities. Our interest income is sensitive to changes in the general level of interest rates in the U.S., particularly since our investments are generally short-term in nature. Due to the nature of our short-term investments, an immediate 100 basis point change in interest rates would not have a material effect on the fair market value of our portfolio.

As a result of our supplier relationship, we have expenses, assets and liabilities that are denominated in foreign currencies. Therefore, a portion of our operating expenses are paid and incurred in the Euro. Our operating results and cash flows may be adversely impacted when the U.S. dollar depreciates relative to other foreign currencies. As we begin building relationships to commercialize our product candidates internationally, our results of operations and cash flows may become increasingly subject to changes in foreign exchange rates.

 

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Recent Accounting Pronouncements

Section 107 of the JOBS Act provides that an “emerging growth company” can take advantage of the extended transition period provided in Section 7(a)(2)(B) of the Securities Act of 1933 for complying with new or revised accounting standards. In other words, an “emerging growth company” can delay the adoption of certain accounting standards until those standards would otherwise apply to private companies. However, we are choosing to “opt out” of such extended transition period, and as a result, we will comply with new or revised accounting standards on the relevant dates on which adoption of such standards is required for non-emerging growth companies. Section 107 of the JOBS Act provides that our decision to opt out of the extended transition period for complying with new or revised accounting standards is irrevocable.

In May 2014, the Financial Accounting Standards Board (FASB) issued Accounting Standards Update (ASU) No. 2014-09, Revenue from Contracts with Customers, which requires an entity to recognize the amount of revenue to which it expects to be entitled for the transfer of promised goods or services to customers. This accounting standards update will replace most existing revenue recognition guidance in U.S. generally accepted accounting principles when it becomes effective. The new standard is effective for our company on January 1, 2017. Early application is not permitted. The standard permits the use of either the retrospective or cumulative effect transition method. We are evaluating the effect that ASU 2014-09 will have on our financial statements and related disclosures. We have not yet selected a transition method nor has we determined the effect of the standard on our ongoing financial reporting.

In June 2014, the Financial Accounting Standards Board issued Accounting Standards Update No. 2014-12, Compensation—Stock Compensation (Topic 718): Accounting for Share-Based Payments When the Terms of an Award Provide That a Performance Target Could Be Achieved after the Requisite Service Period. The amendments in ASU 2014-12 require that a performance target that affects vesting and that could be achieved after the requisite service period be treated as a performance condition. A reporting entity should apply existing guidance in Accounting Standards Codification 718, Compensation—Stock Compensation, as it relates to awards with performance conditions that affect vesting to account for such awards. The amendments in ASU 2014-12 are effective for annual periods and interim periods within those annual periods beginning after December 15, 2015. Early adoption is permitted. Entities may apply the amendments in ASU 2014-12 either: (a) prospectively to all awards granted or modified after the effective date; or (b) retrospectively to all awards with performance targets that are outstanding as of the beginning of the earliest annual period presented in the financial statements and to all new or modified awards thereafter. We believe the adoption of this guidance will not have a material effect on our financial statements.

In August 2014, the Financial Accounting Standards Board issued Accounting Standards Update No. 2014-15, Presentation of Financial Statements—Going Concern (Subtopic 205-40): Disclosure of Uncertainties about an Entity’s Ability to Continue as a Going Concern, which is intended to define management’s responsibility to evaluate whether there is substantial doubt about an organization’s ability to continue as a going concern and to provide related footnote disclosures. The accounting standards update provides guidance to an organization’s management, with principles and definitions that are intended to reduce diversity in the timing and content of disclosures that are commonly provided by organizations today in the financial statement footnotes. The amendments are effective for annual periods ending after December 15, 2016, and interim periods within annual periods beginning after December 15, 2016. Early adoption is permitted for annual or interim reporting periods for which the financial statements have not previously been issued. We do not intend to early adopt this standard. We do not anticipate that the adoption of this standard will have an impact on our financial condition.

 

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JOBS Act

As an “emerging growth company” under the Jumpstart Our Business Startups Act of 2012, or the JOBS Act, we can take advantage of an extended transition period for complying with new or revised accounting standards. This allows an emerging growth company to delay the adoption of certain accounting standards until those standards would otherwise apply to private companies. We have irrevocably elected not to avail ourselves of this extended transition period and, as a result, we will adopt new or revised accounting standards on the relevant dates on which adoption of such standards is required for other public companies.

We are in the process of evaluating the benefits of relying on other exemptions and reduced reporting requirements under the JOBS Act. Subject to certain conditions, as an emerging growth company, we intend to rely on certain of these exemptions, including without limitation (i) reduced financial statement reporting periods, (ii) providing an auditor’s attestation report on our system of internal controls over financial reporting pursuant to Section 404(b) of the Sarbanes-Oxley Act of 2002 and (iii) complying with any requirement that may be adopted by the Public Company Accounting Oversight Board, or PCAOB, regarding mandatory audit firm rotation or a supplement to the auditor’s report providing additional information about the audit and the financial statements, known as the auditor discussion and analysis. We will remain an emerging growth company until the earliest of: (i) the last day of the fiscal year in which we have total annual gross revenues of $1 billion or more; (ii) the last day of the fiscal year following the fifth anniversary of the date of the closing of this offering; (iii) the date on which we have issued more than $1 billion in nonconvertible debt during the previous three years; and (iv) the date on which we are deemed to be a large accelerated filer under the rules of the SEC.

 

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BUSINESS

Overview

We are a Phase 3 clinical-stage biopharmaceutical company that is developing an innovative and proprietary small molecule for the acute treatment of migraine headaches. Our product candidates utilize the first new mechanism of action in the last twenty years, which we believe could address the unmet needs of migraine patients, including those with cardiovascular risk factors or stable cardiovascular disease and those who are dissatisfied with existing therapies. Lasmiditan, our lead product candidate, is an oral tablet for the acute treatment of migraine headaches in adults that does not have the clinical limitations associated with the most commonly used therapies. In our Phase 2b clinical trial of lasmiditan, we met our primary endpoint of headache relief with statistical significance as well as our secondary endpoint of freedom from the associated symptoms of nausea, sensitivity to sound and sensitivity to light. Headache relief is defined as reducing a moderate or severe headache at baseline to mild or none two hours after dosing. In our completed clinical trials, lasmiditan was well tolerated and had a favorable patient global impression of change, an indicator of patient satisfaction.

We are conducting our first pivotal Phase 3 randomized, double-blind, placebo-controlled clinical trial of lasmiditan, or SAMURAI, under a special protocol assessment, or SPA, agreement with the U.S. Food and Drug Administration, or FDA, with top-line data expected in the third quarter of 2016. We also plan to initiate a second pivotal Phase 3 clinical trial of lasmitidan in the first half of 2016. If we successfully complete our two pivotal Phase 3 clinical trials of lasmiditan, we expect to submit a new drug application, or NDA, to the FDA seeking marketing approval for lasmiditan in the United States with a product label that is differentiated from triptans. Triptan product labels include warnings and precautions against use in patients with cardiovascular risk factors or disease and triptans are not indicated to provide freedom from the most bothersome associated symptom. We are also developing intravenous lasmiditan, or IV lasmiditan, for the acute treatment of unspecified headache pain in adults in emergency room and other urgent care settings. We own or have exclusive rights to the intellectual property for lasmiditan and IV lasmiditan, including composition of matter protection. We have commercial exclusivity for lasmiditan and IV lasmiditan in the United States until 2025, which we expect will be extended up to five years to 2030 by obtaining a term extension under the provisions of the Hatch-Waxman Act.

According to the American Migraine Foundation, migraine affects 12% of the population in the United States and is the leading cause of disability among neurological disorders in the United States. The direct and indirect costs of migraine in the United States are estimated at over $20 billion annually. We believe that lasmiditan will be a first line therapy for the acute treatment of migraine in patients with cardiovascular risk factors or disease. Triptans, the current standard of care to treat migraine, use a vasoconstrictor mechanism of action associated with warnings and precautions against use in patients with cardiovascular risk factors or disease. Triptan product labels recommend that migraine patients with risk factors for cardiovascular disease be evaluated for silent myocardial ischemia before receiving a triptan dose, and should have their first dose administered in a medically supervised setting. Based on published studies, we estimate that more than 60%, or 21 million of the 36 million migraine patients in the United States, have cardiovascular risk factors and that triptans are contraindicated in 13%, or 4.7 million. Further, we estimate that approximately 5% of migraine patients may be at risk for silent myocardial ischemia. We believe lasmiditan’s novel, centrally-acting mechanism of action could address this disadvantage of existing therapies because early studies have shown no evidence of vasoconstriction.

We believe that lasmiditan will also be a second line therapy for patients who are dissatisfied with existing therapies, either because of inadequate response or tolerability issues. If approved by the FDA, lasmiditan could also provide an alternative therapy for the more than 40% of patients who fail to respond to triptans or are dissatisfied with treatment.

 

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We have completed seven clinical trials in which we dosed 393 migraine patients and 213 healthy subjects with lasmiditan or IV lasmiditan. Because these trials were conducted outside the United States, we were not required to submit an investigational new drug application, or IND, to the FDA for such trials. If approved, we believe our product candidates could be an attractive option for the acute treatment of migraine and headache pain by providing:

 

   

relief of migraine pain and associated symptoms;

 

   

a novel, centrally-acting mechanism with no evidence of vasoconstriction;

 

   

physician and patient confidence to treat migraine in the presence of cardiovascular risk factors;

 

   

an alternative treatment option for patients who are not adequately managed with triptans;

 

   

favorable patient satisfaction and good tolerability; and

 

   

an additional opportunity for non-opioid treatment of headache in emergency room and other urgent care settings.

Lasmiditan is designed to treat migraine using a novel mechanism by acting as an agonist at the 5-HT1F receptor. In contrast to triptans, which act peripherally, lasmiditan is designed to penetrate the central nervous system, or CNS, and to block the pathway that contributes to headache pain. Triptans were not designed to penetrate the CNS and have limited affinity for 5-HT1F receptors.

The table below summarizes the clinical phase of development for each of our product candidates:

Clinical Phase of Development

LOGO

We believe we have clear guidance for the design of SAMURAI under our successfully negotiated SPA agreement with the FDA. We expect to begin enrolling patients in SAMURAI during the second quarter of 2015, with top-line data expected in the third quarter of 2016. The primary endpoint of SAMURAI is the proportion of lasmiditan patients who are free of headache pain two hours after dosing, which was the secondary endpoint of our Phase 2b clinical trial. The key secondary endpoint of SAMURAI is the proportion of lasmiditan patients who are free from their self-reported, most bothersome associated symptom associated with migraine two hours after dosing: nausea, sensitivity to sound or sensitivity to light. Based on results from our Phase 2b clinical trial of lasmiditan, we believe SAMURAI is sufficiently powered to achieve its primary endpoint and key secondary endpoint.

Our clinical program is designed to support a request for a product label that is differentiated from triptans. Triptan product labels include warnings and precautions against use in patients with cardiovascular risk factors or disease and triptans are not indicated to provide freedom from the most bothersome associated symptom. SAMURAI and our second Phase 3 pivotal trial are expected to enroll migraine patients, including those with cardiovascular risk factors or disease. We plan to complete our two pivotal Phase 3 clinical trials for lasmiditan in the second half of 2017 and if successful, file for marketing approval in the United States. If we receive approval from the FDA, we intend to commercialize lasmiditan in the United States ourselves and co-develop and co-market IV lasmiditan in the United States. If our products are approved by comparable foreign regulators, we plan to establish collaborations to commercialize lasmiditan and IV lasmiditan outside the United States.

 

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Migraine

Migraine is a chronic and debilitating disorder characterized by episodic attacks of moderate to severe throbbing headaches, worsened by physical activity and associated with nausea, sensitivity to sound and sensitivity to light. Some people get migraine headaches only once or twice a year, but about 25% of sufferers experience an attack once or twice a week. Pain can last a few hours or up to 72 hours. About a quarter of all migraine patients experience sensory symptoms leading up to their migraine attack known as aura. More than 90% of sufferers are unable to work or function normally during a migraine attack, and depression, anxiety and sleep disturbances are common comorbid conditions for those with chronic migraine.

Prevalence.    According to the World Health Organization, migraine ranks as the third most common disease in the world. According to the American Migraine Foundation, 36 million people in the United States suffer from migraine, or about 12% of the U.S. population. It is more common among women than men and prevalence peaks between the ages of 25 and 55. U.S. employers lose 113 million work days per year due to migraine and people with migraine use about twice the medical resources as non-sufferers. Migraine accounts for more than 800,000 emergency room visits per year and is the third leading cause for overall emergency room visits. Migraine is the leading cause of disability among neurological disorders.

Causes.    Migraine is a complex disorder that can be triggered by a variety of stimuli or become active spontaneously. Migraine was once considered to be a vascular disease, but it is now established that cerebral vasodilatation is a secondary mechanism in migraine. Although why and how a migraine headache starts is unknown, it is believed that there is an activation of the pain fibers in the membranous layer that surrounds the outside of the brain, called the meninges. The blood supply to the brain is carried in blood vessels that run through the meninges, and around these blood vessels are sensory nerve terminals of the trigeminal nerve pathway (see Figure 1 below). The painful headache of migraine is primarily driven by noxious sensory signals transmitted in the trigeminal nerve pathway, which terminates in the brainstem. From here, the noxious signals are relayed to higher brain centers where they are perceived as pain. During a migraine headache, activation of the trigeminal nerve causes the release of vasodilators, causing the cranial blood vessels to dilate. The shift in focus to consider migraine a neurological disorder, not a vascular disorder, presents new opportunities to treat migraine through a centrally-acting mechanism of action that targets the trigeminal nerve pathways rather than the blood vessels.

Figure 1. Mechanisms Involved in Migraine

 

LOGO

 

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Treatment

Pharmacologic agents are used for the acute treatment and/or prevention of migraine. Products for acute treatment of migraine are used to alleviate pain and symptoms during the attack, also known as the acute phase. Preventative products are used to reduce the frequency of migraine episodes, although most of these patients continue to develop migraine headaches and still require acute therapy.

Acute Treatments.    Triptans, a family of tryptamine-based drugs first sold in the 1990s, account for almost 80% of anti-migraine therapies prescribed at office visits. Triptans are sold in oral, nasal, subcutaneous and transdermal patch formulations. According to Decision Resources, in 2013 oral formulations of sumatriptan (Imitrex) captured more than half of the total first-line patient share for newly diagnosed patients, with rizatriptan (Maxalt) and eletriptan (Relpax) being the second and third most commonly used products. Generic sumatriptan, the most commonly prescribed triptan, has been available since 2009, and the entire class will be generic by the time we expect to launch lasmiditan. Triptans are agonists at the 5-HT1B and 5-HT1D receptors and, through the activation of 5-HT1B receptors expressed on vascular smooth muscle, cause constriction of blood vessels in the meninges and elsewhere in the body. Because they were developed as vasoconstrictors, triptans as a class generally have poor ability to penetrate the CNS.

Other less commonly prescribed acute treatments include ergot alkaloids, analgesics, including opioids, non-steroidal anti-inflammatory drugs, or NSAIDs, acetaminophen and antiemetics. Dihydroergotamine, or DHE, is a grain fungus derivative that, like triptans, is a potent vasoconstrictor. DHE has been used for more than 50 years but physicians rarely prescribe this class, which was largely displaced by the introduction of the triptans. Semprana, previously known as Levadex, is an inhaled form of DHE currently in development.

Opioids are used for the acute treatment of migraine, both in outpatient as well as acute settings. Although their use is controversial, data from a 2009 study conducted by the American Migraine Prevalence and Prevention Study, or AMPP, suggests that about 16% of migraine patients are current opioid users and 16% of those patients are likely dependent. Opioid use for migraine is associated with increased disability and health care utilization.

Patients who experience severe migraine pain and who either have no medicine or insufficient treatment may go to the emergency room. Headache pain accounts for more than 3 million emergency room visits per year, and over 1 million of these visits resulted in a diagnosis of migraine. In the emergency room setting, physicians will most commonly administer opioids, neuroleptics, NSAIDs, corticosteroids and antiepileptics. Opioids, while effective for headache pain, are not approved for migraine and carry risk of abuse and addiction.

Preventative Treatments.    Agents currently used to reduce the frequency of migraine episodes were first approved for other uses. Botox is the only product that has been approved by the FDA for the prevention of chronic migraine, which is defined as having a migraine attack 15 or more days per month for at least three months. About 3 million people in the United States are classified as having chronic migraine. For those patients who do not qualify as having chronic migraine, but still have significant disability due to migraine, there are four products approved by the FDA for use: topiramate (Topamax) and valproic acid (Depakote), both anticonvulsant medicines, and propranolol (Inderal) and timolol (Blocadren), both beta-blockers. Some other beta blockers, such as atenolol, metoprolol and nadalol are also prescribed off-label for prevention, as well as calcium channel blockers such as diltiazem and tricyclic antidepressants such as amitriptyline.

 

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Limitations of Current Acute Treatments

Warning and Contraindications Limiting Use of Triptans by Migraine Patients with Cardiovascular Risk Factors and Disease.    The most widely prescribed acute treatments are all vasoconstrictors. Vasoconstrictors are contraindicated in migraine sufferers with cardiovascular event histories and conditions. Based on published studies, we estimate that more than 60%, or 21 million of the 36 million migraine patients in the United States, have cardiovascular risk factors and that triptans are contraindicated in 13%, or 4.7 million. Further, we estimate that approximately 5% of migraine patients may be at risk for silent myocardial ischemia. Lasmiditan and its non-vasoconstrictor mechanism of action could address this disadvantage of existing therapies.

The vasoconstrictor mechanism of action of triptans confers a risk of serious cardiovascular adverse events, some fatal, in patients with cardiovascular disease. Triptans are contraindicated in patients with cardiovascular, cerebrovascular or peripheral vascular disease. Triptan product labels include warnings and precautions stating that migraine patients with risk factors for cardiovascular disease (such as hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of coronary artery disease, women with surgical or physiological menopause and men over 40 years of age) should be evaluated for silent myocardial ischemia before receiving a triptan dose, and should have their first dose administered in a medically supervised setting. Treatment of migraine patients with cardiovascular risk factors or disease is particularly challenging because the incidence of myocardial infarction, stroke, claudication, diabetes, hypertension and hypercholesterolemia are all higher in migraine patients compared with the general population. Confounding for the treating physician is the fact that up to 24% of patients taking oral triptans and 41% of patients taking subcutaneous triptans in controlled studies report triptan chest symptoms such as chest pressure. These symptoms may be troubling for prescribing physicians and patients because they may be unable to diagnose whether or not the patient is suffering a non-life threatening side effect of the triptan or a serious cardiovascular event. As a precaution, patients presenting with chest symptoms after taking a triptan are often referred for a full cardiovascular evaluation in the emergency room, adding time and expense to the treatment of migraines. Many migraine patients who were previously eligible for triptan therapy may become ineligible as they age and develop cardiovascular disease or associated risk factors.

Patients’ Dissatisfaction with Current Treatments.    The need for an effective acute treatment for migraine headaches is only partially satisfied by triptans. Typically, only 50 to 60% of migraine respond to an oral triptan within two hours and even then symptoms commonly recur within 24 hours. Additionally, although the triptan drug class is the current standard of care for the acute treatment of migraine, more than 40% of patients fail to respond to triptan treatment or are dissatisfied with treatment. Some migraine patients fail to respond consistently to oral triptans. Additional triptan formulations have been developed, but they are all still vasoconstrictors and most of these products have had limited market success due to lack of perceived benefit, lack of patient acceptance and lack of compliance.

Unattractive Options for Headache Patients in Acute Care Settings.    Annually, about 7% of migraine patients go to the emergency room due to headache pain, accounting for between 1% and 4% of all emergency room visits. Few well-controlled studies for the treatment of headache pain in the emergency room have been conducted. The most commonly used treatments in emergency room management of headache pain include opioids, neuroleptics, NSAIDs, corticosteroids and antiepileptics. Triptans and DHE are not widely used in an emergency room due to their perceived cardiovascular safety liabilities. Current treatments used in emergency room management of headache pain present disadvantages for patients as well as hospitals because of the high rate of abuse liability associated with opioids and the warnings and precautions for use of triptans and DHE. Opioids are addictive and prone to overuse and abuse. Opioids contribute to the development of medication overuse headache, or MOH, and the worsening progression of migraine. The U.S. Centers for Disease Control and Prevention, or CDC, has

 

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recognized this growing issue and officially classified prescription opioid abuse as an epidemic. According to the CDC, opioid pain relievers were involved in nearly 17,000 drug overdose deaths in 2011. Furthermore, the nonmedical use of opioid analgesics was responsible for approximately 420,000 emergency room visits that year. Between 1991 and 2010, prescriptions for opioid analgesics increased from about 75.5 million to 209.5 million. As a result, in 2014, hydrocodone combination products were moved from Schedule III to the more-restrictive Schedule II and several states have established task forces to tackle this issue.

Migraine Market Size

There has been a lack of innovation in the migraine market and the generic erosion of the leading products for the prevention and treatment of migraine. Sales for migraine products are often under reported due to off-label usage of prescription drugs and the use of the non-prescription agents. According to Decision Resources, prescription drug sales for migraine in the top seven countries were estimated to be $3.2 billion in 2013, and are expected to grow to $4.4 billion in 2020.

Although the current market is highly genericized, reformulations of triptans are predicted to generate additional sales in the near term but major sales growth for the migraine market is from new therapy classes with novel mechanisms of action in the 2020 time frame. We engaged a third party to conduct primary market research with physicians and based on this research and analysis of the migraine marketplace, we have developed a U.S. revenue forecast for lasmiditan. In addition to secondary research, physicians across specialties, geographies, practice types and size were interviewed to provide insight representative of the migraine market. Qualitative interviews were conducted with neurologists, migraine specialists, primary care physicians and obstetricians and gynecologists. Payors, emergency room physicians and European based key opinion leaders were also included. A quantitative survey of 81 physicians, including neurologists, migraine specialists, primary care physicians, obstetricians and gynecologists was also conducted. Physicians were shown four different potential product profiles of lasmiditan. A key finding was that 98% of surveyed physicians overall suggested they would prescribe lasmiditan to some of their migraine patients, even if efficacy is equivalent to sumatriptan. We also found that physicians expect some level of CNS side effects with anti-migraine agents. Based on this work and our ongoing review of research regarding the migraine marketplace, we believe that lasmiditan, if approved, could achieve peak annual revenue of more than $1 billion. This forecast is based on the expectation that lasmiditan will be the first new chemical entity, or NCE, with a novel mechanism of action in the United States specifically approved for the acute treatment of migraine patients since the U.S. approval of the first triptan, Imitrex, in 1992. We believe competition will be limited to re-formulations of currently available vasoconstrictive products. We also believe that lasmiditan will be a first line therapy for acute treatment of migraine in patients with cardiovascular risk factors or disease and will be a second line therapy for patients who are dissatisfied with existing therapies, either because of inadequate response or tolerability issues. We further believe that lasmiditan has the potential to grow the migraine market by providing a treatment option to migraine patients who were not candidates for currently available agents or who could not take such agents.

Our Solution

We are developing our product candidates to treat unmet needs of migraine and headache pain patients, including those with cardiovascular risk factors or disease and those who are dissatisfied with existing therapies, either because of inadequate response or tolerability issues. If approved, we believe that our product candidates could be an attractive option for the acute treatment of migraine and headache pain by providing:

 

   

Relief of migraine pain and associated symptoms.    We believe lasmiditan has the potential to relieve migraine pain and associated symptoms using a mechanism of action that has not

 

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previously been used for the acute treatment of migraine. In our Phase 2b clinical trial of lasmiditan, we met our primary endpoint of headache relief two hours after dosing with statistical significance as well as our secondary endpoints of freedom from headache pain and freedom from nausea, sensitivity to sound and sensitivity to light.

 

   

A novel, centrally-acting mechanism with no evidence of vasoconstriction.    We designed lasmiditan to treat a migraine without constricting blood vessels unlike existing therapies, which have precautions and warnings against use in migraine patients with cardiovascular risk factors or disease. No evidence of drug-related vasoconstriction or chest symptoms has been reported in our seven completed clinical trials of lasmiditan and IV lasmiditan. Our clinical program is designed to support a request for a product label that is differentiated from triptans. Triptan product labels include warnings and precautions against use in patients with cardiovascular risk factors or disease.

 

   

Physician and patient confidence to treat migraine in the presence of cardiovascular risk factors.    Common side effects of triptans are chest symptoms, which were reported in 24% of patients taking oral triptans, and 41% of patients taking subcutaneous triptans in controlled studies. These triptan symptoms have been described as chest pressure similar to an inner tube being inflated around the patient’s chest. These symptoms are troubling for prescribing physicians and patients because they may be unable to determine whether the patient is suffering a non-life threatening side effect of the triptan or a serious cardiovascular event. In our Phase 2b clinical trial, there was no pattern of triptan-like chest symptoms attributable to increasing doses of lasmiditan. Seven out of 391 patients, or 1.8%, reported chest symptoms in the safety population, and these were similarly distributed across all study groups, including placebo.

 

   

An alternative treatment option for patients who are not adequately managed with triptans.    The need for an effective acute treatment for a migraine attack is only partially satisfied by triptans. Typically, only 50 to 60% of migraine attacks respond to an oral triptan within two hours and even then symptoms commonly recur within 24 hours. Additionally, although the triptan drug class is the current standard of care for the acute treatment of migraine, more than 40% of patients fail to respond to triptan treatment or are dissatisfied with treatment. Some migraine patients fail to respond consistently to oral triptans. Additional triptan formulations have been developed to try to address the limitations of oral triptan therapy, but most of these products have met with limited success due to lack of perceived benefit, lack of patient acceptance and lack of compliance.

 

   

Favorable patient satisfaction and good tolerability.    In our Phase 2b clinical trial, lasmiditan was well tolerated and had a favorable patient global impression of change, an indicator of patient satisfaction. Given lasmiditan’s site of action in the CNS, most side effects noted have been CNS-related, with the most common side effects being mild or moderate dizziness and fatigue that were transient and resolved spontaneously during the course of the migraine attack. The proportion of patients in our Phase 2b clinical trial who reported feeling “much better” or “very much better” according to the patient global impression of change two hours after dosing was meaningfully higher in the lasmiditan groups as compared to the placebo group, and the patient global impression of pain improved with increasing doses of lasmiditan. We believe that this strong patient global impression of change indicates a satisfactory patient response to lasmiditan.

 

   

Additional opportunity for non-opioid treatment of headache in emergency room and other urgent care settings.    We believe there is a significant unmet need for a non-opioid analgesic for emergent use to treat headache pain. Many of the currently-approved migraine therapies are not widely used in emergency room and other urgent care settings due to their vasoconstrictor mechanism of action, and lack of fast-acting formulations. In our Phase

 

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2 clinical trial for IV lasmiditan, we met our primary endpoint of headache relief with statistical significance. Headache relief is defined as reducing the severity of headache pain from moderate or severe to mild or none two hours after dosing. The onset of headache relief in the IV lasmiditan group was evident within 20 to 40 minutes after dosing.

Lasmiditan’s Novel Mechanism of Action.    Lasmiditan is a highly selective 5-HT1F receptor agonist, which is designed to treat a migraine using a novel mechanism of action. Lasmiditan is designed to penetrate the CNS and block the activation of the trigeminal nerve pathway that transmits the sensation of headache pain. Lasmiditan is also designed to block neurogenic inflammation in the meninges, which is believed to contribute to headache pain associated with migraine. Unlike triptans, lasmiditan has no meaningful affinity for 5-HT1B receptors, which mediate vasoconstriction. Lasmiditan has been given the generic stem name “ditan,” which distinguishes it from other drug classes, including triptans. The key non-clinical attributes of lasmiditan, which distinguish it from approved migraine therapies, include:

 

   

unique chemical structure and mechanism of action;

 

   

highly permeable molecule that distributes into the CNS;

 

   

selective activation of neural 5-HT1F receptors in periphery and CNS at therapeutic exposures; and

 

   

lacks the vasoconstrictor characteristics of triptans.

In 1993, the human 5-HT1F receptor was cloned and its messenger RNA, or mRNA, was found to be localized in neurons of the trigeminal ganglia, suggesting a potential novel therapeutic target for migraine. The 5-HT1F receptor agonists were developed as a new class for acute therapy of migraine. The anti-migraine efficacy of LY334370, a prototype selective 5-HT1F agonist, was subsequently established in clinical trials. Lasmiditan is a second generation, highly selective 5-HT1F agonist that was designed to be highly lipophilic and penetrate the CNS freely. Lipophilicity is the ability to dissolve in lipids, such as the lipid layer of cell membranes, and determines the potential to penetrate the CNS. Because migraine is believed to result from dysfunction in sensory pathways located in the brainstem, lasmiditan’s access to the CNS provides a mechanism to alleviate migraine pain.

Consistent with the localization of 5-HT1F receptors on neurons in the trigeminal system, 5-HT1F receptor agonists inhibit activation of the trigeminal pathway in animal models relevant to migraine, without affecting blood vessel constriction. More recent studies from academic laboratories indicate that neurons in the brainstem are a potential site of action of 5-HT1F agonists. It is possible that 5-HT1F receptors located elsewhere in the brain also contribute to the anti-migraine efficacy of lasmiditan.

The lack of vasoconstrictor activity of selective 5-HT1F agonists, including LY334370, has been demonstrated in several studies using human blood vessels, including coronary and middle meningeal arteries. For compound screening purposes, a surrogate animal assay has been shown to be highly predictive of human coronary and cerebral artery contraction. In this preparation, selective 5-HT1F agonists, including lasmiditan, were not vasoconstrictors. Thus, lasmiditan represents a novel class of neurally acting anti-migraine agents that lack the undesirable vasoconstrictor properties of triptans. The table below provides a comparison of lasmiditan’s mechanism of action with triptans:

Comparison of Mechanisms of Action

Lasmiditan versus Triptans

 

Treatment

  

Primary Site of Action

   Receptor    CNS Penetrant    Vasoconstrictor

Lasmiditan

   Trigeminal Pathway    5-HT1F    Yes    No

Triptans

   Blood Vessels    5-HT1B/1D    No    Yes

 

 

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We chose lasmiditan for its selectivity for the 5-HT1F receptor and its ability to penetrate the CNS to access 5-HT1F receptors in the brainstem and brain. These features are unique to lasmiditan and distinguish it from the triptans. Activation of the 5-HT1B receptor by triptans causes vasoconstriction. Lasmiditan has no meaningful affinity or activity at this receptor and does not cause vasoconstriction. Lasmiditan had greater than 470-fold higher affinity for the target 5-HT1F receptor than for 5-HT1B or 5-HT1D receptors, and had greater than 230-fold greater potency to activate 5-HT1F than 5-HT1B and 5-HT1D receptors. The permeability and CNS penetration of lasmiditan was examined using in vitro and in vivo methods, confirming that lasmiditan has distribution characteristics compatible with a CNS site of action. In contrast, triptans were developed for their vasoconstrictor activity, and were not optimized to distribute freely into the CNS. As a class, triptans are considered to have poor CNS penetration.

Our Strategy

Our objective is to establish lasmiditan as a first line therapy in migraine patients with cardiovascular risk factors or disease and as a second line therapy in those patients who are dissatisfied with existing therapies, either because of inadequate response or tolerability issues. To achieve this objective, our strategy is as follows:

 

   

Seek marketing approval from the FDA for lasmiditan with differentiated product label.    We plan to continue development of lasmiditan in a pivotal Phase 3 clinical program. We have an SPA agreement with the FDA for our SAMURAI trial to include two novel endpoints for the approval of acute treatment for migraine. We also plan to seek an SPA for, and conduct, a second pivotal trial with a design similar to SAMURAI prior to filing an NDA. If we successfully complete our two pivotal Phase 3 clinical trials, we expect to submit an NDA to the FDA seeking marketing approval for lasmiditan in the United States with a product label that is differentiated from triptans, whose labels include warnings and precautions against use in patients with cardiovascular risk factors or disease and triptans are not indicated to provide freedom from the most bothersome associated symptom. If approved, lasmiditan will be the first therapy with labeling that would differentiate it from other approved treatments for migraine.

 

   

Commercialize lasmiditan in the United States.    If we obtain approval from the FDA, we plan to commercialize lasmiditan in the United States by building our own focused, specialized sales force of approximately 200 sales representatives to target approximately 15,000 neurologists, 1,500 headache specialists and the top 10% of primary care and women’s health physicians, which we believe will cover physicians who together treat approximately 50% of migraine attacks.

 

   

Seek marketing approval from the FDA for IV lasmiditan.    To advance IV lasmiditan to treat headache pain in the emergency room, we intend to submit an IND with a request for an SPA for a pivotal Phase 3 clinical trial during the second half of 2015. Unlike lasmiditan, our proposed indication for IV lasmiditan is for the acute treatment of headache pain, so our SPA will request a single primary endpoint of headache pain relief. We plan to commence a pivotal Phase 3 clinical trial for IV lasmiditan after entering into an SPA agreement with the FDA and securing a development collaboration.

 

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Selectively establish collaborations for the development and commercialization of lasmiditan and IV lasmiditan.    If we obtain approval for lasmiditan from the FDA, we intend to develop and commercialize it in the United States ourselves. However, we intend to commercialize IV lasmiditan, if approved, through a collaboration. Given the unique call point of emergency rooms and other urgent care settings, which will be outside of our specialty neurology-based sales force, a sales force with expertise in the hospital and urgent care setting would be best positioned for commercialization of IV lasmiditan. If we obtain approval from foreign regulators, we plan to commercialize our product candidates outside the United States by collaborating with third parties who have expertise and resources to drive the development and commercialization in these markets. We have worldwide commercialization rights for our product candidates and have entered into a distribution and supply arrangement covering South Korea and certain Southeast Asian countries for lasmiditan.

 

   

Implement a life cycle management strategy to include development of additional formulations and possible new indications for lasmiditan and IV lasmiditan.    Based on issued patents, we have U.S. patent-based commercial exclusivity for lasmiditan and IV lasmiditan until 2025, which we expect will be extended up to five years to 2030 by obtaining a term extension under the provisions of the Hatch-Waxman Act. We believe this exclusivity will allow us to maintain the competitive market potential of our product candidates and implement a strategy to maximize the commercial life of our product candidates by developing new formulations, such as sublingual or fast melt products; new patient segments, such as pediatrics; and possible new indications and combination products.

The table below summarizes the next steps to execute our strategy:

Next Steps in Our Clinical Program

 

Anticipated Timing

    

Action Item

Lasmiditan

2Q15

    

–  Begin enrolling patients in SAMURAI

2H15

    

–  Submit SPA request for second pivotal Phase 3 trial

1H16

    

–  Begin enrolling patients in second pivotal Phase 3 trial

3Q16

    

–  Receive SAMURAI top-line data

2H17

    

–  Receive top-line data from second pivotal  Phase 3 trial

 

IV Lasmiditan

2H15

    

–  Submit IND and SPA request for Phase 3 trial

1H16

    

–  Reach SPA agreement for Phase 3 trial

 

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Our Product Candidates

Lasmiditan.    We are evaluating lasmiditan in a Phase 3 clinical program for which the primary indication is acute treatment of migraine, with or without aura, in adults.

Clinical Trial Summary.    We have completed four Phase 1 clinical trials and one Phase 2b clinical trial of lasmiditan. These trials included over 478 subjects consisting of both healthy volunteers and migraine patients who received lasmiditan, and investigated the efficacy, tolerability and safety of lasmiditan. Because these trials were conducted outside the United States, we were not required to submit an IND to the FDA for such trials. The table below sets forth information regarding our completed clinical trials of lasmiditan:

Summary of Completed Clinical Trials of Lasmiditan

 

Clinical Trial

   Phase      Lasmiditan Patients   

Trial Objectives

   Date  

Oral Tablet

(COL MIG-202)

     2b       305    Efficacy and safety of a range of oral doses      2009   
   

Oral Tablet

(COL MIG-104)

     1       30    Bioavailability under fed/fasted conditions      2015   
   

Oral Tablet

(COL MIG-105)

     1       55    Thorough QT Study      2011   
   

Oral Solution and Oral Tablet

(COL MIG-103)

     1       44    Bioavailability and pharmacokinetics      2008   
   

Oral Solution and Sublingual

(COL MIG-102)

     1       44    Safety, tolerability and pharmacokinetics      2008   

Completed Phase 2b Clinical Trial.    Our completed Phase 2b clinical trial of lasmiditan, COL MIG-202, was a randomized, double-blind, placebo-controlled parallel group dose-ranging study in which we treated patients for a single migraine attack. The trial was conducted at 43 headache centers in Western Europe, including five centers in Belgium, seven centers in Finland, six centers in France, 16 centers in Germany and nine centers in Spain. Because this trial was conducted outside the United States, we were not required to submit an IND to the FDA for such trial.

Our Phase 2b clinical trial treated 305 patients with lasmiditan and achieved, with statistical significance, its primary endpoint of headache relief, defined as reducing a moderate or severe headache at baseline to mild or none, two hours after dosing, which is the regulatory time point for efficacy assessment. The table below provides a summary of the key aspects of our completed Phase 2b trial:

Trial Design of Completed Phase 2b Clinical Trial of Lasmiditan

 

Objectives

   Patient Population   

Administration

   Lasmiditan Doses
Efficacy of headache relief two hours after dosing    391 patients    Treatment of a single migraine with a single dose of lasmiditan or placebo    50, 100, 200, 400 mg
Dose ranging    Patients with 1-8 attacks
per month
     

 

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Headache relief data was subjected to statistical analysis in order to determine the probability, or “p” value, of any differences observed between the lasmiditan treatment groups and placebo occurring by chance. The lower the p value, the greater the probability that any observed difference from placebo is real. A p value is declared statistically significant if it is less than or equal to 0.05, meaning that there is less than a 5% chance that the differences observed could have been due to chance. There was a statistically significant difference from placebo for all lasmiditan dose groups (50 mg, 100 mg, 200 mg and 400 mg). Headache relief was observed in 64% of patients receiving a 100 mg oral dose of lasmiditan and in 51% of patients receiving a 200 mg oral dose of lasmiditan as compared to 26% of patients receiving placebo (see Figure 2 below).

Figure 2. Headache Relief with Lasmiditan Compared to Placebo

 

LOGO

*p < 0.05 compared with placebo (PBO)

Bars indicate 95% confidence intervals

Number of patients in each group is shown inside the bars

In addition to our primary endpoint of headache relief, a secondary endpoint in this trial was freedom from headache pain two hours after dosing, which is a more rigorous endpoint. We achieved this endpoint with statistical significance and a dose response was observed in 14% of patients receiving a 100 mg oral dose of lasmiditan and in 19% of patients receiving a 200 mg oral dose of lasmiditan, compared to 7% of patients in the placebo group. A dose response was observed across all doses (see Figure 3 below).

 

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Figure 3. Headache Pain Freedom with Lasmiditan Compared to Placebo

 

LOGO

*p < 0.05 compared with placebo

Differences from placebo were analyzed using the Pearson’s x2 test, which is a statistical test applied to sets of data to evaluate how likely it is that any observed difference between the sets arose by chance. The following p values at each dosage level were obtained:

 

Lasmiditan Dose

   Time After Treatment
(hours)
 
   0.5      1      1.5      2      3      4  

50 mg

     0.15         0.30         0.09         0.18         0.051         0.0361   

100 mg

     >0.30         0.17         0.0147         0.19         0.0079         0.0036   

200 mg

     >0.30         0.06         0.0035         0.032         0.0034         0.001   

400 mg

     0.27         0.06         0.0014         0.0007         <0.0001         <0.0001   

In our Phase 2b clinical trial, lasmiditan also achieved the secondary endpoints of the absence of nausea, sensitivity to light and sensitivity to sound two hours after dosing. Dizziness and fatigue were the most common dose-related adverse events, especially at 200 mg and 400 mg dosage levels. No drug-related adverse effects on patients’ vital signs, hematology, clinical chemistry or electrocardiogram, or ECG, were reported during this trial.

 

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Efficacy.    The table below provides a summary of key results of our completed Phase 2b clinical trial of lasmiditan:

Key Results of Phase 2b Clinical Trial of Lasmiditan

 

Efficacy    Clinical Results

Primary Efficacy

   Primary Endpoint
Headache relief two hours after dosing    A higher proportion of patients experienced a headache relief in all lasmiditan groups (43.0% at 50 mg, 64% at 100 mg, 51% at 200 mg, and 65% at 400 mg) compared to the placebo group (26%)

Secondary Efficacy

   Secondary Endpoints
   
Headache free two hours after dosing    A higher proportion of patients experienced headache freedom in all lasmiditan groups (13.6% at 50 mg, 13.9% at 100 mg, 18.8% at 200 mg, and 27.9% at 400 mg) compared to the placebo group (7.4%)
   
Free of nausea, vomiting, sensitivity to sound and sensitivity to light    A higher proportion of lasmiditan patients were free of the associated symptoms as compared to the placebo group
   
Patient global impression two hours after dosing    Patient global impression (feeling much/very much better) improved in the lasmiditan groups (22.8% to 35.8%) compared to the placebo group (16.0%)

Comparison of Our Phase 2b Clinical Trial Results to Published Triptan Trials.    While we have not conducted head-to-head clinical trials comparing lasmiditan to triptans, results from our Phase 2b clinical trial as measured by headache response at two hours was similar to results from published triptan trials as reported in a meta-analysis conducted by Michel D. Ferrari, M.D. in 2002. In our Phase 2b clinical trial, lasmiditan 100 mg achieved a headache response two hours after dosing in 64.2% of patients, which compares similarly to the mean headache response two hours after dosing for all triptans in approximately 60% of patients reported in the meta-analysis. Moreover, the placebo showed a lesser headache response rate at two hours after dosing of lasmiditan 100 mg in 38.3% of patients, which compares similarly to the mean placebo subtracted headache response two hours after dosing for all triptans in approximately 35% of patients reported in the meta-analysis.

Safety.    A total of 680 adverse events were reported by 266 of 391 patients, or 68%. The proportion of patients reporting at least one treatment-emergent adverse event was higher in the lasmiditan groups, between 65% to 85%, than in the placebo group at 22%. Within the lasmiditan groups, the proportion of patients that reported at least one treatment-emergent adverse event was lowest in the 50 mg group compared to other dose groups and was highest in the 200 mg and 400 mg lasmiditan groups. One serious adverse event of dizziness was experienced by a 46 year-old female in the 200 mg lasmiditan group. The event was considered to be of moderate intensity, possibly related to lasmiditan and resolved without recurrence. Specifically, the patient reported moderate dizziness and generalized weakness 30 minutes after taking lasmiditan and because this event led to an overnight hospital admission, it was classified as serious. An ECG performed two hours after dosing was similar to her ECG results recorded at the screening visit to enroll in the study. An ECG performed on the subject five hours after dosing

 

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recorded a heart rate of 41 beats per minute and sinus bradycardia, but no other abnormalities. The patient fully recovered by the next day. The table below sets forth further details regarding adverse events in our completed Phase 2b trial:

Overview of Adverse Events

(Analysis Set for 391 Patients)

 

            Lasmiditan  
     Placebo      50 mg      100 mg      200 mg      400 mg  

Patients with adverse events

     27 (31.4%)         56 (68.3%)         60 (73.2%)         62 (87.3%)         61 (87.1%)   

Patients with treatment-emergent adverse events

     19 (22.1%)         53 (64.6%)         59 (72.0%)         61 (85.5%)         59 (84.3%)   

Patients with serious adverse events

     —           —           —           1 (1.4%)           —     

The most frequently reported adverse events in all lasmiditan groups were dizziness and fatigue, while these adverse events were reported by only one or two patients in the placebo group. The majority of events of dizziness and fatigue were treatment-emergent. The most commonly reported treatment-emergent adverse events with a total incidence in at least 5% of patients in the trial are set forth in the table below:

Patients with Most Commonly Reported Treatment-Emergent Adverse Events

(Analysis Set for 391 Patients)

 

       Lasmiditan  
     Placebo
(86 patients)
     50 mg
(82 patients)
     100 mg
(82 patients)
     200 mg
(71 patients)
     400 mg
(70 patients)
 

Dizziness

     1 (1.2%)         19 (23.2%)         23 (28.0%)         27 (38.0%)         26 (37.1%)   

Fatigue

     2 (2.3%)         10 (12.2%)         17 (20.7%)         15 (21.1%)         17 (24.3%)  

Vertigo

     1 (1.2%)         8 (9.8%)           12 (14.6%)         12 (16.9%)         17 (24.3%)   

Somnolence

     2 (2.3%)         8 (9.8%)           10 (12.2%)         8 (11.3%)         8 (11.4%)   

Paresthesia

     2 (2.3%)         2 (2.4%)           9 (11.0%)         12 (16.9%)         14 (20.0%)   

Sensation of Heaviness

     1 (1.2%)         4 (4.9%)           4 (4.9%)           7 (9.9%)           5 (7.1%)     

Nausea

     —           4 (4.9%)           9 (11.0%)         3 (4.2%)           5 (7.1%)     

Comparison of Lasmiditan’s Side Effect Profile with Triptan Chest Symptoms.    Common side effects of triptans are chest symptoms that were initially reported in 24% of patients taking oral triptans and 41% of patients taking subcutaneous sumatriptan. These triptan chest symptoms have been described as chest pressure similar to an inner tube being inflated around the patient’s chest. These symptoms, which sometimes resemble pectoral angina, are confounding for prescribing physicians and patients because they may be unable to diagnose whether or not the patient is suffering a non-life threatening side effect of the triptan or a serious cardiovascular event. Subsequent reports showed that rates fell as patients became more familiar with the new drug class. Consistent with its distinct mechanism of action, we believe that lasmiditan will not be associated with clinically significant chest symptoms, whose resemblance to angina raises a potential safety concern for triptans. While we have not conducted head-to-head clinical trials comparing lasmiditan to triptans, in our Phase 2b clinical trial, there was no pattern of triptan-like chest symptoms attributable to increasing doses of lasmiditan. Seven out of 391 patients, or 1.8%, reported chest symptoms in the safety population, and these were similarly distributed across all study groups (one received placebo, two received 50 mg of lasmiditan, two received 100 mg of lasmiditan, one received 200 mg of lasmiditan, and one received 400 mg of lasmiditan).

Comparison of Lasmiditan’s Side Effect Profile with CNS Acting Drugs.    Based upon statements from our principal investigators and key opinion leaders, when considered with the favorable patient global

 

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impression of change in our Phase 2b clinical trial, we believe that the side effects observed after treatment with lasmiditan are not concerning for physicians or patients with respect to safety. The majority of lasmiditan adverse events were CNS-related, such as dizziness and fatigue. While we have not conducted head-to-head clinical trials comparing lasmiditan to triptans, triptan CNS-related adverse events are dose-related and typically seen at a lower rate, consistent with their relatively poor CNS penetration. In a dose-ranging study with rizatriptan, a more permeable triptan, supratherapeutic doses of 20 or 40 mg caused dizziness in as high as 30 to 36% of subjects, which decreased to 8% after a therapeutic dose of 10 mg. Our two pivotal Phase 3 clinical trials will provide additional data as to lasmiditan’s adverse event profile. We will conduct a study to examine driving performance and, depending on results, the product labeling may include a warning against operating heavy machinery after taking lasmiditan. However, dizziness and fatigue often accompany a migraine attack and the lifetime prevalence of dizziness is higher in migraine patients than the general population. Physicians and migraine patients are familiar with how to manage these symptoms. Topamax (topiramate), the leading preventative treatment for migraine, is used on a daily basis and has published dizziness rates in controlled trials of up to 32%. Before becoming generic, sales for Topamax reached $1 billion annually for the prevention of migraine alone. Many drugs, including other CNS active agents, are associated with CNS-related adverse events. The majority of patients taking antidepressants experience side effects and most usually subside on their own over time. A review of 31 randomized controlled trials of opioids for neuropathic pain reported that 22% of patients treated with opioids experienced dizziness as compared to 8% of patients receiving placebo. Lyrica is a product used primarily for fibromyalgia and in the Lyrica controlled trials, dizziness was experienced by 31% of Lyrica treated patients compared to 9% of placebo-treated patients. GlobalData estimated that, even with these side effects, sales of Lyrica were $4.8 billion in 2013.

Completed Preclinical Studies and Phase 1 Clinical Trials.    We completed pivotal general toxicology and reproductive toxicology studies, which provided favorable margins of safety for lasmiditan and its major human metabolites across various species. Common dose-limiting adverse effects across species were CNS-related clinical signs, such as tremors, ataxia and convulsions. There was no evidence of lasmiditan-related target organ toxicity across species. There was no evidence of genotoxicity in in vitro and in vivo studies.

We plan to commence a two-year carcinogenicity study in rats and dose range finding for a six-month carcinogenicity study in transgenic RasH2 mice (mice with a gene that makes them more susceptible to tumors) in March 2015.

In addition to our preclinical studies, we completed four Phase 1 clinical trials of lasmiditan. Because these trials were conducted outside the United States, we were not required to submit an IND to the FDA for such trials. The primary objectives of these trials were:

 

   

to characterize the pharmacokinetics, or PK, of lasmiditan and its major human metabolites after single oral administration of escalating doses of an oral solution formulation (COL MIG-102 involving 60 healthy volunteers);

 

   

to assess the relative oral bioavailability of a tablet formulation of lasmiditan, with the secondary objective of evaluating the safety and tolerability of three dose levels of a tablet formulation of lasmiditan (COL MIG-103 involving 44 healthy volunteers);

 

   

to assess the bioavailability of lasmiditan 200 mg administered orally as a tablet formulation under fed and fasted conditions (COL MIG-104 involving 30 healthy volunteers); and

 

   

to determine the effect of lasmiditan given at the intended therapeutic dose and at a supra-therapeutic dose on cardiac de- and re-polarization duration as measured by the QT interval corrected for heart rate by Fridericia’s formula compared to placebo, with secondary objectives to evaluate the effect of lasmiditan on other cardiac safety parameters and to assess the safety and tolerability of single oral doses of 100 and 400 mg lasmiditan (COL MIG-105 involving 56 healthy subjects).

 

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Planned Clinical Trials

The table below provides a summary of the clinical trials we plan to conduct in order to obtain marketing approval:

 

Planned Clinical Trials of Lasmiditan

 

Clinical Trial

   Projected
Lasmiditan
Patients
    

Trial Objective

  

Expected
Trial
Initiation

  

Data
Expected

SAMURAI

(COL MIG-301)

     1,483      

•  Proportion of patients headache pain free two hours after dosing

 

•  Proportion of patients most bothersome associated symptom free two hours after dosing

   1Q15    3Q16

Second Phase 3 Pivotal Trial

(COL MIG-302)

     1,483      

•  Proportion of patients headache pain free two hours after dosing

•  Proportion of patients most bothersome associated symptom free two hours after dosing

   1H16    2H17

Long-Term Open Label Study

(COL MIG-305)

     2,200      

•  Proportion of patients and portion of migraine attacks associated with any adverse event and specific adverse events in three month increments for up to one-year

   2H15    Ongoing at NDA

Following completion of our planned pivotal Phase 3 clinical trials of lasmiditan, we expect to submit our NDA for lasmiditan for the acute treatment of migraine. Although lasmiditan is intended for the acute treatment of migraines, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, or ICH, requires safety data on at least 300 patients treating a minimum of two migraines per month for six months and 100 patients treating a minimum of two migraines per month for 12 months. We intend to include data in our NDA on at least 1,100 patients who have treated at least two attacks per month for six months, of whom at least 550 have treated at least two attacks per month for 12 months. We expect to treat approximately 22,000 single migraine attacks through our two pivotal Phase 3 clinical trials and one long-term, open label study of lasmiditan, providing for a robust safety database.

SAMURAI.    SAMURAI employs two novel endpoints for the approval of an acute treatment for migraine, and we plan to begin enrolling patients during the first half of 2015. We have entered into an SPA agreement with the FDA, which is an agreement that the protocol design, clinical endpoints and statistical analyses are acceptable to support marketing approval of the product candidate with respect to effectiveness in the indication studied. We do not intend to compare lasmiditan to any approved migraine treatments because the FDA does not require an active comparator to support the development of acute treatments for migraine. Moreover, we intend to develop lasmiditan for the acute treatment of migraine without warnings, precautions and contraindications against its use in patients with cardiovascular risk factors or disease. We do not believe the use of a triptan comparator in this patient population is appropriate because of the warnings and precautions against their use in patients with cardiovascular

 

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risk factors or disease. Even though we have an SPA agreement for SAMURAI, there is no guarantee that this study will ultimately be adequate to support an approval of lasmiditan. We believe the minimum acceptable profile needed for lasmiditan to be approved by the FDA will be achieving statistical significance over placebo on the proportion of patients headache pain free two hours after dosing and the proportion of patients most bothersome symptom (nausea, sensitivity to sound or sensitivity to light) free two hours after dosing with at least one dose of lasmiditan. The FDA’s determinations for marketing approval will be made after a complete review of our NDA, which we anticipate will include the results of SAMURAI and our second pivotal Phase 3 study and data from our long-term open label study that we plan to conduct.

SAMURAI is a study of migraine patients treating one attack (see Figure 4 below). The primary efficacy endpoint for SAMURAI will be to evaluate the efficacy two hours after receiving a dose of lasmiditan 100 mg or lasmiditan 200 mg compared to placebo on freedom from migraine headache pain. The key secondary efficacy endpoint will be to evaluate the efficacy two hours after receiving a dose of lasmiditan 100 mg or lasmiditan 200 mg compared to placebo on freedom from the most bothersome symptom associated with migraine, as identified by the individual, from nausea, sensitivity to sound and sensitivity to light. Other secondary endpoints will be used to evaluate the time course and effect of lasmiditan 100 mg and lasmiditan 200 mg on relief of pain, time course of second dose when used for rescue or recurrence of migraine, sustained pain freedom and other endpoints.

The figure below provides details regarding the study schema of SAMURAI:

Figure 4. SAMURAI Study Schema

 

LOGO

We estimate that our trial will randomize 1,483 patients to lasmiditan from approximately 70 general practice and neurology study centers in the United States. We expect that enrollment will last approximately twelve months. Individual patients will be randomized into three groups of equal size to receive lasmiditan 100 mg, lasmiditan 200 mg or placebo. Overall, enrollment in SAMURAI will be

 

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monitored through weekly tracking as discussed below. Since the eligibility criteria for SAMURAI does not exclude subjects with any of the cardiovascular risk factors (such as increased age, diabetes, hypertension, smoking, obesity, hypercholesterolemia, strong family history of coronary artery disease), we expect SAMURAI will include patients with cardiovascular risk factors. Based on published studies, we estimate that 60% of the patients who receive lasmiditan in SAMURAI will have one or more cardiovascular risk factors and this proportion is representative of migraine patients with cardiovascular risk factors in the overall migraine population. In addition, we estimate that approximately 5% of the patients who receive lasmiditan in SAMURAI will have stable cardiovascular disease. These estimates are based on studies conducted by the AMPP that analyzed symptoms and treatment patterns in a representative sample of the U.S. population, which was not restricted to any subgroups of migraine. These estimates are also based on a study we commissioned to analyze 2009 AMPP survey data with the objective of assessing the prevalence of cardiovascular risk factors and cardiovascular medical history in subjects with migraine.

At the time of onset of a migraine headache and prior to dosing, patients will record the severity of their headache pain, indicate which associated symptoms are present, and choose which of the associated symptoms is the most bothersome symptom at that time of dosing. Two hours later, the patient will evaluate both headache pain and the presence or absence of associated symptoms, including the symptom declared by the patient as the most bothersome associated symptom at the time of dosing. Individual patients are not required to become both headache pain free and most bothersome associated symptom free two hours after dosing. Instead, the success of the trial will be determined by the proportion of patients who are headache pain free two hours after dosing, which is our primary endpoint, and the proportion of patients who are free of their most bothersome symptom associated with migraine two hours after dosing, which is our secondary endpoint. Rescue medication will be allowed for patients who feel they have not achieved sufficient relief after two hours. A second dose of either lasmiditan or placebo will be provided to use if the headache pain does not go away after two hours or if the headache pain reoccurs.

The efficacy endpoints of the proportion of lasmiditan patients pain free and most bothersome associated symptom free will be employed for the first time in our pivotal Phase 3 clinical studies of lasmiditan. These endpoints were the result of negotiations between us and the FDA, as well as the FDA’s movement towards more patient-centric endpoints in clinical trials, and are incorporated in a new FDA guidance for the design of acute migraine trials issued in 2014. Previously, the FDA required four co-primary endpoints of freedom from pain, nausea, sensitivity to sound and sensitivity to light at two hours, which increases study sample size and reduces statistical power. Moreover, not all associated symptoms are present in a migraine attack and accordingly this is an insensitive method by which to discern a treatment effect or dose-response.

During our discussions, the FDA proposed the approach of most bothersome associated symptom, which has been adopted for evaluating other conditions considered multi-symptom complexes, whereby patients would declare which associated symptom was the most bothersome associated symptom, and the key secondary endpoint would be the absence of the most bothersome symptom at two hours after dosing. Because the endpoints of freedom from pain and the most bothersome associated symptom at two hours have not been employed previously in a migraine trial, we ran statistical simulations using the prevalence and combination of associated symptoms and response rates observed in our Phase 2b clinical trial in order to provide conservative estimates of the number of patients needed to show a statistically significant effect of lasmiditan versus placebo in SAMURAI. Based on these simulations, we believe that the sample size of evaluable subjects per dose group in SAMURAI will provide greater than 90% power for pain for both the 100 mg and 200 mg lasmiditan dose groups, greater than 90% power for most bothersome associated symptom for the 100 mg lasmiditan dose group and greater than or equal to 80% power for most bothersome associated symptom in the 200 mg lasmiditan dose group.

 

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Second Pivotal Phase 3 Trial.    We expect to commence a second, confirmatory pivotal Phase 3 clinical trial, or COL MIG-302, in the first half of 2016. We expect that COL MIG-302 will be similar in design to SAMURAI and will enroll a similar patient demographic. We plan to submit a request for an SPA to the FDA during the second half of 2015. We will evaluate the addition of a 50 mg oral dose of lasmiditan cohort to this trial. We expect that the study sites will be located both within and outside the United States.

Long-Term, Open Label Study.    Additionally, we plan to commence a long-term, open label study of lasmiditan, or COL MIG-305, in the second half of 2015. All subjects who complete SAMURAI and COL MIG-302 will be eligible to enroll and participate in this study. Subjects who consent to continue to COL MIG-305 will be randomly assigned in a one-to-one ratio, to receive lasmiditan 100 mg or lasmiditan 200 mg for the first dose and the second dose, if needed for rescue or recurrence of migraine.

Subjects will be asked to treat all migraine attacks with the study drug on an outpatient basis for up to 12 months. Each subject’s study participation will consist of a treatment period of up to 52 weeks during which the subject will treat all migraine attacks with a either lasmiditan 100 mg or lasmiditan 200 mg (with a second dose permitted between two and 24 hours for rescue or recurrence of migraine). During the treatment period, subjects will return to the clinic at one, three, six, nine and 12 months. There will be an early termination visit within 14 days of treatment discontinuation for all subjects that discontinue between scheduled visits.

This study will be an open-label study with no control group. The primary endpoint is the proportion of patients and the proportion of attacks associated with any adverse event and with specific adverse events. Efficacy data will be summarized using descriptive statistics. The proportion of attacks treated with study medication that responds two hours after receiving a dose will be calculated for each three-month period.

COL MIG-305 will enroll subjects that complete our two pivotal Phase 3 clinical studies, SAMURAI and COL MIG-302. The sites will be encouraged to enroll all eligible subjects, and especially subjects with cardiovascular risk factors and disease. Similar to SAMURAI and COL MIG-205, based on published studies, we estimate that 60% of the patients who receive lasmiditan in this study will have one or more cardiovascular risk factors and this proportion is representative of migraine patients with cardiovascular risk factors in the overall migraine population. In addition, we estimate that approximately 5% of the patients who receive lasmiditan in this study will have stable cardiovascular disease. Approximately 20% to 30% of the subjects in this study will be patients who previously received placebo in SAMURAI or COL MIG-302.

We believe these enrollment numbers will provide us with a substantial safety database, which we believe will allow us to meet the ICH requirements of 300 subjects treating at least two attacks per month for six months and 100 subjects treating at least two attacks per month for 12 months. However, in any clinical trial, subjects are free to withdraw at any time and this is to be expected in a year-long study. Taking into consideration that subjects will leave the study within the first few months, we expect that there will be approximately 1,100 subjects being treated for two attacks per month for the first six months of the study and approximately 550 subjects being treated for two attacks per month for 12 months of the study. Accordingly, we estimate that the overall number of single migraine attacks treated during the course of this study will be approximately 19,800.

IV Lasmiditan.    We are developing IV lasmiditan for the acute treatment of headache pain in adults, to be used in emergency rooms and urgent care settings. A significant number of patients seek treatment in an emergency room for an unspecified headache that may or may not be associated with migraine and that IV lasmiditan’s non-vasoconstrictive, non-addicting mechanism of action will be beneficial for these patients. We have completed one Phase 1 clinical trial and one Phase 2 clinical trial of IV lasmiditan, with a total of 600 subjects, consisting of both healthy volunteers and migraine patients who received lasmiditan and were evaluated for the acute treatment of migraine in adults. Because these trials were conducted outside the United States, we were not required to submit an IND to the FDA for such trials.

 

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We believe that IV lasmiditan could be an attractive treatment option for physicians and patients in emergency room and other urgent care settings because it is a non-opioid that provides quick headache relief without evidence of vasoconstrictor risk. Currently, subcutaneous sumatriptan and intravenous DHE are the only parenteral products approved for use in the United States for the acute treatment of migraines in emergency settings, and are both underutilized due to their cardiovascular safety profile. While opioids are the prescribed treatment for over 50% of migraine patients in emergency rooms and urgent care settings, we believe that IV lasmiditan offers significant advantages due to the risk of dependence associated with opioids and the fact that they may increase the risk of relapse, induce MOH and promote chronic migraine.

Clinical Trial Summary.    The table below sets forth information regarding our completed clinical trials of IV lasmiditan:

Summary of Completed Clinical Trials of IV Lasmiditan

 

Clinical Trial

   Phase      Lasmiditan Patients     

Trial Objectives

   Date  

IV Infusion

(COL MIG-201)

     2         88       Efficacy and safety of a range of intravenous doses      2007   

IV Infusion

     1         40       Safety, tolerability, and pharmacokinetics      2003   

Completed Phase 2 Clinical Trial.    Our Phase 2 clinical trial of IV lasmiditan, COL MIG-201, was a placebo-controlled, group sequential, adaptive treatment assignment study of IV lasmiditan in patients with acute migraine. This trial was conducted at 18 centers in Western Europe, including three centers in Netherlands, five centers in Finland, and 10 centers in Germany. Because this trial was conducted outside the United States, we were not required to submit an IND for such trial. The table below provides an overview of the design of our Phase 2 clinical trial:

Trial Design of Completed Phase 2 Clinical Trial of IV Lasmiditan

 

Objectives

  

Patient Population

  

Administration

  

Lasmiditan Doses

 
Efficacy of dose ranging    130 patients    Treatment of a new migraine attack      2.5, 5, 10, 20, 30, 45 mg   
Safety and tolerability of a range of doses    Patients with 1-8 attacks
per month
     

Our Phase 2 clinical trial of IV lasmiditan involved treatment of migraine attacks using a sequential adaptive treatment design based on headache relief within two hours of receiving treatment. Eighty-eight patients received IV lasmiditan in doses ranging from 2.5 to 45 mg. A dose-response was observed at two hours after dosing, with 54% of patients achieving headache relief after 10 mg of IV lasmiditan and 75% of patients obtaining headache relief after 45 mg of IV lasmiditan, compared to 45% of patients in the placebo group. No clinically significant abnormalities of heart rate, blood pressure, 12-lead ECG, hematology, biochemistry or urine analysis were reported during this trial.

In our completed Phase 2 clinical trial, IV lasmiditan achieved its primary endpoint of a statistically significant dose response relationship for headache relief two hours after dosing (p=0.0126). This trial was not powered for statistical comparison of individual doses of lasmiditan with placebo. However, numerical superiority of the 20 mg and 30 mg doses of IV lasmiditan was observed over the placebo group (see Figure 5 below). The onset of headache relief was evident within 20 to 40 minutes after dosing. IV lasmiditan doses of 20 mg and 30 mg also achieved the secondary endpoints of numerical superiority in headache relief at various time points, headache freedom, relief from associated symptoms, disability, use of rescue medication, and patient’s global impression as compared with the placebo group. There were also numerical improvements in nausea, sensitivity to sound and sensitivity to light with the 30 mg dose as compared with the placebo group.

 

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Figure 5. Relief of Migraine Headache Pain and Pain Freedom Two Hours after IV Lasmiditan Dose

 

LOGO

Dose of IV Lasmiditan (mg)

Numbers in bars are the numbers of patients treated at each dose

Efficacy.    The table below provides a summary of the key results of our completed Phase 2 clinical trial of IV lasmiditan:

Key Results of Phase 2 Clinical Trial of IV Lasmiditan

 

Efficacy    Clinical Results
Primary Efficacy    Primary Endpoint
Headache response two hours after dosing    A higher proportion of patients showed a headache response at two hours after dosing in the 10, 20, 30, and 45 mg lasmiditan dose groups (54% to 75%) compared to the placebo group (45%)
Secondary Efficacy    Secondary Endpoints
   
Headache response 10 to 240 minutes after dosing    Headache response at 10 to 240 minutes increased with lasmiditan treatment in a dose-dependent manner
   
Patient global impressions at two hours after dosing    A positive linear relationship between dose levels of lasmiditan and global impressions was shown
   
Headache free at 10 to 240 minutes after dosing    The proportion of subjects receiving 20, 30 and 45 mg lasmiditan that were headache free after dosing was numerically higher than placebo
   
Incidence of nausea, vomiting, sensitivity to sound and sensitivity to light at 0 to 240 minutes after dosing    Numerical improvement was shown at the 30 mg dose of lasmiditan

 

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Safety.    No serious adverse events were reported and no patients were withdrawn due to an adverse event. A total of 165 treatment-emergent adverse events were reported by 75 of 130 patients (58%), with 57 of 88 patients (65%) in the IV lasmiditan group reporting 122 treatment-emergent adverse events and 18 of 42 (43%) patients in the placebo group reporting 43 adverse events. The incidence and frequency of treatment-emergent adverse events was greater in the IV lasmiditan group than in the placebo group. The table below sets forth further details regarding adverse events in our completed Phase 2 trial:

Overview of Adverse Events

(Safety Analysis Set for 130 Patients)

 

          IV Lasmiditan  
    Placebo
(42 patients)
    2.5 mg
(4 patients)
    5 mg
(12 patients)
    10 mg
(24 patients)
    20 mg
(28 patients)
    30 mg
(16 patients)
    45 mg
(4 patients)
    Total IV
lasmiditan

(88 patients)
 
Number of adverse events     43        3        3        3        48        33        5        122   
Patients with adverse events     18 (42.9%)        2 (50.0%)        3 (25.0%)        17 (70.8%)        19 (67.9%)        13 (81.3%)        3 (75.0%)        57 (64.8%)   

The most common adverse events were dizziness, paresthesia (tingling sensation) and fatigue. Paresthesia showed a dose response relationship. Sensation of heaviness and fatigue also appeared to be dose-related. The incidence and frequency of treatment-emergent adverse events was greater in the IV lasmiditan group than in the placebo group and the incidence of adverse events with a possible relationship to the study medication was greater in the IV lasmiditan group (74%) than in the placebo group (23%). The most commonly reported adverse events with a total incidence in at least 5% of patients in the trial are set forth in the table below:

Patients with Most Commonly Reported Adverse Events

(Safety Analysis Set for 130 Patients)

 

          IV Lasmiditan  
    Placebo
(42 patients)
    2.5 mg
(4 patients)
    5 mg
(12 patients)
    10 mg
(24 patients)
    20 mg
(28 patients)
    30 mg
(16 patients)
    45 mg
(4 patients)
    Total IV
lasmiditan

(88 patients)
 
Dizziness     6 (14.3%)        2 (50.0%)        1 (8.3%)        8 (33.3%)        7 (25.0%)        3 (18.8%)        1 (25.0%)        22 (25.0%)   
Paresthesia     -        -        -        5 (20.8%)        8 (28.8%)        7 (43.8%)        1 (25.0%)        21 (23.9%)   
Fatigue     4 (9.5%)        -        1 (8.3%)        1 (4.2%)        5 (17.9%)        3 (18.8%)        -        10 (11.4%)   
Sensation of Heaviness     -        -        -        2 (8.3%)        3 (10.7%)        4 (25.0%)        -        9 (10.2%)   
Feeling of Relaxation     -        -        -        -        2 (7.1%)        3 (18.8%)        -        5 (5.7%)   

Completed Preclinical Studies and Phase 1 Clinical Trials.    Intravenous toxicology studies that define the in vivo systemic response to IV lasmiditan were conducted. These studies ranged in time from one day (single dose) to 14 days in two species. Common dose-limiting adverse effects across species after 20 minute intravenous infusions were CNS-related clinical signs (tremors, ataxia, and convulsions). There was no evidence of lasmiditan-related target organ toxicity across species, and no evidence of mutagenicity or teratogenicity in genotoxicity or developmental and reproductive toxicology studies in two species. Toxicokinetic data from the definitive 14-day animal intravenous toxicology studies, as well as the exposures obtained in pivotal oral toxicology studies conducted by us, provide robust margins of exposure for the acute intravenous treatment of headache. 

A Phase 1 clinical trial of IV lasmiditan (then known as LY573144) was also conducted. This Phase 1 clinical trial evaluated the pharmacokinetics, metabolism and safety of increasing intravenous doses of IV

 

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lasmiditan infused over 20 or 60 minutes. Intravenous infusion of lasmiditan in healthy subjects produced a small dose-related decrease in heart rate and increase in blood pressure that was not considered clinically relevant. Most reported adverse events were mild in intensity at all dose levels but there was a dose-related increase in the number of moderate adverse events. Subjects who received the highest doses reported somnolence, paresthesia, dizziness, and hot flushes. Because this trial was conducted outside the United States, we were not required to submit an IND to the FDA.

Planned Clinical Trials.    We plan to submit an SPA request for a pivotal Phase 3 clinical trial during the second half of 2015 and will simultaneously file an IND with the FDA because prior clinical studies were conducted in Europe. The SPA request will propose a single primary endpoint of headache pain relief. We will include the intravenous toxicology and reproductive toxicology studies performed using the IV route and we expect to be allowed to bridge the significant nonclinical data from the IND for lasmiditan to the IND for IV lasmiditan. We plan to commence a pivotal Phase 3 clinical trial for IV lasmiditan after we enter into an SPA agreement with the FDA, if obtained. The pivotal Phase 3 clinical trial for IV lasmiditan will be a four-arm study: two active doses of IV lasmiditan, one “placebo-like” dose of IV lasmiditan and one active comparator. We expect this trial will enroll approximately 600 patients who present to an emergency room or other urgent care setting with headache pain.

Reimbursement in Migraine Market

We have commissioned third-party primary market research to understand how lasmiditan will be evaluated by U.S. managed care organizations and pharmacy benefit managers, commonly referred to as “payors.” This work, a representative sampling of the U.S. payor system, included interviews with 14 medical directors and pharmacy personnel from payor organizations representing more than 111 million covered lives. Respondents were generally aware of the limitations of existing therapies, including the warnings and precautions limiting triptan use in migraine patients with cardiovascular factors or disease. They indicated that there were a substantial number of migraine patients within their respective payor programs who were not able to take triptans either because of cardiovascular risk or because of prior dissatisfaction with triptan therapy,

Approximately 70% of surveyed respondents reacted favorably to the efficacy, safety, and tolerability profile of lasmiditan observed in completed clinical trials. Respondents recognized the potential of a non-vasoconstrictive drug for the at-risk patient population with cardiovascular risk factors. They also identified the potential for significant cost savings to their respective payor programs for a product with the potential to treat patients who do not respond to other therapies. Many respondents indicated that these patients either are untreated or treated off-label with opioids.

Respondents indicated that a new mechanism of action to treat migraine patients within their respective payor programs could decrease emergency room visits by migraine patients, which can cost the payor over $10,000 per visit. Reasons for emergency room visits include a lack of response to acute treatment of migraine. We believe lasmiditan has the potential to decrease the use of opioids for headache by offering a fast-acting, non-addictive, non-vasoconstrictive parenteral formulation for the treatment of headache in the emergency setting in addition to its potential to address the needs of patients who do not respond well to current therapy an on outpatient basis.

Third-party research indicates that most payors will rely on physician judgment to identify the appropriate patients for treatment with lasmiditan. We do not expect these payors to initiate active controls such as step edits or prior authorizations, which may limit product usage. Because of the availability of generic triptans, we expect that, if approved, lasmiditan would be included on most formularies as a “tier 3 product” and would be subject to prescription size and quantity limits similar to those for triptans. We cannot be certain, however, that payors will cover and reimburse lasmiditan, if approved, and if coverage is available, whether they will require step edits, prior authorizations or other approvals before payment is authorized.

 

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Sales, Marketing and Distribution

We do not have a sales, marketing or drug distribution infrastructure. We retain exclusive rights to lasmiditan and IV lasmiditan in all major markets. We have entered into a distribution and supply agreement for lasmiditan that covers South Korea, Taiwan, Singapore, Malaysia, Indonesia, Philippines, Thailand, Myanmar and Vietnam. We generally expect to retain commercial rights in the United States for lasmiditan. If we receive regulatory approval from the FDA for lasmiditan, we plan to commercialize lasmiditan in the United States by building our own focused, specialized sales force of approximately 200 sales representatives to target approximately 15,000 neurologists, 1,500 headache specialists and the top 10% of primary care and women’s health physicians, which we believe will cover physicians who together treat approximately 50% of migraine attacks. We also expect that we will require additional infrastructure and support staff to aid in our commercialization efforts. We intend to evaluate the need for additional physician reach to maximize sales of our product candidates. We expect to commercialize IV lasmiditan, if approved, through a collaboration and secure IV lasmiditan on hospital and urgent care formularies and support the subsequent launch of IV lasmiditan in the emergency room and other urgent care settings.

We intend to control global development of lasmiditan and IV lasmiditan while collaborating with third parties who have expertise and resources to drive the development and commercialization outside of the United States. We expect to enter into additional arrangements with third parties for the development and commercialization of lasmiditan and IV lasmiditan if regulatory approval is received.

Manufacturing

We currently contract with third parties for the manufacture, testing and storage of our product candidates and intend to continue to do so in the future. We do not own and have no plans to build our own manufacturing capabilities for clinical or commercial supply. Because we rely on contract manufacturers, we employ personnel with extensive technical, manufacturing, analytical and quality experience to oversee contract manufacturing and testing activities, and to compile manufacturing and quality information for our regulatory submissions.

Lasmiditan is manufactured through a straightforward six-step synthesis using widely applied production unit operations. The manufacture of lasmiditan could be undertaken by numerous commercial API CMOs. It is a very stable chemical, with no degradation detected after long-term storage for many years, and no special handling or storage conditions required.

Competition

Acute Treatments.    We believe lasmiditan is the only NCE in active clinical development for the acute treatment of migraine.

Products that are currently used for the acute treatment of migraine and headache pain include the following:

 

   

Triptans.    This drug class is the current standard of care for the acute treatment of migraine, which includes sumatriptan, zolmitriptan, rizatriptan, naratriptan, eletriptan, and frovatriptan and the entire class will be generic by the time we expect to launch lasmiditan. Additional formulations of sumatriptan and rizatriptan are in development and, if approved, are expected to compete for market share as branded generic products by the time we have launched the commercialization of lasmiditan. The most advanced formulations include Teva’s Zecuity, Avanir’s AVP-825, and RedHill/IntelGenx’s oral thin film formulation of rizatriptan. Teva’s Zecuity is a transdermal iontophoretic sumatriptan patch. Avanir’s AVP-825 is a fast acting dry powder nasal delivery formulation of sumatriptan, which is expected

 

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to launch during 2015. RedHill/IntelGenx’s oral thin film formulation of rizatriptan for the acute treatment of migraines is currently under review by the FDA. All of these products are expected to have precautions and warnings for patients with cardiovascular risk factors or disease.

 

   

Dihydroergotamine.    The ergotamine drug class has largely been replaced by the triptans. However, an orally inhaled formulation of this drug is currently under development and may be a potential competitor as a branded generic product called Semprana, under development by Actavis, and is expected to launch during the first half of 2016. This drug class is also associated with contraindications, precautions and warnings with cardiovascular risk factors or disease.

 

   

NSAIDs/Aspirin/Acetaminophen.    These agents are generally used for less severe migraine attacks and are available as over-the-counter medications, as well as by prescription.

 

   

Opioids, Barbiturates and Combination Products.    These products are mainly used for rescue therapy or treatment in emergency rooms and other urgent care settings, but have not been approved for the acute treatment of migraine.

Preventative Treatments.    Patients with significant disability or frequent migraine headaches, such as chronic migraine patients, who are those having a migraine attack 15 or more days per month, may also use a preventative agent in an attempt to decrease the frequency and/or severity of migraine symptoms. Despite preventative treatments, most patients continue to develop migraine headaches and still require acute therapy. It is estimated that there are approximately 3 million patients who suffer from chronic migraine in the United States alone.

There are currently five approved therapies for the preventative treatment of migraine. Botox is the only product that has been approved for the prevention of chronic migraine. In those patients who do not qualify as having chronic migraine, but still have significant disability due to migraine, there are four products approved for use: topiramate and valproic acid, both anticonvulsant medicines, and propranolol and timolol, both beta-blockers.

There has been significant clinical activity for the development of antibodies targeting calcitonin gene-related peptide, or CGRP. It is believed that by directly targeting the CGRP neuropeptide with an antibody, or alternatively targeting its ligand, the incidence of migraine attacks can be reduced. By minimizing the bioavailability of CGRP or its ligand, CGRP-evoked dilatation of the cranial vessels can be reduced. The primary endpoint of clinical studies of these antibodies has been a reduction in the number of headache days per month in chronic migraine patients. The following companies are developing anti-CGRP antibodies for preventative treatment of chronic migraine: Amgen (AMG 334), Alder BioPharmaceuticals (ALD403), Eli Lilly (LY2951742) and Teva Pharmaceuticals (LBR-101).

While approved therapies have demonstrated a reduction in the number of headache days per month in controlled clinical studies, they do not eliminate headaches. Chronic migraine patients still experience episodic migraine attacks requiring acute treatment. We anticipate that even if anti-CGRP antibodies are approved for the preventative treatment of chronic migraine, these migraine patients will still have multiple episodic migraine attacks per month requiring acute treatment such as lasmiditan.

 

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Intellectual Property and Proprietary Rights

Patents. We own or have exclusive rights to a significant patent portfolio related to the manufacture, sale and use of lasmiditan and IV lasmiditan. One portion of our portfolio is in-licensed from Eli Lilly and Company, or Eli Lilly, (see below for a description of the material terms), and the other portion is owned by us, through work-for-hire and through the activities of our employee inventors. The table below presents a brief summary of our patent portfolio directed to lasmiditan.

Key Intellectual Property

 

Patent, Publication, or Application No.

  

Jurisdictions

  

Expiration Date

CoLucid Family CLD 01

(Pyridinoylpiperidines as 5-HT1F Agonists)

Patent No. 7,423,050

   United States    April 6, 2025

Patent No. 8,044,207

   United States    March 30, 2025

Patent No. 8,748,459

   United States    March 27, 2023

Pub. No. WO/2003/084949

   Not applicable    Not applicable

App. No. 14/296,911

   United States    Pending

Patent No. AR039150B1

   Argentina    March 26, 2023

Patent No. 2003224719

   Australia    March 27, 2023

Patent No. 2478229

   Canada    March 27, 2023

Patent No. 2694410

   Canada    March 27, 2023

Patent No. 44199

   Chile    March 27, 2023

Patent No. ZL03807363.3

   China    March 27, 2023

Patent No. 565

   Colombia    March 27, 2023

Patent No. 2729

   Costa Rica    March 29, 2022

Patent No. 3826

   Algeria    March 27, 2023

Patent No. 25226

   Egypt    March 26, 2023

Patent No. P20040883

   Croatia    March 27, 2023

Patent No. 0021158

   Indonesia    March 27, 2023

Patent No. 163928

   Israel    March 27, 2023

Patent No. 238831

   India    March 27, 2023

Patent No. 4493345

   Japan    March 27, 2023

Patent No. 10-0985995

   Republic of Korea    March 27, 2023

Patent No. MY-134666-A

   Malaysia    March 27, 2023

Patent No. 247752

   Mexico    March 27, 2023

Patent No. 15220

   Nigeria    March 27, 2023

Patent No. 330394

   Norway    March 27, 2023

Patent No. 534952

   New Zealand    March 27, 2023

Patent No. 4937

   Peru    March 25, 2023

 

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Patent, Publication, or Application No.

  

Jurisdictions

  

Expiration Date

Patent No. 1-2004-501520

   Philippines    March 27, 2023

Patent No. 140189

   Pakistan    March 29, 2023

Patent No. 140193

   Pakistan    March 29, 2023

Patent No. 140195

   Pakistan    March 29, 2023

Patent No. 210019

   Poland    March 27, 2023

Patent No. 106451

   Singapore    March 27, 2023

App. No. E1691-2003

   El Salvador    Pending

Pub. No. 66841

   Thailand    Pending

I263497

   Taiwan    March 27, 2023

Patent No. 77504

   Ukraine    March 27, 2023

Pub. No. 2003-000468

   Venezuela    Pending

Patent No. 2004/07666

   South Africa    March 27, 2023

Eurasian Patent No. 007966

   Armenia, Azerbaijan, Belarus, Kazakhstan, Kyrgyz Republic, Moldova, Russia, Tajikistan, Turkmenistan    March 27, 2023

European Patent No. 1 492 786

   Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Luxembourg, Monaco, Netherlands, Portugal, Romania, Slovakia, Spain, Sweden, Switzerland, Turkey (200607295T4), United Kingdom, Hong Kong (reg HK1073464)    March 27, 2023

CoLucid Family CLD 02

(Compositions and Methods of Synthesis of Pyridinoylpiperidine 5-HT1F Agonists)

Patent No. 8,697,876

   United States    March 31, 2031

CoLucid Family CLD 03

(Composition of 2,4,6-Trifluoro-N-[6-(-1-methyl-piperidin-4-carbonyl)-pyridin-2-yl]-benzamide)

Pub. No. 2010-0256187A1

   United States    Pending

App. No. 2010/232497

   Australia    Pending

App No. 2757019

   Canada    Pending

Pub. No. 102753171

   China    Pending

Pub. No. 2413933

   Europe    Pending

Pub. No. 1177139A

   Hong Kong    Pending

App. No. 4453/KOLNP/2011

   India    Pending

App. No. 215483

   Israel    Pending

Pub. No. 2012-522805

   Japan    Pending

 

106


Table of Contents

Patent, Publication, or Application No.

  

Jurisdictions

  

Expiration Date

App. No. 10-2011-7026185

   Republic of Korea    Pending

Patent No. 313228

   Mexico    April 2, 2030

Patent No. 596161

   New Zealand    April 2, 2030

App. No. 1-2011-501972

   Philippines    Pending

App. No. 2011/501972

   South Africa    Pending

Pub. No. WO 2010/115125

 &