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| EX-99.3 - EXHIBIT 99.3 - BeiGene, Ltd. | h2hpressrelease1.htm |
| EX-99.2 - EXHIBIT 99.2 - BeiGene, Ltd. | esmoiopressrelease.htm |
| 8-K - 8-K - BeiGene, Ltd. | a8-kx16dec19.htm |
Exhibit 99.1 ASPEN Results Conference Call December 16, 2019
Howard Liang, Ph.D. CFO and Chief Strategy Officer 2
Agenda Welcome – Howard Liang Introduction – John Oyler ASPEN Results – Jane Huang BRUKINSA Development – Eric Hedrick BRUKINSA Commercialization – Josh Neiman Concluding Remarks – John Oyler Q&A 3
• Certain statements contained in this presentation and in the accompanying oral presentation, other than statements of fact that are independently verifiable at the date hereof, may constitute forward-looking statements. Examples of such forward-looking statements include statements regarding clinical data for patients from the ASPEN trial and advantages compared to ibrutinib; plans for regulatory discussions and submission of data from the ASPEN trial; the launch and potential commercial opportunity of BRUKINSA in the United States; BeiGene’s plans and expectations for Disclosures further development and potential commercialization of XGEVA, KYPROLIS, BLINCYTO and Amgen’s oncology pipeline assets; the timing of approvals of BeiGene’s commercial products in China; BeiGene’s further advancement of, and anticipated clinical development, regulatory milestones and commercialization of its drug candidates; and continuing and further development and commercialization efforts and transactions with third parties. Such statements, based as they are on the current analysis and expectations of management, inherently involve numerous risks and uncertainties, known and unknown, many of which are beyond BeiGene’s control. Such risks include but are not limited to: the impact of general economic conditions, general conditions in the pharmaceutical industries, changes in the global and regional regulatory environments in the jurisdictions in which BeiGene does business, market volatility, fluctuations in costs and changes to the competitive environment. Consequently, actual future results may differ materially from the anticipated results expressed in the forward-looking statements. In the case of forward-looking statements regarding investigational drug candidates and continuing further development efforts, specific risks which could cause actual results to differ materially from BeiGene’s current analysis and expectations include: failure to demonstrate the safety, tolerability and efficacy of our drug candidates, final and quality controlled verification of data and the related analyses, the expense and uncertainty of obtaining regulatory approval, including from the FDA, NMPA (formerly CFDA/CDA) and EMA, the possibility of having to conduct additional clinical trials and BeiGene’s reliance on third parties to conduct drug development, manufacturing and other services. Further, even if regulatory approval is obtained,1 pharmaceutical products are generally subject to stringent on-going governmental regulation, challenges in gaining market acceptance and competition. These statements are also subject to a number of material risks and uncertainties that are described in BeiGene’s filings with the Securities and Exchange Commission (SEC) and Hong Kong Stock Exchange. The reader should not place undue reliance on any forward-looking statements included in this presentation or in the accompanying oral presentation. These statements speak only as of the date made, and BeiGene is under no obligation and disavows any obligation to update or revise such statements as a result of any event, circumstances or otherwise, unless required by applicable legislation or regulation. • Some of the clinical data in this presentation relating to BeiGene’s investigational drug candidates is from early phase, single-arm trials. When such data or data from later stage trials are presented in relation to other investigational or marketed drug products, the presentation and discussion are not based on head-to-head trials between BeiGene’s investigational drug candidates and other products. BeiGene is still conducting clinical trials and, as additional patients are enrolled and evaluated, data on BeiGene’s investigational drug candidates may change. • This presentation and the accompanying oral presentation contains data and information obtained from third-party studies and internal company analysis of such data and information. BeiGene has not independently verified the data and information obtained from these sources. Forward-looking information obtained from these sources is subject to the same qualifications noted above. 4
John V. Oyler Chairman, Co-founder & CEO 5
Jane Huang, M.D. Chief Medical Officer, Hematology 6
Executive Summary • ASPEN is the first randomized Phase 3 study comparing two BTK inhibitors in any indication & the largest prospective randomized Phase 3 study in Waldenström’s Macroglobulinemia (WM) • The difference in the primary endpoint of the study (VGPR+CR rate: 28.9% zanubrutinib vs 19.8% ibrutinib, 2-sided p=0.116) in relapsed/refractory patients did not meet statistical significance • PFS and OS data at 12 months were consistent with the higher rate of VGPR with zanubrutinib ─ Supports our underlying hypothesis that sustained target occupancy may produce meaningful improvement in efficacy ─ Further follow-up will be required to ultimately define the clinical benefit of zanubrutinib relative to ibrutinib in WM • Importantly, the safety analysis showed clinically meaningful differences in favor of zanubrutinib, including differences in atrial fibrillation, serious bleeding, serious infection, diarrhea, and events leading to treatment discontinuation 7
ASPEN: A Phase 3 Study of Zanubrutinib vs Ibrutinib in Waldenström’s Macroglobulinemia Study Design Primary endpoint: CR or VGPR, per modified IWWM6, by independent review Arm A Cohort 1: R/R or TN* WM with MYD88L265P mutation Secondary Endpoints: Zanubrutinib 1) MRR (>PR) 160 mg BID until PD 2) PFS N=102 3) Duration of response MYD88MUT WM (R/R=83, TN=19) 4) Safety R patients Analysis Populations: (N=201, 164 R/R) 1:1 - Efficacy: ITT, R/R and Overall Arm B - Safety: all patients receiving at least 1 dose Ibrutinib Stratification factors: Analysis Plan: • CXCR4 status (WHIM vs WT) 420mg QD until PD - Hierarchical analysis: relapsed/ refractory • No. of lines of prior therapy N=99 population followed by overall population (if (0 vs 1-3 vs >3) (R/R= 81, TN= 18) endpoint met in relapsed/ refractory *TN must be unsuitable for standard chemoimmunotherapy population) Cohort 2: WM with wild type MYD88 Enrollment Period: 1/2017-7/2018 Enrollment by region: Cohort 1 Arm C - Europe: 120 pts (59.7%) MYD88WT WM patients Zanubrutinib - Australia: 62 pts (30.8%) (N = 26) 160 mg BID until PD - US: 19 pts (9.5%) Data Cut-off: August 31, 2019 Median Follow-up: 19.4 months WM=Waldenström’s macroglobulinemia, BID=twice daily, CR=complete response, MUT=mutation, PD=progressive disease, QD=once daily, R=randomization, R/R=relapsed/refractory, TN=treatment naïve, VGPR=very good partial response, WT=wild type. This study is registered at ClinicalTrials.gov (NCT03053440) Source: EHA 2019, abstract PF487. a. One patient achieved IgM complete response (normalized IgM and negative immunofixation since Cycle 11, with bulky extramedullary disease improving). b. Including pts confirmed by next-generation sequencing of no other activating MYD88 mutations: 3 of 6 VGPR (including IgM CR); 3 of 8 PR. 8
Efficacy Summary Primary Endpoint Response Rate Relapsed or Refractory Overall Zanubrutinib Ibrutinib Zanubrutinib Ibrutinib (N = 83) (N = 81) (N = 102) (N = 99) CR 0 0 0 0 VGPR 24 (28.9) 16 (19.8) 29 (28.4) 19 (19.2) PR 41 (49.4) 49 (60.5) 50 (49.0) 58 (58.6) MR 13 (15.7) 11 (13.6) 17 (16.7) 15 (15.2) No response 4 (4.8) 4 (4.9) 5 (4.9) 5 (5.0) VGPR+CR rate, % 24 (28.9) 16 (19.8) 29 (28.4) 19 (19.2) (CI) (19.5, 39.9) (11.7, 30.1) (19.9, 38.2) (12.0, 28.3) Major response rate (PR+), % 65 (78.3) 65 (80.2) 79 (77.5) 77 (77.8) (CI) (67.9, 86.6) (69.9, 88.3) (68.1, 85.1) (68.3, 85.5) Objective response rate (MR+), % 78 (94.0) 76 (93.8) 96 (94.1) 92 (92.9) (CI) (86.5, 98.0) (86.2, 98.0) (87.6, 97.8) (86.0, 97.1) * Groups were generally well-balanced for number of prior therapies, IPSS score, baseline IgM, and baseline hematologic parameters. Overall CXCR4 mutation was 10.9%
Efficacy Summary Landmark Data PFS and OS* Relapsed or Refractory Overall Zanubrutinib Ibrutinib Zanubrutinib Ibrutinib (N = 83) (N = 81) (N = 102) (N = 99) 6-month PFS, % 96.3 91.1 95.0 91.6 (CI) (88.9 - 98.8) (82.3 - 95.7) (88.4 - 97.9) (83.9 - 95.7) 12-month PFS, % 92.4 85.9 89.7 87.2 (CI) (83.8 - 96.5) (75.9 - 91.9) (81.7 - 94.3) (78.6 - 92.5) 6-month OS, % 98.8 95.0 98.0 95.9 (CI) (91.6 - 99.8) (87.3 - 98.1) (92.2 - 99.5) (89.5 - 98.4) 12-month OS, % 98.8 92.5 97.0 93.9 (CI) (91.6 - 99.8) (84.1 - 96.6) (90.9 - 99.0) (86.8 - 97.2) * Groups were generally well-balanced for number of prior therapies, IPSS score, baseline IgM, and baseline hematologic parameters. Overall CXCR4 mutation was 10.9%. 12-month landmark data are mature.
Safety: Overall Summary Overall Zanubrutinib Ibrutinib (N =101) (N = 98) Any Adverse Event (AE) 98 (97%) 97 (99.0%) Grade 3 or Higher AE 59 (58.4%) 62 (63.3%) Serious Adverse Event (SAE) 40 (39.6%) 40 (40.8%) Fatal AE 1 (1%) 4 (4.1%) AE Leading to Treatment Discontinuation 4 (4%) 9 (9.2%) AE Leading to Leading to Dose Reduction 14 (13.9%) 23 (23.5%) 11
Adverse Events of Special Interest Overall Zanubrutinib Ibrutinib (N = 102) (N = 99) AEs of Interest, n, % Atrial fibrillation/flutter (all grades) 2 (2.0%) 15 (15.3%) Minor bleeding 49 (48.5%) 58 (59.2%) (bruising, contusion, petechiae) Major hemorrhage* 6 (5.9%) 9 (9.2%) Diarrhea (all grades) 21 (20.8%) 31 (31.6%) Infection 67 (66.3%) 66 (67.3%) Pneumonia/Lower respiratory 9 (8.9%) 19 (19.4%) tract infections Hypertension 11 (10.9%) 17 (17.3%) Hematologic Neutropenia 30 (29.7%) 13 (13.3%) Anemia 12 (11.9%) 10 (10.2%) Thrombocytopenia 10 (9.9%) 12 (12.2%) * Bleeding > grade 3, or CNS bleeding of any grade
ASPEN: Conclusions and Next Steps • In this Phase 3 study, the first randomized comparison of a highly-selective BTK inhibitor (zanubrutinib) with ibrutinib: ─ Statistical significance for the primary endpoint (VGPR or better) was not met ─ Clinically meaningful differences in safety favoring zanubrutinib were demonstrated ─ Early, landmark PFS and OS analyses are directionally consistent with the higher VGPR rate observed in the zanubrutinib arm • Next Steps: ─ Plan to present ASPEN data and submit manuscript for publication in 2020 ─ Discuss ASPEN data with both US FDA and EMA in 1H 2020 ─ Longer-term PFS and OS follow-up 13
BRUKINSA Development Update Eric Hedrick, M.D., Chief Advisor 14
Zanubrutinib Development Program • Broad clinical trials program intended to support the approval of zanubrutinib in MCL, WM, CLL, MZL, and FL • Best-in-class hypothesis (safety and efficacy) is being tested in head-to-head trials versus ibrutinib in WM and CLL ─ Complete and sustained BTK occupancy efficacy distinctions vs ibrutinib ─ Higher selectivity for BTK safety and tolerability advantages over ibrutinib • Recent US FDA approval in patients with relapsed/refractory (R/R) MCL • Anticipated China approval (1H 2020) in R/R MCL and R/R CLL • Key Phase 3/ registrational trials either completed (1L CLL) or expected to soon complete (1Q 2020 for R/R CLL and MZL) • Potential interim analysis read-out in 1L CLL in 2020 15
Brukinsa Broad Clinical Development Program Nine ongoing potentially registration-enabling studies Pivotal Phase 2 (n=86) in R/R MCL Filed, In NDA review zanu monotherapy, PE: ORR Phase 3 (n=500) in 1L MCL Phase 1/2 cohort (n=45) in MCL Initiated: Mar 2017, Enrollment complete: Sep 2017 R+zanu vs. R+chemo, PE: PFS zanu monotherapy, PE: Safety RP2D MCL Enrollment Complete NDA accepted by NMPA and approved by U.S. FDA in Initiated: Nov 2019 Initiated: Aug 2014 Nov. 2019 Enrolling Phase 3 (n=229) in WM (ASPEN) Pivotal Phase 2 (n=44) in R/R WM Phase 1/2 (n=73) in WM zanu vs. ibrutinib, PE: VGPR/CR, WM zanu monotherapy, PE: MRR zanu monotherapy, PE: Safety, RP2D Planned Initiated: Jan 2017, Enrollment complete: Jul 2018, Top- Initiated: Aug 2017, Enrollment complete: May 2018 Initiated: Aug 2014, Enrollment complete: July 2018 line data: Dec 2019 Filed or potentially registrational Pivotal Phase 2 (n=91) in R/R CLL/SLL Phase 3 (n=550) in 1L CLL/SLL (SEQUOIA) Phase 3 (n=400) in R/R CLL/SLL (ALPINE) zanu monotherapy, PE: ORR zanu vs. BR, PE: PFS, zanu vs. ibrutinib, PE: ORR Initiated: Mar 2017, Enrollment complete: Dec 2017 Initiated: Nov 2017, Enrollment complete^: Aug 2019 Initiated: Nov 2018 China CLL/ NDA accepted: NMPA SLL Phase 2 (n=60) in previously treated CLL/SLL Global Phase 1 cohort (n=69) in CLL/SLL (ibrutinib intolerant) zanu monotherapy, PE: Safety RP2D zanu monotherapy, PE: Frequency and severity of Initiated: Aug 2014 treatment-emergent AEs of interest Initiated: Nov 2019 Pivotal phase 2 (n=210) in R/R FL Phase 21 (n=65) in R/R MZL FL Obinutuzumab ± zanu, PE: ORR MZL zanu monotherapy, PE: ORR Phase 1b: zanu + ME-401, in B-cell malignancies Initiated: Nov 2017 Initiated: Feb 2019 Phase 2: zanu / venetoclax / Phase 1b/2: zanu + tislelizumab, Phase 1b: zanu + obinutuzumab, Phase 2: Monotherapy, R/R obinutuzumab in 1L CLL Non-GCB DLBCL B-cell malignancies R/R CLL (MSKCC study) CLL DLBCL Phase 1 in hematologic malignancies Phase 2: zanu / venetoclax / Phase 1b: zanu + Revlimid, Phase 1b: zanu + R-chemo, Bcl-2 inhibitor BGB-11417 Combination obinutuzumab in 1L CLL R/R DLBCL 1L and 2L DLBCL monotherapy and comb. with zanu (GCLLSG study) Planned: 1H 2020 ^Time of the announcement of the enrollment completion; 1L: First Line; CLL/SLL: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; CR: Complete Response; DLBCL: Diffuse Large B-Cell Lymphoma; FL: Follicular Lymphoma; GCB: Germinal Center B-cell-like; MCL: Mantle Cell Lymphoma; MRR: Major Response Rate; MZL: Marginal Zone Lymphoma; NHL: Non-Hodgkin’s Lymphoma; ORR: Overall Response Rate; PCNSL: Primary Central Nervous System Lymphoma; PE: Primary endpoint; PFS: Progression-Free Survival; RP2D: Recommended Phase 2 Dose; R/R: Relapsed / Refractory; RT: Richter’s Transformation; VGPR: Very Good Partial Response; WM: Waldenström’s Macroglobulinemia. 1. global trial and potentially registration-enabling in certain countries. 16
Ongoing Global Phase 3 Studies in CLL/SLL SEQUOIA and ALPINE Zanubrutinib vs. BR in 1L CLL/SLL Zanubrutinib vs. Ibrutinib in R/R CLL/SLL Cohort 1: Non–17p del TN CLL Arm A Must be not suitable for FCR Zanubrutinib Relapsed/Refractory CLL/SLL 160 mg BID until PD Arm A Previously (received ≥ 1 prior treatments) untreated R Zanubrutinib 160mg BID CLL patients 1:1 (N=420) (n = 200) Arm B R/R CLL/SLL ≥ 1 prior Bendamustine R Primary endpoint: PFS treatment + Rituximab (BR) 1:1 × 6 cycles (N=400) Arm B Ibrutinib 420mg QD Cohort 2: 17p del TN CLL (n = 200) Previously untreated Arm C Primary Endpoint: ORR (non-inferiority and superiority) 17p del CLL patients Zanubrutinib (N=110) 160 mg BID until PD Full trial enrollment completed in June 2019 Complete enrollment expected by early 2020 1L=first-line treatment, BID=twice daily, CLL=chronic lymphocytic leukemia, del=deleted, FCR=fludarabine, cyclophosphamide, and rituximab, ORR=overall response rate, PD=progressive disease, PFS=progression-free survival, QD=once daily, R=randomized, SLL=small lymphocytic lymphoma, TN=treatment naïve. These studies are registered at ClinicalTrials.gov (NCT03734016) and (NCT03336333). 17
Zanubrutinib Near-Term Events • Broad clinical trial program continues in multiple indications • We plan to discuss ASPEN data with U.S. FDA and EMA • SEQUOIA Phase 3 study in 1L CLL (zanubrutinib vs BR): enrollment completed ─ Potential interim PFS analysis and top-line read out in 2020 • ALPINE Phase 3 study in R/R CLL (zanubrutinib vs ibrutinib): expected enrollment completion by year end 2019 • MAGNOLIA Phase 2 in R/R MZL: enrollment complete expected in early 2020 • Approval of zanubrutinib in China for R/R MCL and R/R CLL expected in 1H 2020 18
BRUKINSA Commercial Update Josh Neiman, Head, U.S. Commercial 19
U.S. BRUKINSA Launch Progress BRUKINSA made commercially available within four days of November approval Josh Neiman Head, U.S. Commercial Flatiron Onyx Pharmaceuticals Genentech • patient support program launched within BRUKINSA™ (zanubrutinib) is minutes of approval approved in the U.S. for R/R MCL1 • Commercial team in field and focused on driving awareness of BeiGene and BRUKINSA BRUKINSA is the only FDA-approved BTK inhibitor shown to deliver 100% • Initial feedback from clinicians: median occupancy in peripheral blood cells ─ Impressed by response rates from 206 and 003 studies and the only BTK inhibitor with the ─ Appreciate QD / BID dosing flexibility and ability to flexibility to be taken once or twice daily combine with PPIs and H2-RAs ─ Encouraged by 100% median BTK occupancy ─ See BRUKINSA as a differentiated BTKi 1. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. PPIs = proton pump inhibitors; H2-RAs = H2 receptor antagonists. 20
John V. Oyler Chairman, Co-Founder & CEO 21
Concluding Remarks • Zanubrutinib’s broad program on track ─ Despite not reaching primary endpoint of superiority, ASPEN provides evidence suggesting differentiation in both efficacy and safety / tolerability for zanubrutinib in the first randomized comparative trial within the BTK inhibitor class. ─ Running broad clinical program including 9 pivotal trials continues with potential 1L CLL readout as early as 2020. ─ Given the efficacy and safety/tolerability differences seen in ASPEN are consistent with our mechanistic hypothesis, we look forward to understanding if these will read through to other indications • Company-wide continued execution on broader commercial and pipeline programs ─ A total of up to 9 Phase 3 or pivotal Phase 2 trial readouts expected in 2020 ─ China Tislelizumab approval expected for cHL in 2019 and for UC in 2020; we are launch ready ─ China Zanubrutinib approval expected 1H 2020 for CLL and MCL ─ Clinical/commercial pipeline of 14 assets entering 2020 (does not including Amgen portfolio of 23 assets) • On track to close Amgen transaction in early 2020 ─ Regulatory reviews completed ─ Shareholders’ meeting scheduled for December 27 • Solid financial position 22
Q&A
Thank You
Supporting Information
ASH 2019 - SEQUOIA 1L CLL/SLL BRUKINSA VS Bendamustine Rituximab del(17p) Cohort 26
SEQUOIA Study Design NCT03336333 Arm A: zanubrutinib Cohort 1 open-label without del(17p) Key Eligibility R 1:1 n ~ 450 Arm B: bendamustine + rituximab • Treatment-naïve CLL/SLL • Met iwCLL criteria for zanubrutinib Requirement for Arm C Cohort 2 Arm C: treatment 160 mg bid until PD, Central assessment of • ≥ 65 y of age OR with del(17p) del(17p) by FISH with unsuitable for n ~ 100 intolerable toxicity, or > 7% aberrant nuclei treatment with FCR end of study presenta • Anticoagulation and Opened After CYP3A inhibitors Accrual of allowed Cohort 3 Cohort 2 with del(17p) Arm D: zanubrutinib + venetoclax Recruiting n ~ 50 Endpoints for Arm C: ORR (IRC and investigator assessments), PFS, DOR, safety Response assessment: per modified iwCLL criteria for CLL1,2 and Lugano criteria for SLL3 (IRC and investigator assessments) bid, twice daily; CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; DOR, duration of response; FCR, fludarabine, cyclophosphamide, and rituximab; FISH, fluorescence in situ hybridization; IRC, independent review committee; iwCLL, international workshop on CLL; ORR, overall response rate; PD, progressive disease; PFS: progression-free survival; R, randomized. aTP53 mutational status was not centrally assessed prior to enrollment. 1. Hallek M, et al. Blood. 2008;111:5446-5456. 2. Cheson BD, et al. J Clin Oncol. 2012;30:2820-2822. 3. Cheson BD, et al. J Clin Oncol. 2014;32:3059-3067 27
Best Overall Response Investigator assessment Best Response, n (%) n = 109 Safety ORR (CR, PR, or PR-L), n (%) [95% CI]a 101 (92.7) [86.0-96.8] • 36.7% of patients (40/109) experienced CR 2 (1.9) at least one grade ≥3 adverse event (AE) PR 86 (78.9) and three patients discontinued PR-L 13 (11.9) treatment due to AEs; • The most common grade ≥3 AEs, SD 6 (5.6) occurring in more than two patients, PD 1 (0.9) were neutropenia (10.1%), pneumonia First assessment not reachedb 1 (0.9) (3.7%) and hypertension (2.8%); Media follow-up months (range) 10.0 (5.0-18.1) • 23.9% of patients (26/109) experienced at least one serious AE; and Months to response, PR-L or higher, median 2.79 (1.9-11.0) • One patient experienced a fatal AE, (range) pneumonia leading to sepsis and death, Months to response, PR or higher, median 2.81 (1.9-11.1) which was considered related to (range) treatment drug by the study investigator. Duration of response ≥ 6 mo, % [95% CI]a 95 [88-98] Data cutoff: August 7, 2019. a2-sided Clopper-Pearson 95% confidence intervals. bPatient missed first 2 response assessments due to injury and inability to undergo imaging. After data cutoff, best response assessment was reported as PR. CR, complete response; NE, not evaluable; ORR, overall response rate; PD, progressive disease; PR, partial response; PR-L, PR with lymphocytosis; SD, stable disease. 28
ASH 2019 - Global Phase 1/2 – CLL/SLL Cohort First in Human Study 29
AU-003 Study Schema Indication-Specific Expansion Cohorts RP2D DOSE ESCALATION RP2Da 320 mg DOSE EXPANSION All Dosed BID 320 mg qd RP2D All Dosed Dose (CLL/SLL) Pop Disease or Dose (CLL/SLL) 40 mg qd 3 (0) 160 mg bid R/R qd All B-cell 18 (2) 80 mg qd 4 (0) R/R bid All B-cell 21 (4) 160 mg qd 5 (2) R/R bid Non-GCB DLBCL 37 R/R bid CLL/SLL 71 (71) 320 mg qd 1 (0) R/R bid WM 20 160 mg bid 4 (2) R/R qd CLL/SLL 20 (20) Eligibility: Any Any WM 50 • WHO-defined B-cell malignancy R/R Any MCL 20 • >1 Prior therapy (relapsed cohorts only) TN Any CLL/SLL 21 (21) • No available higher priority treatment TN Any MCL 20 R/R Any HCL 11 • ECOG PS 0-2 R/R bid iNHL 40 • ANC >1000/µL, platelets >100000/µLb R/R bid Richter Transformation 15 • Adequate renal and hepatic function; no significant cardiac diseasec R/R bid All B-cell (prior BTKi) 3 (1) aBoth doses RP2D but as of protocol v.6, all patients were encouraged to switch to 160 mg bid. bGrowth factor/transfusion allowed. cAnticoagulation allowed. ANC, absolute neutrophil count; bid, twice daily; BTKi, Bruton tyrosine kinase inhibitor; ECOG PS, Eastern Cooperative Oncology Group performance status; GCB-DLBCL, germinal center B- cell–like diffuse large B-cell lymphoma; HCL, hairy cell leukemia; iNHL, indolent non-Hodgkin lymphoma; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; qd, every day; R/R, relapsed/refractory; RP2D, recommended phase 2 dose; TN, treatment naïve; WM, Waldenström's macroglobulinemia. 30
Disease Response by Investigator Assessment R/R Overall TN (n=22) (n=101) (N=123) Overall Safety 31.7 (11.1- 24.3 (3.7- Follow-up, median (range), mo 29.5 (3.7-52.0) 47.6) 52.0) • 61.8% of patients (76/123) experienced at least one grade ≥3 AE and five Best response, n (%) patients discontinued treatment due to AEs; ORR 22 (100.0) 96 (95.0) 118 (95.9) • The most common AEs (≥ 20%) were CR 5 (22.7) 14 (13.9) 19 (15.4) contusion (47.2%), upper respiratory CRi tract infection (42.3%), diarrhea (31.7%), 0 1 (1.0) 1 (0.8) cough (29.3%), headache (23.6%), and PR 17 (77.3) 73 (72.3) 90 (73.2)a fatigue (20.3%); PR-L 0 8 (7.9) 8 (6.5) • 47.2% of patients (58/123) experienced SD at least one serious AE; and 0 4 (4.0) 4 (3.3) • One patient experienced a fatal AE, Discontinued before first 0 1 (1.0) 1 (0.8) assessment, n (%) neoplasm-malignant recurrent squamous cell carcinoma, considered unrelated to treatment drug by the study investigator. Event rate remaining in response 95.2 (70.7- 97.6 (90.8- 97.2 (91.5- at 12 mo, % (95% CI)b 99.3) 99.4) 99.1) Data cutoff: May 8, 2019. CR, complete response; CRi, complete response with incomplete bone marrow recovery; ORR, overall response rate; PR, partial response; PR-L, partial response with lymphocytosis; R/R, relapsed/refractory; SD, stable disease; TN, treatment-naïve. aAs of data cutoff (May 8, 2019), 4 patients met criteria for CR except required bone marrow to confirm; of these, 2 submitted bone marrow after data cutoff and confirmed CR. B Duration of response is summarized only for responders. Estimated using Kaplan-Meier method. 31
Disease Response by Investigator Assessment Patients With Del(17p) Overall TN (n=3) R/R (n=13) (n=16) Overall Safety Follow-up, median 34.8 (31.8- 24.5 (9.4- 31.2 (9.4- • 61.8% of patients (76/123) experienced at (range), mo 35.3) 43.5) 43.5) least one grade ≥3 AE and five patients discontinued treatment due to AEs; Best response, n (%) • The most common AEs (≥ 20%) were ORR 3 (100.0) 12 (92.3) 15 (93.8) contusion (47.2%), upper respiratory tract infection (42.3%), diarrhea (31.7%), cough CR 0 1 (7.7) 1 (6.3) (29.3%), headache (23.6%), and fatigue PR 3 (100.0) 9 (69.2) 12 (75.0) (20.3%); • 47.2% of patients (58/123) experienced at PR-L 0 2 (15.4) 2 (12.5) least one serious AE; and SD 0 1 (7.7) 1 (6.3) • One patient experienced a fatal AE, neoplasm-malignant recurrent squamous Event rate remaining cell carcinoma, considered unrelated to in response at 12 mo, 100 (NE-NE) 100 (NE-NE) 100 (NE-NE) treatment drug by the study investigator. % (95% CI)a Data cutoff: May 8, 2019. CR, complete response; CRi, complete response with incomplete bone marrow recovery; NE, not evaluable; ORR, overall response rate; PR, partial response; PR-L, partial response with lymphocytosis; R/R, relapsed/refractory; SD, stable disease; TN, treatment-naïve. a Duration of response is summarized only for responders. Estimated using Kaplan-Meier method. 32
Waldenström’s Macroglobulinemia 33
Zanubrutinib Efficacy in WM Favorable response depth and durability Overall Response Rate (ORR) Progression Free Survival (PFS) Best Response in zanubrutinib WM Overall TN RR Evaluable for 73 24 49 efficacy, n 95% CI Median Follow-up 23.9 mo 12.3 mo 24.8 mo Mod. 6th IWWM Response Criteria (IgM decreases only, and not extramedullary disease) Median Prior Lines 0 2 (1-8) of Therapy ORR 92% 96% 90% MRR 82% 87% 78% No. of patients at risk CR/VGPR1 42% 29% 49% PR 40% 58% 31% 1 One R/R patient achieved a CR, TN: treatment naïve; RR: relapsed refractory; Data cutoff 16 September 2018. Source: Trotman et al. EHA 2019 34
Ibrutinib Efficacy in WM Overall Response Rate (ORR) Progression Free Survival (PFS) Best Response ibrutinib Enrolled, n 63 100 Median Time-on-Treatment 19.1 months free 90 80 Modified 3rd IWWM 70 Response Criteria (IgM only) 60 50 Median Prior Lines of Tx 2 (1-9) 40 Survival (%) 30 20 ORR, n (%) 57 (90%) 10 Probability - Progression of Probability 0 MRR 46 (73%) VGPR 10 (16%) 0 3 6 9 12 15 18 21 24 27 30 No. of Subjects at Risk Month Median IgM Reduction (g/L) 35.2 to 8.8 (75%) 63 62 59 55 50 50 45 37 24 17 8 Median Hb Change (g/dl) 10.5 to 13.8 Source: Treon et al., NEJM, 2015 35
Mantle Cell Lymphoma 36
Zanubrutinib Efficacy in R/R MCL From U.S. approved label Best Response Zanubrutinib RR RR Study BGB-3111-206 BGB-3111-AU-003 Source Ph2 study Ph1/2 study Evaluable for efficacy, n 86 32 Median DoR in months 19.5 (16.6, NE) 18.5 (12.6, NE) Response Criteria Lugano 2014 Median Prior Lines of Therapy 2 (1-4) 1 (1-4) ORR 84% 84% CR 59% 22%* PR 24% 62% The most common adverse reactions (> 10%) with BRUKINSA were decreased neutrophil count, decreased platelet count, upper respiratory tract infection, decreased white blood cell count, decreased hemoglobin, rash, bruising, diarrhea, cough, musculoskeletal pain, pneumonia, urinary tract infection, blood in the urine (hematuria), fatigue, constipation, and hemorrhage. The most frequent serious adverse reactions were pneumonia (11%) and hemorrhage (5%). Of the 118 patients with MCL treated with BRUKINSA, eight (7%) patients discontinued treatment due to adverse reactions in the trials. The most frequent adverse reaction leading to treatment discontinuation was pneumonia (3.4%). One (0.8%) patient experienced an adverse reaction leading to dose reduction (hepatitis B). * FDG-PET scans were not required for response assessment. RR: relapsed refractory; NE: not estimable; DoR: duration of response. Source: BrukinsaTM U.S. label 37
CLL/SLL 38
Zanubrutinib Efficacy in CLL/SLL Frequent and durable responses – Phase 1/2 Overall Response Rate (ORR) Progression Free Survival (PFS) zanubrutinib TN CLL R/R CLL Total CLL n 16 50 66 Median follow- - free 7.6 14.0 10.5 up (mo) Best Response ORR 16 (100%) 46 (92%) 62 (94%) CR 1 (6%) 1 (2%) 2 (3%) Survival (%) PR 13 (81%) 41 (82%) 54 (82%) PR-L 2 (13%) 4 (8%) 6 (9%) Probability Progression of Probability SD 0 3 (6%) 3 (5%) Non-evaluable* 0 1 (2%) 1 (2%) No. of Subjects at Risk Month 66 66 62 53 45 37 27 25 19 11 9 6 4 *Discontinuation prior to first assessment Source: Seymour et al. 14-ICML 2017 (abstract 237) poster 39
Zanubrutinib Efficacy in CLL/SLL Frequent and durable responses – Phase 2 Best Overall Response by IRC (ORR) Progression Free Survival by IRC (PFS) zanubrutinib Total CLL n 91 Median follow-up (mo) 15.1 Best Response ORR 77 (84.6%) CR 3 (3.3%) PR 54 (59.3%) PR-L 20 (22.0%) SD 4 (4.4%) Non-evaluablea 3 (3.3%) aMissing anatomy imaging for 2 patients, and without evidence of response maintenance for at least 2 months for 1 patient, separately. Source: Xu et al. 15-ICML 2019. 40
Ibrutinib Efficacy in CLL/SLL Overall Response Rate (Relapsed / Refractory) Progression Free Survival (Relapsed / Refractory) n 85 free Median FU (mo) 20.9 Best Response ORR 75 (88%) CR 2 (2%) PR 58 (68%) Survival PR-L 15 (18%) SD NR PD NR Probability - Progression of Probability Overall Response Rate (Treatment-Naïve) Progression Free Survival (Treatment-Naïve) n 136 free Median FU (mo) 18.4 - Best Response ORR 117 (86%) CR 5 (4%) PR 107 (79%) PR-L 5 (4%) Survival (%) SD NR PD NR Probability Progression of Probability Source: For TN, Burger, et al New Engl J Med 2015. For R/R, Byrd, et al New Engl J Med 2013 41
Follicular Lymphoma 42
Zanubrutinib Plus Obinutuzumab Combination in Follicular Lymphoma Data from separate trials Zanubrutinib + FL Zanubrutinib Ibrutinib Obinutuzumab Idelalisib Obinutuzumab Source ICML 20191 ASH 20172 ASH 20163 JCO 20134 NEJM 20145 n 36 17 110 34 72 prior alkylator and CD20, prior alkylator and CD20, median 2 prior lines of mixed rituximab-sensitive alkylator and rituximab- Population mixed rituximab-sensitive last response <12 therapy, range 1-8 and -refractory refractory relapse and -refractory months Follow-up (med) 20.1 mo 7.8 mo 27.7 mo 33.7 mo NR ORR 72% 41% 21% 50% 54% CR 39% 18% 11% 18%6 6% • Overall response rate and complete responses to date compare favorably to those achieved with respective single-agents and recently approved therapies Notes: data on slide are cross-trial comparison; Source: 1. Tam et al., ICML 2019; 2. Tam et al., ASH (abstract 152), 2017; 3. Gopal, et al ASH 2016; 4. Salles, et al J Clin Oncol 2013; 5. Gopal, et al N Engl J Med 2014; 6. 18% represents complete response rate in the 40 indolent lymphoma patient population that include 34 FL patients. 43
Various B-cell Malignancies 44
Zanubrutinib Responses Across Additional B-Cell Malignancies MZL MCL MCL FL FL DLBCL China CSCO Source ASH 20171 ICML 20193 pivotal data ASH 20171 ASH 20171 20184 ASH20182 n 9 48 85 17 26 26 Follow-up 7.0 mo 16.7 mo 35.9 wk 7.8 mo 9.5 mo 4.2 mo (med) Prior Lines 2 (1-8) 1 (1-4) 2 (1-4) 2 (1-8) 3 (1-9) 2 (1-10) (med) ORR 78% 85% 84% 41% 42% 31% CR 0 29%* 59%** 18% 8% 15% VGPR -- -- -- -- -- -- PR/PR-L 78% 56% 25% 24% 35% 15% MR -- -- -- -- -- -- • Despite relatively early follow-up, responses were observed in multiple B-cell malignancies • Consistency across tumor types suggests that zanubrutinib is a highly active BTK inhibitor * CT response assessment; ** PET-CT response assessment. Source: 1. Tam et. al., ASH 2017; 2. Song et al., ICML 2019; 3. Tam et al., ICML 2019; 4. Song et. al., CSCO 2018 45
Pooled Safety 46
Pooled Safety Data* Zanubrutinib Zanubrutinib Acalabrutinib6 Ibrutinib Background EHA 20181 EHA 20192 Rate n 476 682 612 7565; 1,124b; 2,0904-2,1523 1,605c Major hemorrhage % 2% 2.5% 2.8% 4%5 (Gr≥3) (2%) (2.1%) (2.0%) (3%)5 [events/100 pt. yrs.] [2.07] - [3.0]3 [1.9]3 Atrial fibrillation % ~2% 1.9% 2.9% 9%c (Gr≥3) (0.2%) (0.6%) (1.0%) (4.1%)c [events/100 pt. yrs.] [1.56] - [3.3]4 [0.84]4 Diarrhea ~15% 19.4% 40% 39%c (Gr≥3) (1%) (0.9%) (2.1%) (3%)c Median exposure, mo 7.0 (0.02-36.05) 13.4 (6.1-19.6) 18.5 (0.03- 14.8moc a (25th-75th percentile) 37.4)# (range)# * Pooled safety data from separate trials and sources. Limitations regarding cross-trial comparisons apply. Sources: 1 Tam et al, EHA 2018; 2 Tam et al, EHA 2019; 3 Caron, F Blood Advances 1:12 2019; 4 Leong, D Blood 128:1 2016; 5 O’Brien S Clin Lymphoma Myeloma & Leukemia 18:10 2018; 6 Byrd et al, ASH 2017; a Median treatment duration; b Data from label out of 1,124 patients; c Data from label out of 1,605 patients 47