Charting the path from pioneering biology to impactful therapeutics

Transcription

1 Charting the path from pioneering biology to impactful therapeutics Q NASDAQ: SRRA

2 SAFE HARBOR STATEMENT Except for statements of historical fact, any information contained in this presentation may be a forward-looking statement that reflects the Company s current views about future events and are subject to risks, uncertainties, assumptions and changes in circumstances that may cause events or the Company s actual activities or results to differ significantly from those expressed in any forward-looking statement. In some cases, you can identify forward-looking statements by terminology such as may, will, should, plan, predict, expect, estimate, anticipate, intend, goal, strategy, believe, and similar expressions and variations thereof. Forward-looking statements may include statements regarding the Company s business strategy, cash flows and funding status, potential growth opportunities, preclinical and clinical development activities, the timing and results of preclinical research, clinical trials and potential regulatory approval and commercialization of product candidates. Although the Company believes that the expectations reflected in such forward-looking statements are reasonable, the Company cannot guarantee future events, results, actions, levels of activity, performance or achievements. These forward-looking statements are subject to a number of risks, uncertainties and assumptions, including those described under the heading Risk Factors in documents the Company has filed with the SEC. These forwardlooking statements speak only as of the date of this presentation and the Company undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date hereof. Certain information contained in this presentation may be derived from information provided by industry sources. The Company believes such information is accurate and that the sources from which it has been obtained are reliable. However, the Company cannot guarantee the accuracy of, and has not independently verified, such information. TRADEMARKS: The trademarks included herein are the property of the owners thereof and are used for reference purposes only. Such use should not be construed as an endorsement of such products.

3 Addressing Unmet Medical Needs with a Broad Pipeline DDR Network Programs momelotinib TARGETING JAK1/2 AND ACVR1 SRA737 TARGETING Chk1 SRA141 TARGETING Cdc7 THERAPEUTIC FOCUS Myelofibrosis THERAPEUTIC FOCUS High Grade Serous Ovarian Cancer Squamous Cell Carcinoma & Other Solid Tumors THERAPEUTIC FOCUS Colorectal Cancer 3

4 Our Pipeline of Targeted Therapeutics MOMELOTINIB Simplify 1 Simplify 2 Additional Registration Study Preclinical Phase 1 Phase 2 Phase 3 Focus Myelofibrosis Myelofibrosis Myelofibrosis SRA737 SRA Monotherapy SRA LDG Combination PARP Inhibitor Combination I/O Combination SRA141 Monotherapy Preclinical Phase 1 Phase 2 Phase 3 Focus Preclinical Phase 1 Phase 2 Phase 3 Focus High Grade Serous Ovarian High Grade Serous Ovarian Prostate Solid Tumors Colorectal 4

5 MOMELOTINIB Targeting JAK1, JAK2 and ACVR1

6 >20 studies Phase 1, 2 and 3 MOMELOTINIB Uniquely positioned to provide robust benefits in myelofibrosis: spleen, symptoms and anemia >1,200 people dosed with momelotinib >550 patients with myelofibrosis treated >7 years on treatment for several patients 6

7 Momelotinib Potentially Addresses Key Needs in Myelofibrosis Treatment Opportunity 2 nd -line myelofibrosis = anemic and transfusion dependent; large unmet need with no approved therapies Robust Data Two Phase 3 SIMPLIFY studies support efficacy profile Benefit Only agent to impact all three myelofibrosis hallmarks: anemia, enlarged spleen and constitutional symptoms Registration Totality of data supports potential path to registration; strong KOL support for momelotinib 7

8 Inefficient hematopoiesis ANEMIA Myelofibrosis A Chronic Myeloproliferative Neoplasm (MPN) Myelofibrosis Extramedullary hematopoiesis SPLENOMEGALY Inflammation CONSTITUTIONAL SYMPTOMS Chronic, progressive myeloid cancer Bone marrow disorder disrupting the body s normal production of blood cells Leads to fibrosis of bone marrow limiting blood cell production 8

9 The Three Hallmarks of Myelofibrosis a Progressive Disease The Challenge of Anemia Anemia is major area of unmet need. That s one of the major problems a quarter of the patients at the beginning may require transfusions, and after one year of therapy almost half of the patients already require transfusion. Anemia and transfusion dependency are important prognostic factors. Srdan Verstovsek, MD, PhD Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, Houston Unmet Medical Needs In Myelofibrosis; company conference call October 2018 Three Hallmarks of a Progressive Disease >1 YEAR AFTER DIAGNOSIS 64% 46% 34% ANEMIA Progressive bone marrow fibrosis due to inflammation; decreased erythropoiesis 45% Transfusion Dependent SPLENOMEGALY Extramedullary hematopoiesis in the spleen and other organs CONSTITUTIONAL SYMPTOMS Anemia, chronic inflammation, and splenomegaly lead to constitutional symptoms Tefferi A, et al. Mayo Clin Proc

10 Myelofibrosis: More Treatment Options Needed INITIAL TREATMENT: Only one agent approved: ruxolitinib (Jakafi ) for 1 st -line myelofibrosis Ruxolitinib: Addresses ~70% 1 st -line patients Projected global market: >$2B Only treats spleen and symptoms Anemia is not addressed by ruxolitinib UNMET MEDICAL NEEDS: Optimal myelofibrosis therapeutic would address all three hallmarks: Anemia and transfusion dependency Splenomegaly Constitutional symptoms Physicians need more choices after ruxolitinib TREATING ANEMIA AND TRANSFUSION DEPENDENCY REMAIN SIGNIFICANT UNMET MEDICAL NEEDS 10

11 MOMELOTINIB Addresses all Three Hallmarks of Myelofibrosis INHIBITS ACVR1 ANEMIA Hepcidin impaired erythropoiesis INHIBITS JAK1 CONSTITUTIONAL SYMPTOMS Aberrant cytokine production and immune dysregulation INHIBITS JAK2 SPLENOMEGALY JAK-STAT-driven clonal myeloproliferation 11

12 10 Anemia Critical Prognostic Factor in Myelofibrosis Survival No anemia Median survival 7.9 years Mild anemia Median survival 4.9 years Moderate anemia Median survival 3.4 years Severe anemia Median survival 2.1 years 2 P< Years Baseline Anemia: Mild = Hgb 10 g/dl but below lower limit of normal Moderate = Hgb between 8 g/dl and <10 g/dl Severe = Hgb <8 g/dl or transfusion dependent Nicolosi et al; Leukemia

13 Multiple Pathways to Anemia in Myelofibrosis BONE MARROW FIBROSIS INFLAMMATION HEPCIDIN JAK THERAPY Displacement of marrow erythropoietic tissue by fibrosis Alterations in bone marrow cytokine expression Activated ACVR1 JAK inhibitor therapy induced myelosuppression Extramedullary hematopoiesis and splenomegaly Pro-inflammatory cytokine profile Elevated hepcidin Inadequate extramedullary erythropoiesis and red blood cell sequestration Impaired erythroid differentiation Impairment of iron metabolism ANEMIA 13

14 Momelotinib Mechanism of Action: Reducing Hepcidin Restores Red Blood Cell Production Fe2+ Hepcidin Hepcidin PLASMA IRON DEFICIENCY PLASMA IRON NORMALIZATION Erythroblast Precursors Hgb Accumulation Reticulocytes RBCs Momelotinib-mediated plasma iron elevation leads to stimulation of erythropoiesis and red blood cell production 14

15 The KOL View on Myelofibrosis Thoughts from: Srdan Verstovsek, MD, PhD Professor in the Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston Ruxolitinib may control the signs and symptoms of the disease for some time but it doesn t prevent progression. The leading cause of loss of response that has been published is anemia. Three quarters of the patients would be candidates for a second line therapy. The majority of patients need another agent to salvage their quality of life, to control spleen, symptoms, and to improve the anemia, if possible. Momelotinib unlike any other JAK inhibitor, can benefit patients to a great extent on all three aspects. Unmet Medical Needs In Myelofibrosis KOL Presentation, October 17, 2018; ASH Analyst Call, December 3,

16 Completed Phase 3 Studies with Momelotinib Simplify 1 1 st -Line Population: Previously untreated with JAKi Simplify 2 2 nd -Line Population: Anemic or thrombocytopenic subjects previously treated with ruxolitinib Primary Endpoint Primary Endpoint Day 1 Week 24 Year 7 Day 1 Week 24 Year 7 JAK Naïve Double-blind, N=432 1:1 randomization Double-blind treatment Open label LTFU Momelotinib 200 mg QD Ruxolitinib 20 mg BID Momelotinib 200 mg QD JAK Exposed Open label, N=156 RBC transfusions on RUX = 64% RUX dose adjustment for: thrombocytopenia = 21% anemia/hematoma = 35% 2:1 randomization Randomized treatment Extension LTFU Momelotinib 200 mg QD Best available therapy 90% = RUX/RUX+ Momelotinib 200 mg QD Goal: Primary Endpoint MMB: N=215 RUX: N=217 Non-Inferiority Splenic Response Rate Secondary Endpoints Total Symptom Score Effects on red blood cell transfusion requirements Goal: Primary Endpoint Superiority MMB: N=104 RUX: N=52 Splenic Response Rate Secondary Endpoints Total Symptom Score Effects on red blood cell transfusion requirements 16

17 Maintenance of Transfusion Independence Simplify 1 PREVENTS TRANSFUSIONS 66% Simplify 2 PREVENTS TRANSFUSIONS 43% vs 49% ruxolitinib vs 21% best available therapy Statistically significant transfusion independence rate (p < 0.001) of patients were transfusion independent at week 24 on momelotinib 17

18 Conversion from Transfusion Dependent to Transfusion Independent Simplify % Simplify % 12 WEEK TRANSFUSION INDEPENDENCE RATE 12 WEEK TRANSFUSION INDEPENDENCE RATE Data from Sierra s post-hoc analyses of SIMPLIFY-1 & SIMPLIFY-2 studies 18

19 Hemoglobin Improvement after Momelotinib Crossover Simplify 1 13 Double-Blind Phase Open-Label Phase 12 Crossover All patients on momelotinib HGB (g/dl) 11 Baseline 10 Momelotinib Ruxolitinib 9 BL Weeks 19

20 Non-Inferior Head-to-Head Activity on Splenomegaly Simplify % SRR vs 29% ruxolitinib Momelotinib statistically non-inferior to ruxolitinib on spleen (p=0.011) Only JAKi to show equivalent splenic response to ruxolitinib in 1 st -line SRR: Splenic Response Rate 20

21 Pronounced Activity on Symptoms in Phase 3 Studies Simplify 1 Clinically Comparable H2H Symptom Benefit Simplify 2 Statistically Significant Symptom Response Median Baseline and Median Week 24 4-Week Average Symptom Score worst absent Baseline TSS Ab Discomfort Median Pain Under Left Ribs MMB arm: More symptomatic at baseline Mean Early Satiety Night Sweats Itching Bone Pain MMB RUX Baseline Week 24 Tiredness Momelotinib compared to best available therapy (~90% ruxolitinib) in 2 nd -line patients 26.2% TSS vs 5.9% best available therapy (p < 0.001) Both momelotinib and ruxolitinib substantially improved all symptoms relative to baseline* TSS: Total Symptom Score *Momelotinib marginally missed Total Symptom Score (TSS) non-inferiority to RUX in SIMPLIFY-1: 28.4% vs. 42.2% (Noninferior Proportion Difference 0.00 (-0.08, 0.08)). Mean & Median Baseline TSS higher in momelotinib arm vs. RUX. No stratification for baseline symptoms in SIMPLIFY-1. 21

22 Noteworthy Survival Post- Ruxolitinib vs Historical Controls Simplify 2 28 months Median Overall Survival vs 7-14 months* Momelotinib compared to historical controls in post-ruxolitinib treated patients Mehra et al. Blood 2016; Newberry et al, Blood

23 Momelotinib Poised to be the Only Treatment Addressing All Three Hallmarks of Myelofibrosis Momelotinib (MMB) Ruxolitinib (RUX) Fedratinib (FED) Pacritinib (PAC) Status in Myelofibrosis Phase 3 (Two completed P3s; P2 translational biology) Approved (intermediate / high-risk; platelets /dl) Post-Phase 3 (P3 safety and efficacy study; NDA TBD) Phase 2 (P3 trial requested by FDA; EU MAA refiled) Targets JAK1, JAK2, ACVR1 JAK1, JAK2 JAK2, FLT3 JAK2, FLT3 Splenic Response Symptom Benefit Anemia Benefit Toxicity: Anemia and Thrombocytopenia LOW HIGH HIGH HIGH 23

24 Momelotinib 2 nd -Line Market Opportunity* Diagnosis ~50K patients living with myelofibrosis ~75% are intermediate risk 1 st -Line ~70% receive 1 st -line treatment 2 nd -Line >75% will need 2 nd -line treatment >70% of INT-2/High myelofibrosis patients have anemia >50% of patients are transfusion dependent The majority of patients in second line would potentially be candidates for momelotinib. Dr. Srdan Verstovsek Analyst Call, December 3, 2018 *Company estimates in US and EU 24

25 Momelotinib Registration Strategy: Addressing 2 nd -Line Medical Needs Reviewing and mining the robust body of existing clinical data generated by Gilead Focus on 2 nd -line anemic and transfusion dependent patients, major unmet need in myelofibrosis CONSTITUTIONAL SYMPTOMS Improve constitutional symptoms ANEMIA Convert TD patients to TI Reduce transfusions Increase hemoglobin SPLENOMEGALY Maintain maximal/stable spleen response 2 ND -LINE DEVELOPMENT STRATEGY Planning for near-term regulatory interactions to determine registration path and requirements for additional Phase 3 study in 2 nd -line setting Registration plan clarity projected for H

26 SRA737 + SRA141 Targeting the DNA Damage Response

27 SRA737: Chk1i Program Focused on Ovarian Cancer SRA737 has significant anti-tumor activity and profound survival benefit in CCNE1-driven background HGSOC preclinical models PARP inhibitors inactive in this population Supports focus on development for ovarian cancer Orthotopic PDX (CCNE1 amplified + TP53 mutated) Phase 2 study of Lilly s Chk1i prexasertib in BRCA wild type (PARPi-insensitive) high-grade serous ovarian cancer demonstrates clinical efficacy in CCNE1-driven genetic background Prexasertib Efficacy 33% ORR (8/24) Evaluable 42% ORR (8/19) CCNE1 (All) 33% ORR (4/12) CCNE1 amplification Hong et al. Lancet Oncology

28 SRA Monotherapy: Program Expansion and Prioritized Design Dose Optimization (non-selected) Dose escalation (non-selected) Phase 2 cohorts Prospective patient selection using NGS technology PRIORITIZING FOR OVARIAN CANCER Target enrollment N=65 Ovarian (CCNE1) Ovarian (non-ccne1) Focus on geneticallydefined replication stress driven patient populations Tumor Suppressor TP53, RAD50... Oncogenic Drivers CCNE1, MYC Prostate Target enrollment N=80 (20x4) Continuous, daily oral administration Replicative Stress ATR, CHEK1 DNA Repair Machinery BRCA1, FANCA Non-Small Cell Lung Head & Neck + Anus Colorectal 28

29 SRA LDG Combination: Program Expansion and Amended Design Continued dose escalation to MTD (non-selected) Dose escalation (non-selected) Phase 2 cohorts Prospective patient selection using NGS technology PRIORITIZING FOR OVARIAN CANCER Target enrollment N=80 (20x4) Ovarian Low dose gemcitabine (day 1) followed by intermittent oral dosing of SRA737 (days 2 & 3); Administer weekly for 3 weeks every 28 days Tumor Suppressor TP53, RAD50... Oncogenic Drivers CCNE1, MYC Replicative Stress ATR, CHEK1 DNA Repair Machinery BRCA1, FANCA Small Cell Lung Sarcoma Cervical + Anogenital *One or more mutations required for eligibility. 29

30 SRA141: Cdc7i Program Focused on Colorectal Cancer SRA141: potent, orally bioavailable, selective cell division cycle 7 (Cdc7) inhibitor Cdc7 (serine/threonine kinase): emerging next-generation DDR target Phase 1/2 clinical trial focused on colorectal cancer Takeda Cdc7i clinical data demonstrate preliminary monotherapy responses; P2 ongoing in colorectal Key regulator of both DNA replication and DNA damage response, as well as mitosis COLO205 model: TP53 & MSS - relevant genetics for Cdc7i. Tumor growth inhibition (TGI) = 99%; CRs in 4/7 (57%) animals. 30

31 2019 Milestones MOMELOTINIB 1H 2019 Registration Plan Clarity SRA737 SRA Monotherapy SRA LDG Combination SRA PARP Inhibitor Combination 1H 2019 Preliminary Clinical Data 1H 2019 Preliminary Clinical Data TBD Initiate Phase 1b/2 SRA141 t TBD Initiate Phase 1/2 31

32 Targeted Hematology and Oncology Therapeutics We are a clinical stage drug development company advancing targeted therapeutics for the treatment of patients with unmet medical needs in hematology and oncology Bold drug development company oriented to registration and commercialization Lead asset, momelotinib, for the treatment of myelofibrosis with large 2 nd -line market opportunity Two assets focused on DNA Damage Response (DDR) targeting: SRA737 and SRA141 Highly experienced management team with proven track record in drug development Strong financial standing: Shares (as of September 30): 74.4M outstanding 85.2M fully diluted $116.1M in cash and cash equivalents (as of September 30) $5M borrowed in structured debt 32