Building Momentum for Patients with Myelofibrosis ASH Annual Meeting December 8, 2019 NASDAQ: SRRA
S A F E H A R B O R S TAT E M E N T 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 forward-looking 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. T R A D E M A R K S : 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.
Sierra’s Proven Nick Glover, PhD Leadership in President and CEO Drug Barbara Klencke, MD Development Chief Development Officer Mark Kowalski, MD, PhD Chief Medical Officer Sukhi Jagpal, CA, CBV, MBA Chief Financial Officer Gregg Smith, PhD, MBA Senior Vice President, Drug Development 3
Dr. Ruben Mesa: Director of the Mays Cancer Center • Dr. Mesa is Director of the Mays Cancer Center, home of UT Health San Antonio MD Anderson Cancer Center. • He has been involved in MPN research for more than 20 years. • Dr. Mesa led the development of the National Comprehensive Cancer Network’s panel guidelines, the first US guidelines on the diagnosis and treatment of myelofibrosis (MF), polycythemia vera and essential thrombocythemia. • Dr. Mesa has been the Principal Investigator of more than 70 clinical trials. He co-led the research team leading to the FDA’s approval of ruxolitinib for polycythemia vera and myelofibrosis. He is currently leading the investigation of several other drugs for the treatment of myeloproliferative disorders. Ruben Mesa, MD • Dr. Mesa has been involved in the development of momelotinib from Director of the Mays Cancer initial Phase 1 clinical trials through Phase 3. He is an investigator on Center, home to UT Health the MOMENTUM confirmatory Phase 3 trial. San Antonio MD Anderson Cancer Center 4
> 20 studies Phase 1, 2 and 3 > 1,200 people MOMELOTINIB dosed with momelotinib > 820 patients Positioned to potentially provide benefits on all three myelofibrosis hallmarks: with myelofibrosis treated symptoms, anemia and spleen incl. SIMPLIFY 1 & 2 P3 trials > 8 years on treatment for several patients 5
Myelofibrosis Biology: JAK1, JAK2 & ACVR1 Drive MF Disease Hallmarks Interleukins Ligand BMP2, BMP6 Interferons ACVR1 EPOR / MPL Cytokine Receptors JAK2 JAK2 JAK2 JAK1 STAT STAT SMAD1,5 P P P • Clonal proliferation leading to • Aberrant activation of hepcidin • Inflammation and aberrant extramedullary hematopoiesis transcription via hyperactivated cytokine signaling producing and burdensome ACVR1 signaling resulting in profound debilitating constitutional splenomegaly. functional iron deficiency anemia. symptoms. 6
Momelotinib: SIMPLIFY Data Support Benefits in 3 Hallmarks of MF ANEMIA Increased hemoglobin: lower rates of RBC INHIBITS transfusion, fewer transfusion dependent ACVR1 patients, etc. in 1L & 2L CONSTITUTIONAL SYMPTOMS INHIBITS Pronounced TSS benefit: clinically JAK1 consistent symptom improvement across all domains in 1L & 2L SPLENOMEGALY INHIBITS JAK2 Only JAKi to show equivalent splenic response to ruxolitinib in 1L 7
Three Hallmarks of a Progressive Disease The Three Hallmarks of >1 Y E A R A FTE R DI A G NO S I S Myelofibrosis a Progressive Disease ANEMIA 64% The Challenge of Anemia Progressive bone marrow fibrosis due to inflammation; decreased erythropoiesis. 45% Transfusion Dependent “Anemia is major area of unmet need. That’s one of SPLENOMEGALY the major problems… a quarter of the patients at the 46% beginning may require transfusions, and after one Extramedullary hematopoiesis in the spleen and other organs. year of therapy almost half of the patients already require transfusion. Anemia and transfusion dependency are important prognostic factors.” CONSTITUTIONAL Srdan Verstovsek, MD, PhD 34% Professor in the Department of Leukemia at SYMPTOMS The University of Texas MD Anderson Cancer Center, Houston Anemia, chronic inflammation, and Unmet Medical Needs In Myelofibrosis; company conference call October 2018 splenomegaly lead to constitutional symptoms. 8 Tefferi A, et al. Mayo Clin Proc. 2012
Myelofibrosis Anemia: Severe Anemia &Transfusion Dependency Predict Poor Survival Transfusion dependency results in Anemia predicts poor survival in myelofibrosis substantially shortened survival 10 1.0 No anemia Median survival 7.9 years 8 Cumulative proportion surviving 0.8 Mild anemia Transfusion-independent Median survival 4.9 years Survival Moderate anemia 6 0.6 Median survival 3.4 years Severe anemia 4 Median survival 2.1 years 0.4 Transfusion-dependent 2 0 P<0.0001 0 0 10 18 0 2 4 6 8 12 14 16 10 15 20 25 30 35 0 5 Time since diagnosis Years Time since diagnosis Nicolosi M et al; Leukemia. 2018. http://www.haematologica.org/content/96/1/167 9
Anemia in • Time Consuming and Costly • Impacts patients, caregivers and health care systems. Myelofibrosis: • Costs include clinic visits, blood banking & associated processing. The Burden of • Management of transfusion-related complications. Transfusions • Acute Health Risks • Transfusion reactions. • Fluid overload. • Chronic Health Risks • Iron overload with subsequent end organ damage. • Risk of transmission of blood borne pathogens. • Transfusions Only Offer Transient Benefits • Must be continually repeated. • Regular blood count monitoring required. 10 Jochen Sands/Digital Vision/Thinkstock
Myelofibrosis Anemia: Momelotinib Positively Impacts Multiple Pathways to Anemia FIBROSIS & INFLAMMATION HEPCIDIN EXTRAMEDULLARY OTHER JAKi (JAK1) (ACVR1) HEMATOPOIESIS (JAK2) THERAPIES Alterations in Displacement of marrow Other JAK inhibitors bone marrow cytokine Activated ACVR1 erythropoietic tissue by fibrosis induce myelosuppression expression Extramedullary hematopoiesis Pro-inflammatory cytokine Elevated hepcidin and splenomegaly profile Inadequate extramedullary Impaired erythroid hematopoiesis and red blood cell Impairment of iron metabolism differentiation sequestration ANEMIA 11
Myelofibrosis Anemia: High Hepcidin Correlates With Severe Anemia Hepcidin predicts poor survival in myelofibrosis Anemia predicts poor survival in myelofibrosis 10 10 No anemia Median survival 7.9 years 8 8 Mild anemia Cumulative Survival Median survival 4.9 years Survival 6 Moderate anemia 6 Median survival 3.4 years Severe anemia 4 4 Median survival 2.1 years 2 2 P<0.0001 0 0 10 15 20 25 30 35 0 5 0 5 15 10 Years Years Pardanani et al; American Journal of Hematology 2013. Nicolosi M et al; Leukemia. 2018. 12
Clinical Validation of Anemia Mechanism: Acute & Chronic Hepcidin Suppression by Momelotinib • Phase 2 Translational biology study (GS-US-352-1672), N=41 transfusion dependent subjects. • Primary endpoint: Transfusion independence. • 34% 12 Week TI response rate; 39% TI for ≥ 8 Weeks. • PD analyses demonstrates consistent effects on hepcidin, hematocrit, Hgb and serum iron consistent with increased momelotinib-driven erythropoiesis. Hepcidin Levels At every study visit, median blood hepcidin decreased 6 hours after Pre-dose 6 hours post-dose dosing with momelotinib. Median actual value (Q1, Q3) Overall trend to reduced hepcidin over time. Reinforces ACVR1i mechanism of action. Baseline Enrollment Week 2 Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 Visit: Timepoint 13 Oh et. al. ASH 2018. Abstract# 4282.
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