Sierra Oncology, Inc. (Nasdaq: SRRA), a clinical stage drug development company focused on advancing targeted therapeutics for the treatment of patients with significant unmet needs in hematology and oncology, today reported clinical data for its lead drug candidate, momelotinib, a potent, selective and orally-bioavailable JAK1, JAK2 and ACVR1 inhibitor for the treatment of myelofibrosis.

“Many myelofibrosis patients develop anemia and transfusion dependency as a result of disease progression, and sometimes also as a consequence of therapy they are given, like with selected JAK inhibitors. Momelotinib, however, has consistently demonstrated a broad range of clinically relevant anemia-related benefits, including transfusion independence,” noted Dr. Srdan Verstovsek, MD, PhD, Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, Houston, Texas. “The newly reported transfusion independence data presented at the ASH meeting are noteworthy, and confirm momelotinib’s ability to eliminate the need for transfusions in a high number of transfusion dependent patients, further reinforcing momelotinib’s differentiated activity in myelofibrosis. In my opinion, a good proportion of myelofibrosis patients in the second line setting would be candidates for momelotinib treatment due to its ability to improve both quality of life and transfusion dependency in a significant number of patients.”

“Momelotinib’s positive anemia benefits have been well documented in numerous clinical studies, including recently in the SIMPLIFY-1 and SIMPLIFY-2 Phase 3 trials. We are pleased to present these previously unreported data that further elaborate upon momelotinib’s meaningful array of clinical benefits,” added Dr. Nick Glover, President and CEO of Sierra Oncology. “Today we report aggregated transfusion independence responses from over 150 intermediate and high-risk transfusion dependent myelofibrosis patients demonstrating robust and consistent response rates across and within clinical studies. More than 44% of these patients became transfusion free for at least 12 weeks, and nearly half were transfusion independent for at least 8 weeks.”

“Myelofibrosis is a disease typified by chronic anemia, associated with functional iron deficiency. As presented today at ASH, clinical data reinforce that momelotinib’s anemia benefits are driven by its unique pro-erythropoietic mechanism of action, achieved by inhibiting both JAK1 and JAK2 as well as ACVR1,” continued Dr. Christian Hassig, Chief Scientific Officer of Sierra Oncology. “As this translational biology study shows, momelotinib positively impacts both the inflammatory JAK-STAT and the iron-sensing BMP-ACVR1 pathways, resulting in reduced hepcidin transcription and increased serum iron. This provides a bolus of iron to erythroblasts to facilitate red blood cell (RBC) maturation. As erythropoiesis is restored, iron levels subsequently normalize while hemoglobin, RBCs and platelets continue to increase.”

The clinical data reported today were collated from the two completed SIMPLIFY Phase 3 clinical trials and from a translational biology study in transfusion dependent patients with myelofibrosis. Data from the latter study are being presented in a poster at the 60^th American Society of Hematology (ASH) Annual Meeting & Exposition in San Diego, California.

ASH 2018 Poster #4282

Protocol ‘1672: Translational biology study in transfusion dependent patients with myelofibrosis

This single arm, open-label study evaluated momelotinib for 24 weeks in patients with myelofibrosis who were transfusion dependent at baseline. A high rate (73%) of advanced (Grade 3) bone marrow fibrosis was noted in this population.

• 34.1% of patients were transfusion independent for at least 12 weeks, achieving the primary endpoint of the study.
• 39.0% were transfusion independent for at least 8 weeks, achieving the secondary endpoint.
• Median blood hepcidin levels consistently decreased 6 hours after dosing with momelotinib, with a progressive reduction in serum hepcidin evident over the entire dosing period versus baseline, consistent with the ACVR1 inhibitory activity of momelotinib.
• Serum iron peaked at Week 2 and subsequently decreased, consistent with restoration of iron homeostasis.
• Amongst those patients who achieved transfusion independence, reticulocytes, hemoglobin, transferrin and hematocrit increased through the 24 weeks, consistent with improved erythropoiesis. The platelet count also increased in those patients over that period.
• 77.8% of those patients who did not reach the transfusion independence endpoint achieved at least a 50% decrease in transfusion frequency for any 8-week period.

Poster Title: Hepcidin Suppression by Momelotinib is Associated with Increased Iron Availability and Erythropoiesis in Transfusion-Dependent Myelofibrosis Patients

Authors: Stephen T. Oh, Moshe Talpaz, Aaron T. Gerds, Vikas Gupta, Srdan Verstovsek, Ruben Mesa, Carole Miller, Candido Rivera, Angela Fleischman, Swati Goel, Mark Heaney, Casey O’Connell, Murat Arcasoy, Yafeng Zhang, Jun Kawashima, Tomas Ganz, Carrie Baker Brachmann

SIMPLIFY-1 Phase 3 – Transfusion Dependent to Transfusion Independent Response Rates

• First line, double blind, randomized study versus ruxolitinib in JAKi naïve MF patients (N=432).
• 49.1% of patients who were transfusion dependent at baseline became transfusion independent for at least 12 weeks following momelotinib treatment.
• 58.5% were transfusion independent for at least 8 weeks.

SIMPLIFY-2 Phase 3 – Transfusion Dependent to Transfusion Independent Response Rates

• Second line, randomized study versus BAT (~90% ruxolitinib) in patients previously treated with ruxolitinib (N=156).
• 46.6% of patients who were transfusion dependent at baseline became transfusion independent for at least 12 weeks following momelotinib treatment.
• 46.6% were transfusion independent for at least 8 weeks.

Combined Transfusion Dependent to Transfusion Independent Response Rates from SIMPLIFY-1, SIMPLIFY-2 & ‘1672*

• 44.1% of patients who were transfusion dependent at baseline (multi-study aggregate n=152) became transfusion independent for at least 12 weeks.
• 48.7% were transfusion independent for at least 8 weeks.

*post-hoc analysis; aggregate data representative of a continuum of Intermediate/High Risk myelofibrosis patients.

About Sierra Oncology

Sierra Oncology is a clinical stage drug development company advancing targeted therapeutics for the treatment of patients with unmet medical needs in hematology and oncology. Our lead drug candidate, momelotinib, is a potent, selective and orally-bioavailable JAK1/JAK2 (Janus kinase) inhibitor and ACVR1 (Activin A receptor type 1) inhibitor that has been investigated in two completed Phase 3 trials for the treatment of myelofibrosis and has demonstrated a potentially differentiated therapeutic profile encompassing anemia-related benefits, as well as achieving substantive spleen and constitutional symptom control.

Sierra is also advancing SRA737 and SRA141. SRA737 is a potent, highly selective, orally bioavailable small molecule inhibitor of Checkpoint kinase 1 (Chk1), a key regulator of cell cycle progression and the DNA Damage Response (DDR). SRA737 is currently being investigated in two Phase 1/2 clinical trials primarily focused on patients with ovarian cancer: SRA737-01, a monotherapy study, and SRA737-02, a drug combination study evaluating SRA737 potentiated by low dose gemcitabine. Sierra has also prepared for a potential clinical study of SRA737 in combination with a PARP inhibitor. SRA141 is a Phase 1 ready, potent, selective, orally bioavailable small molecule inhibitor of Cell division cycle 7 kinase (Cdc7). Cdc7 is a key regulator of DNA replication and is involved in the DDR network, making it a compelling emerging target for the potential treatment of a broad range of tumor types.