Key Inclusion CriteriaAge 18 years old with diagnosis of primary MF P - PDF document

Key Inclusion CriteriaAge 18 years old with diagnosis of primary MF (PMF), postpolycythemia MF PV MF), or postessential thrombocythemia MF (postET MF) and requiring MF therapy (in the opinion of the investigator)High risk or intermediate2 risk defined by the dynamic international prognostic scoring system (DIPSS), or intermediate1 risk defined by DIPSS and associated with symptomatic splenomegaly and/or hepatomegalyTD at baseline, defined as 4 U red blood cell (RBC) transfusion in the 8 weeks prior to thefirst dose of MMBAcceptable organ function as determined by laboratory values; platelet count ≥50x10Key Exclusion CriteriaPrior splenectomy or splenic irradiation within 3 months prior to the first dose of MMBPrior treatment with MMB, a JAK inhibitor within 21 days of the planned first dose of MMB, or use of strong cytochrome P450 enzyme (CYP) 3A4 inducer within 2 weeks prior to the first dose of MMBDocumented myocardial infarction or unstable/uncontrolled cardiac diseasePresence of peripheral neuropathy Grade 2HIV positive; chronic active or acute viral hepatitis A, B, or C infection (testing required for hepatitis B and C); or hepatitis B or C carrierStudy DesignThis was an exploratory singlearm, openlabel study (NCT02515630) of MMB in subjects with PMF, postPV MF, or postET MF who were TD Subjects received MMB (first dose at enrollment visit) for 24 weeks (7 days) on studyProgressive splenomegaly or symptomatology were not required for study inclusionMeasurementsHepcidin: because of diurnal variation in hepcidin levels, samples were drawn in the morning (normal trough) prior to receiving MMB, and in the afternoon/6 hours postMMB dosing at the following times: Baseline visit (no MMB), enrollment, Weeks 2, 4, 8, 12, 16, 20, and 24hsCRP: measured at Baseline and Weeks 2, 12, and 24 using the highsensitivity Creactive protein (hsCRP) testLiver iron content: measured by MRI at Baseline and Week 24OutcomesPrimary endpoint: transfusion independence response (TIR) rate by Week 24, defined as becoming transfusion independent for ≥12 weeks at any time on studySecondary endpointsResponse rate for transfusion independence ≥8 weeks, defined as no RBC transfusions for at least 8 weeks at any time on studyBaseline and change in hepcidin, anemiarelated biomarkers, liver iron content and CRPSplenic response rate (SRR) at Week 24, defined as the proportion of subjects who achieved a ≥35% reduction in spleen volume at Week 24 from Baseline as measured by MRIResponse rate in total symptom score (TSS) at Week 24, defined as the proportion of subjects who achieved a 50% reduction from Baseline to Week 24 in TSS based on the modified Myeloproliferative Neoplasm Symptom Assessment Form Washington University School of Medicine, St Louis, MO; SAFETY RESULTSHepcidin Suppression by Momelotinib Is Associated With Increased Iron Availability and Erythropoiesis in TransfusionDependent Myelofibrosis PatientsStephen T. Oh, Moshe Talpaz, Aaron T. Gerds, Vikas Gupta, SrdanVerstovsek, Ruben Mesa, Carole Miller, Candido Rivera, Angela Fleischman, Swati Goel, Mark Heaney, Casey O'Connell, Murat Arcasoy, YafengZhang, Jun Kawashima, Tomas Ganz, Carrie Baker Brachmann Abstract #4282: Presented at ASH 60th Annual Meeting & Exposition: December 14, 2018, San Diego, CA INTRODUCTIONPatients develop anemia as a result of myelofibrosis (MF) development, progression, and/or its treatment, including with ruxolitiniband other experimental Janus kinase (JAK) inhibitors1,2Momelotinib (MMB) is a JAK1/2 and Activin A receptor type I (ACVR1) inhibitor with demonstrated clinical activity for the splenomegaly and symptomatology common in MF3,4MMB also improved anemia endpoints and transfusion independence in prior clinical trials3,4JAK1/2 and ACVR1 respond to inflammation and iron stores to control iron availability through hepcidin, the key regulator of iron entry into circulationLike other inflammatory diseases, MF is characterized by high hepcidin. MMB inhibited ACVR1 to modulate hepcidin, increase hemoglobin and ameliorate anemia in a rodent modelIn this translational biology study, we determined the impact of MMB on plasma hepcidin, markers of iron storage and availability, erythropoiesis, and inflammation to explore mechanisms of the favorable effects of MMB on MFassociated anemia and transfusion independence OBJECTIVESPrimary objective: determine the transfusion independence response rate for transfusiondependent (TD) subjects with MF treated with MMBSecondary objectives: Evaluate baseline levels and changes in markers of iron metabolismAssess inhibition of JAK1/2Evaluate MMB pharmacokinetics in TD subjects with MF CONCLUSIONSFigure 2. Level of A) iron, B) reticulocytes, C) hemoglobin, and D) platelets by TIR and TINR subgroupsAdverse events (AEs, Table 5) were consistent with previous studies of MMB in MFTable 5. Summary of treatmentemergent AEs and deaths N=41AE category, n (%)Any AE all; [Related to MMB]39 (95.1); [22 (53.7)]Grade 3 or 4 all; [Related to MMB]20 (48.8); [9 (22.0)]Serious AE all; [Related to MMB]14 (34.1); [2 (4.9)]AE leading to dose modification/interruption10 (24.4)AE leading to study drug discontinuation6 (14.6)Death from any cause, n (%)3 (7.3)AE occurring in ≥15% of patients, n (%); any causalityCough12 (29.3)Diarrhea10 (24.4)Nausea9 (22.0)Fatigue8 (19.5)Dizziness7 (17.1)Pruritus7 (17.1)Thrombocytopenia7 (17.1)Vomiting7 (17.1)Grade ≥3 AEs occurring in ≥5% of patients, n (%); [Related to MMB]Anemia5 (12.2); [0 (0.0)]Neutropenia5 (12.2); [4 (9.8)]Thrombocytopenia3 (7.3); [3 (7.3)] MMB treatment elicited a significant rate of transfusion independence in this advanced, TD population (34.1% for ≥12 weeks and 39.0% for ≥8 weeks) These findings were consistent with the optimized and differentiated activity of MMB against JAK1, JAK2, ACVR1 leading to decreased plasma hepcidin, improved iron homeostasis and increased erythropoiesisIn this exploratory study, TIR was associated with reduced inflammation, lower hepcidin, and improved erythropoiesis and bone marrow function at BaselineAnemia benefit may also have been observed in TIresponders where decreased transfusion requirements were evident in most patients versus BaselineRates of TIR were similar to those for TD MF patients in other MMB trialsSafety was consistent with previous studies of MMB in MFOverall, the study suggests that modulation of hepcidin by MMB is sufficient to boost erythropoiesis, particularly in MF patients with lower baseline inflammation and greater erythropoietic potential. MMB’s net anemia benefit differentiates it from other JAK inhibitorsIn this exploratory study, TIR was associated with lower baseline hepcidin, liver iron SPONSORSHIPThis study was funded by Gilead Sciences, Inc (NASDAQ: GILD). Sierra Oncology Inc. (NASDAQ: SRRA) acquired MMB in August 2018 and is now the compound sponsor. VariableComparisonOdds ratio (90% CI)valueBaseline hemoglobin≥8 g/vs 8 g/27.96 (2.04, 383.32)0.036Predose morning hepcidin≥median vs