Momelotinib Versus Ruxolitinib in Subjects With Myelofibrosis (Simplify 1)

• Response rate in total symptom score at Week 24 [ Time Frame: Week 24 ]
  Total symptom score (TSS) is defined as the proportion of participants who achieve a ≥ 50% reduction in TSS from baseline to Week 24 as measured by the modified Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPNSAF TSS) v2.0 diary.
• Rate of red blood cell (RBC) transfusion through Week 24 [ Time Frame: Baseline to Week 24 ]
  Rate of RBC transfusion is defined as the average number of RBC units per participant per month.
• RBC transfusion independence rate at Week 24 [ Time Frame: Week 24 ]
  RBC transfusion independence is the proportion of participants who are transfusion independent at Week 24, defined as absence of RBC transfusions and no hemoglobin level below 8 g/dL in the prior 12 weeks.
• RBC transfusion dependence rate at Week 24 [ Time Frame: Week 24 ]
  RBC transfusion dependence is the proportion of participants who are transfusion dependent at Week 24, defined as at least 4 units of RBC transfusions, or a hemoglobin level below 8 g/dL in the prior 8 weeks.

• Rate of red blood cell (RBC) transfusion through Week 24 [ Time Frame: Baseline to Week 24 ]
  Rate of RBC transfusion is defined as the average number of RBC units per participant per month.
• RBC transfusion independence rate at Week 24 [ Time Frame: Week 24 ]
  RBC transfusion independence is the proportion of participants who are transfusion independent at Week 24, defined as absence of RBC transfusions and no hemoglobin level below 8 g/dL in the prior 12 weeks.
• RBC transfusion dependence rate at Week 24 [ Time Frame: Week 24 ]
  RBC transfusion dependence is the proportion of participants who are transfusion dependent at Week 24, defined as at least 4 units of RBC transfusions, or a hemoglobin level below 8 g/dL in the prior 8 weeks.
• Response rate in total symptom score at Week 24 [ Time Frame: Week 24 ]
  Total symptom score (TSS) is defined as the proportion of participants who achieve a ≥ 50% reduction in TSS from baseline to Week 24 as measured by the modified Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPNSAF TSS) v2.0 diary.

This study is to determine the efficacy of momelotinib (MMB) versus ruxolitinib in participants with primary myelofibrosis (PMF) or post-polycythemia vera or post-essential thrombocythemia myelofibrosis (post-PV/ET MF) who have not yet received treatment with a Janus kinase inhibitor (JAK inhibitor).

Participants will be randomized to receive either MMB or ruxolitinib for 24 weeks during a double-blind treatment phase, after which they will be eligible to receive open-label MMB for up to an additional 168 weeks. After discontinuation of study medication, assessments will continue for 12 additional weeks, after which participants will be contacted for survival follow-up approximately every 6 months for up to 5 years from the date of enrollment.

• Primary Myelofibrosis
• Post-Polycythemia Vera Myelofibrosis
• Post-Essential Thrombocythemia Myelofibrosis

• Drug: Momelotinib
  Momelotinib tablet administered orally once daily
  Other Names:

  • GS-0387
  • CYT387
• Drug: Ruxolitinib
  Ruxolitinib tablets administered orally twice daily
• Drug: Placebo to match momelotinib
  Placebo to match momelotinib tablets administered orally once daily
• Drug: Placebo to match ruxolitinib
  Placebo to match ruxolitinib tablets administered orally twice daily

• Experimental: Momelotinib
  Participants will receive momelotinib plus placebo to match ruxolitinib.
  Interventions:

  • Drug: Momelotinib
  • Drug: Placebo to match ruxolitinib
• Active Comparator: Ruxolitinib
  Participants will receive ruxolitinib plus placebo to match momelotinib.
  Interventions:

  • Drug: Ruxolitinib
  • Drug: Placebo to match momelotinib

Key Inclusion Criteria:

• Palpable splenomegaly at least 5 cm below the left costal margin
• Confirmed diagnosis of PMF or post-PV/ET MF
• Requires myelofibrosis therapy, in the opinion of the investigator
• Classified as high risk OR intermediate-2 risk as defined by the International Prognostic Scoring System (IPSS) for PMF, or intermediate-1 risk (IPSS) associated with symptomatic splenomegaly, hepatomegaly, anemia (hemoglobin < 10.0 g/dL), and/or unresponsive to available therapy

• Acceptable laboratory assessment obtained within 14 days prior to the first dose of study drug:

  • Absolute neutrophil count (ANC) ≥ 0.75 x 10^9/L in the absence of growth factor in the prior 7 days
  • Platelet Count ≥ 50 x 10^9/L (≥ 100 x 10^9/L if aspartate aminotransferase [AST] or alanine aminotransferase [ALT] is ≥ 2 x the upper limit of the normal range [ULN]) in the absence of platelet transfusion(s) or thrombopoietin mimetics in the prior 7 days
  • Peripheral blood blast count < 10%
  • AST and ALT ≤ 3 x ULN (≤ 5 x ULN if liver is involved by extramedullary hematopoiesis as judged by the investigator or if related to iron chelator therapy that was started within the prior 60 days)
  • Calculated creatinine clearance (CrCL) of ≥ 45 mL/min
  • Direct bilirubin ≤ 2.0 x ULN
• Life expectancy of > 24 weeks
• Males and females of childbearing potential must agree to use protocol-specified method(s) of contraception
• Females who are nursing must agree to discontinue nursing before the first dose of study drug
• Able to understand and willing to sign the informed consent form

Key Exclusion Criteria:

• Prior splenectomy
• Splenic irradiation within 3 months prior to the first dose of study drug
• Eligible for allogeneic bone marrow or stem cell transplantation
• Uncontrolled inter-current illness, per protocol.
• Known positive status for human immunodeficiency virus (HIV)
• Chronic active or acute viral hepatitis A, B, or C infection, or a hepatitis B or C carrier
• Prior use of a JAK1 or JAK2 inhibitor
• Use of chemotherapy, immunomodulating therapy, biologic therapy, radiation therapy, or investigational therapy within 4 weeks of the first dose of study drug
• Presence of peripheral neuropathy ≥ Common Terminology Criteria for Adverse Events (CTCAE) Grade 2
• Unwilling or unable to undergo a magnetic resonance imaging (MRI) or computed tomography (CT) scan

Note: Other protocol defined Inclusion/Exclusion criteria may apply.