This study is to determine the efficacy of momelotinib (MMB) versus ruxolitinib (RUX) 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 216 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 or until study termination. For those participants planning to continue treatment with MMB following the end of the study, the Early Study Drug Discontinuation (ESDD), 30-day, 12-Week, and survival follow-up visits are not required.

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.