This study is to determine the efficacy of momelotinib (MMB) versus best available therapy (BAT) in anemic or thrombocytopenic adults with primary myelofibrosis (PMF), or post-polycythemia vera or post-essential thrombocythemia myelofibrosis (Post-PV/ET MF) who were treated with ruxolitinib as measured by splenic response rate at Week 24 (SRR24).

Participants will be randomized to receive either MMB or BAT for 24 weeks during the randomized treatment phase, after which they will be eligible to receive MMB in an extended treatment phase for up to an additional 204 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 subjects planning to continue treatment with MMB following the end of the study, the End of Treatment, 30-day, 12-Week, and survival follow-up visits are not required.

Key Inclusion Criteria:

• Palpable splenomegaly at least 5 cm below left costal margin

• Confirmed diagnosis of PMF in accordance, or Post-PV/ET MF

• Currently or previously treated with ruxolitinib for PMF or Post-PV/ET MF for at least 28 days, and characterized by

  • Requirement for RBC transfusion while on ruxolitinib treatment, OR

  • Dose adjustment of ruxolitinib to < 20 mg twice daily at start of or during ruxolitinib treatment AND at least one of the following while on ruxolitinib treatment:

    • ≥ Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 thrombocytopenia, OR
    • ≥ CTCAE Grade 3 anemia, OR
    • ≥ CTCAE Grade 3 hematoma (bleed)

• High risk OR intermediate-2 risk as defined by Dynamic International Prognostic Scoring System (DIPSS), OR intermediate-1 risk as defined by DIPSS and associated with symptomatic splenomegaly, and/or hepatomegaly

• If receiving myelofibrosis therapy, must be on a stable dose of the same regimen for at least 2 weeks prior to screen date and through the screening period

• If not receiving myelofibrosis therapy, must remain off therapy for at least 2 weeks prior to screen date and through the screening period

• Acceptable laboratory assessments obtained within 14 days prior to Randomization

  • Absolute neutrophil count (ANC) > 0.75 x 10^9/L in the absence of growth factor in the prior 7 days
  • Peripheral blood blast count < 10%
  • Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x the upper limit of the normal range (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 of ≥ 45 mL/min
  • Direct bilirubin ≤ 2.0 x ULN

• Life expectancy > 24 weeks

• Negative serum pregnancy test for female subjects (unless surgically sterile or greater than two years post-menopausal)

• 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 MMB

• Able to understand and willing to sign informed consent form (ICF)

Key Exclusion Criteria:

• Prior splenectomy
• Splenic irradiation within 3 months prior to Randomization
• Use of investigational agent within 28 days prior to Randomization
• Prior treatment with MMB
• Hematopoietic growth factor (granulocyte growth factor, erythropoiesis stimulating agent, thrombopoietin mimetic) within 28 days prior to Randomization
• 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 hepatitis B or C carrier
• Presence of peripheral neuropathy ≥ CTCAE Grade 2
• Unwilling or unable to undergo a MRI or CT Scan per study protocol requirements

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