Momelotinib — Drug Monograph

Brand names: Ojjaara

Drug class: Other

Mechanism of Action

JAK1/2 and ACVR1 (activin A receptor type 1, also known as ALK2) inhibitor. JAK1/2 inhibition reduces splenomegaly and constitutional symptoms in myelofibrosis. Crucially, ACVR1 inhibition suppresses hepcidin production by blocking SMAD1/5/8 signaling in hepatocytes, increasing iron availability for erythropoiesis and directly improving anemia — a mechanism unique among approved JAK inhibitors (ruxolitinib and fedratinib worsen anemia). This addresses the hallmark problem of myelofibrosis-associated anemia.

FDA Indications

• Intermediate- or high-risk myelofibrosis (primary or post-PV/ET) with anemia, in patients who have been treated with a JAK inhibitor (FDA approved September 2023; MOMENTUM trial: superior total symptom score improvement and transfusion independence vs danazol at 24 weeks)

Common Side Effects

• Thrombocytopenia (22%)
• Diarrhea (18%)
• Nausea (17%)
• Fatigue (16%)
• Peripheral neuropathy (15%)
• Dizziness (13%)
• Abdominal pain
• Increased ALT/AST

Clinical Pearl

Momelotinib is the only JAK inhibitor that addresses myelofibrosis-associated anemia through ACVR1 inhibition, making it the preferred choice for myelofibrosis patients with significant anemia who require a JAK inhibitor. Unlike ruxolitinib (which causes or worsens anemia due to JAK2 inhibition of erythropoietin signaling), momelotinib can reduce transfusion requirements while controlling splenomegaly and symptoms.

Related Therapies & Mechanisms

• Arsenic Trioxide (Trisenox) — Other · Leukemia
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• Enasidenib (Idhifa) — Other · Leukemia
• Glasdegib (Daurismo) — Other · Leukemia