What is momelotinib (Janus Kinase (JAK) inhibitor)?

Momelotinib: A JAK1/2 and ACVR1 Inhibitor for Myelofibrosis

Momelotinib is a novel JAK1/2 and ACVR1 inhibitor specifically approved for patients with myelofibrosis with anemia, offering the unique ability to improve splenomegaly, constitutional symptoms, and anemia simultaneously. 1

Mechanism of Action

Momelotinib works through dual inhibitory mechanisms:

1. JAK1/2 Inhibition:

   • Inhibits wild-type Janus Kinase 1 and 2 (JAK1/JAK2) and mutant JAK2V617F
   • Blocks dysregulated JAK-STAT signaling that contributes to inflammation and symptoms in myelofibrosis 2
   • Reduces splenomegaly and constitutional symptoms

2. ACVR1 (ALK2) Inhibition:

   • Uniquely inhibits activin A receptor type 1 (ACVR1), also known as ALK2
   • Suppresses liver hepcidin expression
   • Increases iron availability for erythropoiesis
   • Improves anemia and reduces transfusion dependence 2, 1

Clinical Benefits

Momelotinib demonstrates three key clinical benefits in myelofibrosis patients:

• Spleen Response: Achieves ≥35% reduction in spleen volume in approximately 45-50% of JAK inhibitor-naïve patients 3
• Symptom Improvement: Reduces total symptom score by ≥50% in approximately 33% of patients 3
• Anemia Benefit: Uniquely improves anemia and reduces transfusion requirements compared to other JAK inhibitors 4, 3

Pharmacokinetics

• Dosing: Recommended dose is 200 mg orally once daily 1
• Absorption: Median time to peak concentration is 2 hours 2
• Metabolism: Primarily metabolized by multiple CYP enzymes (CYP3A4 36%, CYP2C8 19%, CYP2C9 17%, CYP2C19 19%, CYP1A2 9%) 2
• Active Metabolite: M21 is an active metabolite with approximately 40% of the pharmacological activity of the parent compound 2, 5
• Elimination: Half-life of 4-8 hours; 69% excreted in feces, 28% in urine 2
• Food Effect: No clinically significant effect with food intake 2, 6

Safety Profile

Based on pooled data from three randomized phase 3 trials:

• Most common adverse events (≥20%):

  • Diarrhea (27%, grade ≥3: 3%)
  • Thrombocytopenia (25%)
  • Anemia (23%)
  • Neutropenia (7%) 4

• Peripheral neuropathy is a notable adverse effect requiring monitoring 7

• Long-term safety analysis shows no increase in adverse events of clinical importance (infections, malignant transformation, peripheral neuropathy, hemorrhage) over time 4

Clinical Development History

Momelotinib has been evaluated in multiple clinical trials:

• MOMENTUM: Trial in JAK inhibitor-experienced patients
• SIMPLIFY-1: Head-to-head comparison with ruxolitinib in JAK inhibitor-naïve patients
• SIMPLIFY-2: Comparison with best available therapy in JAK inhibitor-experienced patients 4

Clinical Considerations

• Patient Selection: Most appropriate for myelofibrosis patients with anemia, where other JAK inhibitors might worsen anemia 1
• Monitoring: Regular monitoring for thrombocytopenia (most common reason for discontinuation at 4%) 4
• Drug Interactions:
  • OATP1B1/1B3 inhibitors may increase momelotinib exposure
  • Momelotinib may increase exposure of BCRP substrates like rosuvastatin 2
  • No clinically significant interactions with strong CYP3A4 inducers/inhibitors 2

Advantages Over Other JAK Inhibitors

Unlike ruxolitinib and fedratinib which can exacerbate myelofibrosis-related anemia, momelotinib's unique ACVR1 inhibition allows it to improve anemia while also addressing splenomegaly and constitutional symptoms 1, making it particularly valuable for patients with myelofibrosis who have anemia or are transfusion-dependent.