Background
Phase 3, double-blind, randomized, controlled trial. 195 patients with JAK-inhibitor-exposed, symptomatic, anemic (Hgb <10 g/dL or RBC transfusion-dependent), intermediate- or high-risk MF. Randomized 2:1. Momelotinib uniquely inhibits JAK1, JAK2, AND ACVR1 (activin A receptor type 1/ALK2): ACVR1 inhibition suppresses hepcidin production, reducing iron-restricted erythropoiesis and improving anemia. 107 sites across 21 countries.
Interventions and follow up
Arm A: Momelotinib 200 mg orally once daily + danazol placebo (n=130)
Arm B: Danazol 300 mg orally twice daily + momelotinib placebo (n=65)
Primary endpoint: TSS response rate at week 24 (≥50% reduction in mean MFSAF TSS over 28 days before week 24)
Median follow up: 24 weeks (randomized period)
Arm B: Danazol 300 mg orally twice daily + momelotinib placebo (n=65)
Primary endpoint: TSS response rate at week 24 (≥50% reduction in mean MFSAF TSS over 28 days before week 24)
Median follow up: 24 weeks (randomized period)
Results
TSS response rate at week 24: 25% (32/130) vs 9% (6/65), proportion difference 16% (95% CI 6–26), P=.0095
Spleen volume reduction ≥35%: Met (secondary endpoint), favoring momelotinib
Transfusion independence rate: Improved with momelotinib (secondary endpoint)
Spleen volume reduction ≥35%: Met (secondary endpoint), favoring momelotinib
Transfusion independence rate: Improved with momelotinib (secondary endpoint)
Adverse events
Hematologic (grade ≥3): Anemia 61% (momelotinib) vs 75% (danazol); thrombocytopenia 28% vs 26%
Non-hematologic (grade ≥3): Acute kidney injury 3% vs 9%; pneumonia 2% vs 9%. Overall hematologic toxicity was lower and non-hematologic toxicity comparable or better with momelotinib
Non-hematologic (grade ≥3): Acute kidney injury 3% vs 9%; pneumonia 2% vs 9%. Overall hematologic toxicity was lower and non-hematologic toxicity comparable or better with momelotinib
Conclusions
Momelotinib significantly improved symptom burden, spleen volume, and transfusion independence compared with danazol in JAK-inhibitor-exposed, anemic MF patients. The simultaneous improvement in symptoms, spleen, and anemia — three key disease dimensions — distinguishes momelotinib from other JAK inhibitors that do not meaningfully address anemia.
Key Limitations
Danazol is a weak active comparator (not standard of care), making the benefit hard to quantify versus placebo or other JAK inhibitors. The spleen and transfusion endpoints were secondary; the trial was powered only for TSS. Absolute TSS response rate of 25% is modest in a heavily pre-treated, symptomatic population. OS benefit was not demonstrated. ACVR1 inhibition and its relationship to the BMP/hepcidin pathway requires further characterization for long-term iron homeostasis effects.
Clinical Context
MOMENTUM supported FDA approval of momelotinib (Ojjaara) in September 2023 for intermediate- or high-risk MF with anemia, positioning it as the preferred agent when anemia management is a primary treatment goal. Momelotinib's ACVR1/JAK1/2 triple inhibition defines a mechanistically distinct niche among MF JAK inhibitors. It is used post-ruxolitinib or as first-line when significant anemia is present. ESMO guidance positions JAK inhibitors as standard for symptomatic intermediate/high-risk MF. Head-to-head data versus other JAK inhibitors are limited.