Odyssey: A Phase 2 Open-Label Study of Momelotinib in Combination with Luspatercept in Patients with Transfusion-Dependent Myelofibrosis

Background and Significance: Anemia is a prevalent, progressive, and multifactorial clinical feature of myelofibrosis (MF) associated with negative impacts on health-related quality of life, survival, and healthcare resource utilization. Red blood cell (RBC) transfusions are frequently used to manage anemia, with nearly 50% of patients with primary MF becoming transfusion dependent (TD) by 1 year after diagnosis. Momelotinib is a JAK1/JAK2/ACVR1 inhibitor approved for the treatment of adult patients with intermediate- or high-risk MF who have anemia. Across 3 phase 3 trials in MF, momelotinib provided spleen, symptom, and anemia-related benefits, the last of which is linked to its inhibition of ACVR1. While most patients derive some anemia-related benefit from momelotinib, including >50% of patients in both the JAK inhibitor-naive and -experienced settings who were transfusion independent (TI) by week 24 (Gale criteria) in the phase 3 SIMPLIFY trials (Klencke B, et al. Future Oncol. 2024), it is hypothesized that deeper reductions in transfusion burden in more patients may be achieved through combination with an additional anemia-directed therapy. Luspatercept, approved for the treatment of anemia in β-thalassemia and lower-risk myelodysplastic syndromes, is thought to improve anemia by promoting late-stage RBC maturation through sequestration of TGF-β superfamily ligands. In combination with the JAK inhibitor ruxolitinib, luspatercept was associated with anemia improvements in a phase 2 trial of JAK inhibitor-experienced patients with TD MF (TI by week 24 [Gale criteria], 26.3% [Gerds A, et al. Blood Adv. 2024]); the ongoing phase 3 INDEPENDENCE trial is investigating luspatercept in patients with MF who are receiving a stable dose of a JAK2 inhibitor and require RBC transfusions. The complementary mechanisms of action of momelotinib and luspatercept may provide anemia improvement for patients with TD MF by promoting both early- and late-stage erythropoiesis, while also damping inflammation and impacting various disease manifestations of TD MF; this combination will be evaluated in the phase 2 trial described here. Study Design and Methods: ODYSSEY is an open-label, multicenter, global, phase 2 study of patients aged ≥18 years with TD (≥4 units transfused or a hemoglobin of <8 g/dL in the 8 weeks before enrollment) primary or secondary MF and intermediate-1-, intermediate-2-, or high-risk disease per DIPSS/DIPSS-plus. Patients may be JAK inhibitor naive (cohort 1; approximate n=28) or experienced (cohort 2; approximate n=28); previous or current ruxolitinib or fedratinib use is permitted in cohort 2, and all other MF-directed therapy must be discontinued ≥28 days before enrollment in both cohorts. Exclusion criteria include platelet counts of <50×109/L; prior treatment with any ACVR1 inhibitor, luspatercept, or sotatercept; history of gastrointestinal disease likely to alter absorption of momelotinib; clinically significant anemia due to mechanisms other than MF; uncontrolled infections, bleeding, acute/chronic liver disease, or hypertension; stroke or other thromboembolic events in the prior 6 months; and grade ≥2 peripheral neuropathy. Patients will receive momelotinib 200 mg orally once daily plus a starting dose of luspatercept 1 mg/kg subcutaneously every 3 weeks through week 24. In the absence of safety concerns, luspatercept may be titrated to 1.33 mg/kg and up to a maximum of 1.75 mg/kg. Patients may discontinue treatment at any time due to disease progression, death, unacceptable toxicity, or withdrawal of consent. Safety follow-up will continue for 42 days following the last dose of study treatment. The primary endpoint is TI rate by week 24 (no RBC transfusions for any ≥12-week period through the end of week 24). Secondary endpoints include safety and tolerability, plasma concentrations of momelotinib and its major metabolite, and TI rate at week 24 (no RBC transfusions and no hemoglobin of <8 g/dL for ≥12 weeks immediately preceding week 24). Exploratory endpoints include assessments of symptoms and quality of life, additional measures of anemia-related benefit and pharmacokinetics, spleen size reduction, and peripheral blood-based biomarkers including iron metabolism and inflammatory cytokines. All analyses will be descriptive. ODYSSEY is registered at ClinicalTrials.gov(NCT06517875) and will begin enrolling in late 2024.

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