ASH 2025 | Early analysis of ODYSSEY: momelotinib plus luspatercept in transfusion-dependent myelofibrosis

ODYSSEY is a very common sense, practically useful trial of momelotinib plus luspatercept for patients with myelofibrosis and anemia. And in this case, the anemia has to be either less than 8 grams per deciliter of hemoglobin or transfusion-dependent patients. So this is obviously a combination of two drugs that are both on the market, momelotinib for myelofibrosis with anemia and luspatercept for MDS, lower-risk with anemia. So physicians and patients are familiar with both agents and it makes sense to combine them. One, because they both have excellent tolerability profiles and they could add to each other’s efficacy. But also mechanistically, the way momelotinib works through ACVR1/ALK2 inhibition and downregulation of hepcidin, it ultimately impacts SMAD4 and 5 signaling. Whereas luspatercept, being an activin-receptor ligand trap, it sequesters the ligands that bind to the activin-receptor and then sort of repress terminal erythropoiesis. So we call luspatercept an erythroid maturation agent, and that impacts signaling through SMAD2 and 3. So they’re kind of complementary. Additive is what you would expect. So this trial was designed for 56 patients total, 28 in each arm, JAK inhibitor naive or JAK inhibitor exposed. Like I said, transfusion dependent or hemoglobin less than 8. So the results that we have at ASH are still early and we are clearly seeing activity. The study is enrolling ahead of schedule, so that’s very exciting. And yes, the combination has been well tolerated as you would expect from these individual drugs’ safety profiles and clearly seem to be benefiting in terms of anemia.

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