EHA 2025 | Momelotinib in the treatment of myelofibrosis: pivotal Phase III trials

Yes, so first of all I give the credit for the alliteration or the clever use of alliteration in the title to my co-author Pankit Vachani. So like you said, a tale of trials, tribulations, transfusion, independence and triumph. So you know, again as our audience knows, momelotinib is the latest of the four commercially available JAK inhibitors to hit the market. It was approved in the U.S. in September 2023 and then subsequently in the EU fairly soon thereafter. So, momelotinib is a unique drug. It’s a JAK1 and JAK2 inhibitor like ruxolitinib, but we know that it improves anemia and does a really good job at that. And that, we feel, is because of its inhibition of ACVR1, also known as ALK2. And when you inhibit ACVR1, you downregulate hepcidin. And doing so means that iron is more freely available for erythropoiesis because hepcidin blocks the absorption of iron and also sequesters it away in the reticuloendothelial system. So more of it is available and that helps the hemoglobin. So that’s the theoretical consideration there. Now in terms of data, really quick, three large phase three trials, Simplify 1, Simplify 2 and Momentum. Simplify 1 was a head-to-head against ruxolitinib, where momelotinib was non-inferior for spleen but not so for symptoms. The anemia endpoints all favored momelotinib. Simplify 2 was in the post-ruxolitinib setting and momelotinib was compared to BAT, but BAT was mostly ruxolitinib. So it was almost like momelotinib versus ruxolitinib all over again in a second-line setting post-ruxolitinib. And there was no washout. So patients went straight on to momelotinib from ruxolitinib or just continued ruxolitinib. We think for all these reasons this was a negative trial in the sense that the primary endpoint of spleen superiority was not met. And because of that the statistical significance could not be claimed for the other endpoints which were hierarchically tested like symptoms, anemia, etc. Although of note, momelotinib was better for all of those things, not for spleen, but for symptoms and all the anemia-related endpoints. That brings us to Momentum, the most recent trial that was published in the Lancet in 2023. Now, Momentum took patients who were JAK inhibitor exposed and either gave them momelotinib or danazol in a two-to-one randomized fashion. All patients had to be anemic and symptomatic. So this trial was a little bit different in the sense that the primary endpoint was symptoms, not spleen. And then everything else that you would normally look for in an MF trial, like spleen and transfusion independence and number of units transfused, all those things were secondary endpoints. So Momentum met all its endpoints. It met the primary endpoint of superior symptom control with momelotinib over danazol. Spleen was superior as well. Now, important to mention, because danazol is an active control for anemia, that particular comparison for transfusion independence was a non-inferiority comparison. And that was in favor of momelotinib as well. As well as were several other anemia parameters like rate of zero units transfused and things like that. So, Momentum was a universally positive trial. One interesting sub-analysis of Momentum showed us that even in patients with low platelets, momentum went down as low as 25 for eligibility. So even in patients with 25 to 100 platelets, momelotinib maintained its superiority against danazol. And also strikingly, once the crossover occurred after the 24-week time point, you could see the danazol patients who crossed over to momelotinib, you know, improving and approaching the momelotinib graph on the Kaplan-Meier, you know, in terms of their responses, especially for anemia.

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