Novel Therapy in Myelofibrosis: Momelotinib

Switching their focus to myelofibrosis management, expert panelists reflect on clinical data behind momelotinib, a novel JAK2 inhibitor.


Naveen Pemmaraju, MD: It sets the stage, this exciting discussion, because now we move into myelofibrosis. Going back to Ruben, and I’ll probably ask each of you about your thoughts. This ASH [2022 American Society of Hematology Annual Meeting & Exposition] was very exciting. Ruben, if you can take us through the momelotinib agent. We have 3 approved agents, and we’ll talk about each of them, ruxolitinib, fedratinib, and pacritinib. I’ll have you talk about what we hope will be the fourth JAK [janus kinase] inhibitor, momelotinib. If you can tell us about your leadership and your work in this new JAK inhibitor, what should we know about and what to expect?

Ruben Mesa, MD: Sure. First, like all of these things, I like to say that battling against cancer or myelofibrosis, it’s a team sport. It takes a cast of thousands to put these on, but momelotinib is a JAK1 and JAK2 inhibitor, and it has a significant impact on MF [myelofibrosis]; it’s one that we’ve been studying for a long time. Like many of these agents, it’s had a variety of names and acronyms over the years, but one of the early observations of this therapy is that in addition to impacting splenomegaly and symptoms in MF, it has the potential to improve anemia, which is difficult. As someone who’s been involved with [more than] 100 different trials for [patients with] MPN [myeloproliferative neoplasm], it is much easier to drop blood counts than to increase them. As they say, in nature, it is much easier to destroy than to create, and enticing a damaged fibrotic marrow to function better is not a simple matter. There are several kind of key data sets. The most recently updated at this meeting was by our colleague, Aaron Gerds, MD: the momentum study. This was a second-line study of patients with myelofibrosis [for whom ruxolitinib didn’t work] and were heavily symptomatic, so there was a key eligibility criteria, which I thought was very cool because it reflects the difficulty that they face. They’re symptomatic, ruxolitinib [did not work], they’re anemic, and then they were [randomly assigned] between momelotinib or danazol. [You ask,] “Well, why danazol?” Because danazol is active against anemia in patients with MF. We have no approved agents for anemia in myelofibrosis, and danazol has probably been about as helpful as anything, and globally, it’s oral, it’s cheap.

We did a prior trial, John [Mascarenhas, MD,] and I, with ruxolitinib and danazol, and it has some activity. We felt very strongly that it was a reasonable comparison. Does it fix everything about the disease? No, and that highlights the gap that we have. We don’t have therapies that improve anemia, spleen, and symptoms, and hopefully impact the disease further, so with that study, we saw improvements [and it] clearly met all its primary end points. One was clearly superior to danazol for improvement in symptoms, and it was superior for improvement in spleen. In the initial part, we decided to have it be nonaffirming for danazol for anemia, because danazol is active for anemia yet it’s very close to achieving that statistical significance, even though that wasn’t the goal. The rate of achieving transfusion independence went from 13% to 31% with momelotinib and 17% to 21% with danazol. Right on that cost, but consistent improvement in all 3 parameters. What Aaron updated at this meeting is that those results were durable, in terms of spleen symptoms, anemia, transfusion, independence, no longer-term safety signal, [and] others. Other key things we presented at this meeting are related to the longer term data we have with momelotinib. First, we had the prior simplified study. That was a study where patients were [randomly assigned] to ruxolitinib or momelotinib. This was several years ago and many of us were involved with that study in a frontline setting. Momelotinib was noninferior for spleen, and at the time, we thought it was slightly inferior for symptom as we’ve done other analysis. Really, they’re probably about the same and better in terms of anemia. We did an interesting analysis that we presented at this year’s ASH that was in that study. They had been an open-label extension, so we asked patients who were on ruxolitinib and then went to momelotinib, “How did that go?” And we saw a nice increase in the hemoglobin in individuals who switched. We saw that it was safe for them to switch, and that there were many issues with dosing of ruxolitinib on the ruxolitinib arm and very stable dosing on the momelotinib arm. So kind of a mature data set now from multiple phase-free studies showing that it’s a beneficial therapy. It’ll be a helpful addition to the armamentarium, spleen, symptoms, anemia, and hopefully [it will] be approved in 2023 to be an option for our patients.

Naveen Pemmaraju, MD: Well, that’s wonderful.

Transcript edited for clarity.

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