Current and Future Trends in Myeloproliferative Neoplasms - Episode 12
Ruben Mesa, MD, discusses updates on the novel agent momelotinib from an abstract he presented at ASCO 2022.
Rami Komrokji, MD: Now we can move to an even more exciting area in which we’ll hopefully have more clinical trials to bring to our patients in the near future. Let’s talk about another JAK2 inhibitor that has a unique niche: momelotinib. Dr Mesa presented that at ASCO [American Society of Clinical Oncology Annual Meeting] this year, and I’d like him to give us the update on momelotinib. Where is it going to fit in our treatment for our patients?
Ruben Mesa, MD: Momelotinib has a very interesting history, and it will become our fourth approved JAK inhibitor for patients with myelofibrosis. We’ve learned a lot more about each of these drugs over their long arc. Momelotinib was first tested in the SIMPLIFY-1 and SIMPLIFY-2 studies. It’s a JAK1 and JAK2 inhibitor that we had noticed early on could help improve anemia. Just as we had learned early on that pacritinib may have less thrombocytopenia, momelotinib had something different. It might help to improve anemia and have less drug-emergent anemia.
There were prior studies, SIMPLIFY-1, front line vs ruxolitinib, that showed that it wasn’t inferior for splenomegaly, and slightly inferior for symptoms. If we look at that analysis now, not inferior probably would have been more accurate. But without question, it was better for anemia. There was an analysis. Jeanne and I participated in this multicenter analysis looking at mechanism. Why was it getting better? It seemed that the anemia improved because hepcidin was being suppressed. We’ve previously talked about ramping up hepcidin in PV [polycythemia vera] to create anemia. Here, let’s suppress hepcidin and decrease that inflammation, that anemia chronic disease. It might help improve anemia. It ended up being through an additional inhibition that the drug accomplishes through ACVR1.
Rami Komrokji, MD: TGF-β.
Ruben Mesa, MD: The SIMPLIFY-1 study was front line, and SIMPLIFY-2 was second line. It was positive, but the data were a little muddy. The control arm was the best alternative therapy in ruxolitinib failures, but because there were so few options, almost everybody in the control arm were on ruxolitinib, so it was a little muddy. We created the MOMENTUM study to have a very specific additional set of data that we thought were critical: second-line, symptomatic, and anemic patients who failed ruxolitinib, and with a control arm that we think was arguably demonstrating that we don’t have a lot as it relates to anemia. But we do have danazol, an androgen.
When I was at Mayo Clinic in Arizona, we did trials adding danazol to ruxolitinib. It has some activity, so they’d be randomized to danazol or momelotinib, momelotinib in a 2:1 randomization. I presented at this year’s ASCO that it was a very positive study. It was a study led by Srdan Verstovsek and me. It was very international in scope, had 195 patients, and it met all its key end points. First, it was clearly superior for control of symptoms compared with danazol. It wasn’t even close. Second, it was clearly superior for reduction of splenomegaly, whether you look at 35% volume reduction or what we think is a bit probably more fair, 25% volume reduction in the second line. You have a 35% volume reduction. The number was a very arbitrary number. We’ve recognized over time that a 10% reduction or more is probably linked to improvement in survival, so it’s probably overly strict. It’s clear in both of those.
Finally, in anemia, noninferiority was the goal. Danazol is active in anemia. It was very close to being significantly superior, but at least we’re at that end point of being noninferior. It went from 13% to 31% transfusion independent in the momelotinib arm. Danazol has some activity. It went from 15% to 20%. If we had more numbers, more power, it would be clearly better. We also saw that if we looked at it from a variety of ways—including not requiring any transfusions—it was clearly superior for the momelotinib arm vs the danazol arm. The safety was good. It was well tolerated. We were able to walk away with a positive study, with an improvement in splenomegaly, symptoms, and anemia.
What does it mean? When we look at the experience of momelotinib in aggregate, it clearly paints a picture of a drug that would be very helpful to have in myelofibrosis. Here are specific data in the second-line setting, particularly in the setting of anemia. SIMPLIFY-1 was helpful, particularly in terms of anemia in the frontline setting. There will be a lot of discussion at the NCCN [National Comprehensive Cancer Network] regarding how each of these fits. Is the anemia in everyone? It will have roles in some patients in the front line and clearly some patients in the second line. It will make a significant addition to the armamentarium if the drug is approved after all these data are reviewed by the FDA.
Transcript edited for clarity.