Potential Role of Momelotinib in Myelofibrosis

EP: 1.Overview of Myelofibrosis Types and Presentations

EP: 2.Myelofibrosis: Molecular Pathways and Prognostic Factors

EP: 3.Approved Therapies for Myelofibrosis

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EP: 4.Potential Role of Momelotinib in Myelofibrosis

EP: 5.Treatment Sequencing Considerations in Myelofibrosis

EP: 6.Emerging Research in Myelofibrosis Treatment

EP: 7.Closing Remarks on the Future Treatment Landscape of Myelofibrosis

Transcript:

Aaron Gerds, MD, MS: In our armamentarium of approved drugs to treat myelofibrosis, we already have ruxolitinib [Jakafi], fedratinib [Inrebic], and pacritinib [Vonjo]. On the horizon is a drug called momelotinib. The MOMENTUM study is a prospective randomized trial of momelotinib vs danazol in patients with previously treated myelofibrosis who are anemic and have a significant symptom burden. This study aims to show that momelotinib is an effective agent in this population.

There have been 2 prior randomized controlled phase 3 trials, the SIMPLIFY-1 and SIMPLIFY-2 trial, but these trials prove to be challenging to get consistent results primarily because of trial design. MOMENTUM is kind of a refocusing of efforts on this very active agent in myelofibrosis. The reason there’s keen interest in momelotinib is because it is a JAK [Janus kinase] inhibitor like the others that I mentioned. It does have an effect on JAK1 and JAK2 but it also has an effect on these ACVR1 or ALK2 molecules. Again, ALK2 and ACVR1 are key regulators of hepcidin, hepcidin being the master iron regulator in the body. In anemia of chronic disease or anemia of inflammation, hepcidin levels are elevated, and by inhibiting this, we can potentially improve anemia due to inflammation, which is a key component and contributor to anemia in myelofibrosis patients.

In earlier studies, we noticed that patients treated with momelotinib often had improvements in their anemia and became transfusion-independent. In fact, there was a prospective phase 2 trial where 40% of transfusion-dependent patients became transfusion-independent. This study also showed some of the background mechanisms for why momelotinib might do this. This was published by Steve Oh [MD, PhD, Washington University School of Medicine, St. Louis, MO] in Blood Advances a few years ago.

The MOMENTUM study was conducted and has finished enrolling patients, and the primary results were presented at a prior oncologic congress. In that presentation at week 24, it showed that momelotinib was better at shrinking spleens and improving symptom burdens compared with danazol and was not inferior to danazol in terms of anemia responses, particularly transfusion independence.

At this year’s 2022 ASH [American Society of Hematology] annual meeting, we also presented an updated result of the 48-week observation period. For the first 24 weeks of the study, patients were blinded, as well as the investigators. At week 24 or earlier, if there were disease progression, patients were allowed to cross over to open-label momelotinib. At this year’s annual meeting, we presented the data from week 24 through week 48, the open-label period. The ultimate key points from that analysis were patients who had responses on momelotinib at week 24 maintained them through week 48, so responses were durable, whether we’re talking spleen volume response, symptom response, or transfusion-independence response. There were actually a few patients on momelotinib at week 24 who were not symptom-burden responders, but with additional treatment did get symptom responses. Perhaps a longer duration of therapy may be important for these patients.

Secondly, we saw that patients who crossed over from danazol to momelotinib did have an improvement in symptom burden, spleen volume responses, and even continued anemia improvements. The crossover patients benefited equally as much as the patients who were originally treated on momelotinib in the study. There were additional abstracts presented, one showing that patients who have anemia responses on momelotinib have better than anticipated survivals, to really try and bring together this whole story. We know that anemia is an adverse prognostic marker in myelofibrosis. Now we have therapies that can improve anemia. And by improving anemia, can we ultimately improve survival? Again, bringing that story full circle. That’s really kind of a focus of where momelotinib is going.

Transcript edited for clarity.