Momelotinib: Update On MOMENTUM Trial Dr. Gerds ASH 2022

Momelotinib: Update On MOMENTUM Trial Dr. Gerds ASH 2022

By Aaron Gerds, MD

What is the difference between the Momelotinib arm and the Danazol arm of the trial? It’s a great question, and Momelotinib has been around for a while. It is a JAK inhibitor primarily and was tested in two large randomized phase 3 trials. The SIMPLIFY-1 and 2, and both of those studies did not reach their primary endpoints, largely due to poor trial design. And ultimately, when the compound changed hands, it was sold to a couple of different companies, and now it is resurrected.

And the reason why us in the field feels so passionately about this therapeutic option is the fact that it is a JAK inhibitor, so it can shrink spleens and improve symptom burdens. But also, we’ve observed in the earlier studies improvements in some patients’ anemia. And there was a phase 2 trial that was done that kind of dug a little bit deeper into this and did some biologic correlates and really filled in the story that mechanism is due to an inhibition of a molecule called ACVR1, which is a regulator of hepcidin, hepcidin being an iron regulator in the body.

We know that people who have inflammatory anemias, like the anemia that’s due to myelofibrosis, have elevated levels of hepcidin. So if we block that upstream effect, we can thus improve anemia of inflammatory block. And it’s a very cool time in myeloproliferative neoplasms because we’re targeting hepcidin in both directions.

So with Momelotinib, we’re trying to lower hepcidin levels to improve anemia. And actually in Polycythemia Vera, we’re using drugs like Rusfertide to do the opposite, to basically act as if it were hepcidin, to lower erythrocyte production, to treat the Polycythemia Vera. So really, it’s cool that these two drugs are being developed independently, but attacking the same pathway in different ways to affect different effects for these patients.

But Momelotinib again, as I mentioned, is a drug that’s been around for a while. It’s been through a couple of large studies, and really, this MOMENTUM study, pitting Momelotinib versus Danazol is intended to be the basis for regulatory approval for this agent.

What Is the Standard of Care For Patients with Myelofibrosis?

So the standard of care for patients with myelofibrosis right now includes three approved JAK Ruxolitinib, Fedratinib, and Pacritinib. Pacritinib has limited effects on lowering (red blood cell) blood counts. Certainly we do see the worsening anemia in patients treated with Ruxolitinib and Tofacitinib. And Momelotinib being an agent that can potentially approve anemia does prove to be a very advantageous target and in concept and often with the treatment of myelofibrosis patients with myelofibrosis who already may be anemic. With a JAK inhibitor that’s approved, we may see their anemia get worse and have to add on another medication, say an ESA or Luspatercept and, or just do transfusions.

And Momelotinib is provides the opportunity where we can do both with a single oral agent, which is very exciting and I think can be an important step forward in managing MF patients with (treatment of) myelofibrosis.

What Is The Trial Design In Patients Previously Treated With JAK Inhibitor Therapy?

Yeah, so the MOMENTUM study is a prospective blinded, randomized phase 3 trial pitting, Momelotinib versus Danazol. So within the study, it’s really focusing on symptomatic patients with palpable spleen sizes (Eg. enlarged spleen). And significant disease risk factors, and the randomization is a two to one randomization between Momelotinib and Danazol.

And again, it is placebo controlled and blinded. At week 24 is the primary endpoint and the primary evaluation of the efficacy of Momelotinib versus Danazol. And then after that, there is allowance for crossover in the study. So this does have a crossover, the week 24 data has already been presented at the 2022 ASCO meeting and at the ASH annual meeting for 2022, the week 48 data will be presented.

How Was the MOMENTUM Trial Set Up For Clinical Testing?

One of the major questions we get when discussing the MOMENTUM study is why was Danazol chosen as a comparator arm? Danazol is a treatment used to treat anemia in myelofibrosis. It is recommended by both the NCCN and ELN guidelines to treat (baseline) anemia in patients with myelofibrosis. There’s a good phase 2 single-arm studies supporting its use in this population. And so thinking of Momelotinib as a anti-anemia agent it was pitted against another anti-anemia agent in Danazol.

What are the Inclusions And Exclusions of the Momelotinib Clinical Trial?

So the MOMENTUM study included patients with Myelofibrosis who were previously treated with a JAK inhibitor. They had to be symptomatic with a total symptom score of greater than or equal to 10. They had to be anemic with a hemoglobin levels less than 10 and have platelet counts greater than 25,000.

Patients were stratified by symptom score, palpable spleen lake and prior transfusions in the 8 weeks leading into the study, as well as by study site. So there was some stratification for these patients.

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5 Key Takeaways from the MOMENTUM Clinical Trial

1. MOMENTUM is a randomized study, double-blind, active-control (arm) Phase 3 trial designed to confirm the differential clinical benefits of momelotinib (MMB) versus danazol (DAN) in symptomatic and anemic myelofibrosis patients who have previously received an approved Janus kinase inhibitor (medications called JAK inhibitors (JAKi)) therapy for myelofibrosis (MF).

2. At screening, participants must be symptomatic with an MFSAF v4.0 Total Symptom Score 10 and anemic with Hgb 10 g/dL (red blood cell).

3. Subjects will be randomly assigned to receive either MMB plus placebo or DAN plus placebo, both self-administered orally.

4. Subjects randomized to receive MMB who complete the randomized treatment period to the end of Week 24 may continue to receive MMB in the open-label extended treatment phase to the end of Week 204 (a total treatment length of nearly 4 years) if they continue to tolerate and benefit from MMB.

5. Participants randomized to receive DAN who are experiencing clinical benefit at the end of Week 24 have the option to continue DAN therapy through Week 48. The comparative drug, DAN, is approved in the United States and a few other nations and is recommended by national recommendations for the treatment of anemia in myelofibrosis (MF).

What Was the Trial Endpoint?

The primary endpoint for the MOMENTUM study was a reduction in the total symptom score. Of at least 50% at week 24. And so the, again, the primary endpoint was met, so just shy of 25% of patients had at least a 50% reduction, their total symptom burden at week 24, where only 9.2% of patients on the Danazol arm had at least a 50% reduction in their total symptom score. Moreover, key secondary endpoints such as a blood transfusion, independence, and spleen (size) volume responses were also met at the 24 week analysis.

Secondary Outcome Measures and Clinical Trial Data?

In the updated clinical data presented at the ASH annual meeting for 2022 the week 48, data was reviewed. And I really think the key take home points from this updated data was that the responses that were seen with Momelotinib were durable. This wasn’t a short-lived effect of spleen volume response, symptom burden improvement, and transfusion independence.

Again, these things were maintained and the trends for better survival were also maintained. Lastly, no new emerging adverse events were seen. One initial concern with the during the development of Momelotinib was the incidents of peripheral neuropathies. This was seen in some of the earlier studies, but again, the rates of peripheral neuropathy were very low for the initial report for the MOMENTUM study, as well as this follow-up report indicating the no emergence of new side effects attributed to Momelotinib. Lastly, some key sub-analyses include looking at patients with thrombocytopenia.

We know that doses of Ruxolitinib and Fedratinib can be limited somewhat by platelet count, and we wanted to look more closely at Momelotinib to see if the treatment responses occurred with the similar frequency in patients with thrombocytopenia as it did with preserved platelet counts. And in fact, that was the results that we saw in the sub-analysis that patients with platelet counts less than a 100,000 or 50,000, still had similar rates of responses as those who had baseline platelet counts over 150,000.

Final Thoughts

So the key points with the MOMENTUM study are that Momelotinib can reduce spleen volumes, improve symptom burdens, as well as, improve anemia in many patients. And these are key features that are serving as the foundation for the new drug application for this medication. And we do eagerly await the regulatory authorities review of this which should occur in early 2023. There is a PDUFA date of June 16th. And we hope to have a new treatment for our patients with myelofibrosis in the very near future.

Aaron Gerds, MD – About The Author, Credentials, and Affiliations

Dr. Aaron Gerds earned his Bachelor of Arts in biology and chemistry with honors from Hope College in Holland, Michigan. Then, he received his medical degree from the Loyola University Chicago Stritch School of Medicine. Dr. Gerds completed his Internal Medicine residency at Loyola University Hospital, where he also served as head resident. Dr. Patrick Stiff was his mentor when he initially became interested in hematology while reviewing the findings of clinical studies. During his residency, he pursued a master’s degree in clinical research methodologies and epidemiology because to this experience.

Dr. Gerds then traveled to Seattle, where he completed his hematology/oncology fellowship at the Fred Hutchinson Cancer Research Center of the University of Washington. During his fellowship, he received the New Investigator Award from the ASBMT. In Dr. Gerds’ clinical practice he subspecialized in the treatment of patients with myeloproliferative neoplasms (MPNs) such as polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), as well as myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), with a focus on allogeneic hematopoietic.

Dr. Gerds is also an active member of the American Society of Hematology, having participated in the Advocacy Leadership Institute, Clinical Research Training Institute, and Test Materials Development Committee. As an Assistant Professor in Medicine (Hematology and Medical Oncology) at the Cleveland Clinic Taussig Cancer Institute, Dr. Gerds serves as the principal investigator for a number of clinical trials for the treatment of MPNs and is dedicated to the development of novel therapies for these patients.

Reference

Clinical Trials gov – A Study of Momelotinib Versus Danazol in Symptomatic and Anemic Myelofibrosis Patients (MOMENTUM). Clinical Trials gov, February 11, 2022