Lead Investigator Provides Insight Into FDA Approval of Momelotinib for Myelofibrosis

Pharmacy Times interviews Ruben A. Mesa, MD, FACP, president and executive director of Atrium Health Levine Cancer and Atrium Health Wake Forest Baptist Comprehensive Cancer Center and a lead investigator of both the SIMPLIFY-1 (NCT01969838) and MOMENTUM (NCT04173494) trials, on how data from SIMPLIFY-1 and MOMENTUM helped to lead to the FDA approval of momelotinib (Ojjaara; GSK). The FDA had approved momelotinib to treat intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis (post-polycythemia vera and post-essential thrombocythemia), in adult patients with anemia.

Pharmacy Times: The FDA recently approved momelotinib to treat myelofibrosis in patients with anemia based on data from the MOMENTUM and SIMPLIFY-1 trials. What was the purpose of each trial and what was your involvement as an investigator?

Ruben A. Mesa: I’m very excited about this approval. Let me walk you through these 2 phase 3 trials. I was 1 of the co-leads on each of the studies, first author on SIMPLIFY-1, and senior author on MOMENTUM.

The SIMPLIFY-1 study was a randomized study, head-to-head, frontline against ruxolitinib, where over 400 patients were enrolled, it was blinded, and what was found is that momelotinib was non-inferior for reduction in splenomegaly—so relatively similar reductions in splenomegaly—and slightly inferior in relation to improvement in symptoms. We’ve done a variety of analyses since. I’d say that it's probably fairly equivalent in terms of symptom improvement, and then data clearly shows a much more significant impact on anemia in the frontline, and again, thinking of anemia in terms of improving baseline anemia as well as less drug emergent anemia.

MOMENTUM was a second-line study, so these were individuals that had failed ruxolitinib, they were symptomatic, had splenomegaly, and therefore, of course, the comparator was not ruxolitinib, it was momelotinib versus danazol, which has largely been used globally as the most common treatment for anemia. The trial met of all of its primary endpoints including being superior for reduction in disease-associated symptoms, being superior for reduction in splenomegaly, and meaning non-inferior as related to improving anemia. Indeed, the trend was that it almost reached statistical superiority over the danazol—even though that was not one of their pre specified endpoints—so overall, very positive study.

I think the FDA really looked at both of these pieces of complementary evidence and came up with the indication saying momelotinib could help to improve anemia in the front and secondline setting, and in my mind, also helping to improve splenomegaly and symptoms as key parts of the disease.

I think the FDA really looked at both of these pieces of complementary evidence and came up with the indication saying momelotinib could help to improve anemia in the front and secondline setting. Image Credit: © LASZLO - Adobe Stock

Pharmacy Times: What were some of the key data that likely informed the FDA decision to approve momelotinib?

Mesa: I think the most important thing is the FDA having been in front of the many times in having been involved with the approval process, and the clinical trials have led to approval for ruxolitinib, dratinum and pacritinib, the other 3 JAK inhibitors. So, with momelotinib, first, clearly the clinical benefit that was distinct from the others in terms of improving anemia, and that was seen both with SIMPLIFY-1 and with MOMENTUM data. Second, that it's very active overall as a model fibrosis drug for reduction in splenomegaly as well as improvement in symptoms. The FDA really is focused on clinical benefit and patients with myelofibrosis being able to benefit from all 3 of those components. Third, safety. Again, with all of these therapies, particularly as a non-curative therapy, but 1 that has an impact is always balanced against toxicity. Fortunately, the toxicities were overall very manageable, can be so low-grade GI toxicities, there are some individuals who still can have some cytopenias despite those benefits, elevation and liver function tests, there are some of the broad class, low-incidence things that need to be watched for…low risk of skin cancers, rare infections, rare cardiovascular events…but overall, pretty well-tolerated drug.

Pharmacy Times: How will this FDA approval of momelotinib help to address some of the key manifestations of myelofibrosis, and what are the implications for patients?

Mesa: So, myelofibrosis is a heterogeneous disease and it affects people in several different parameters: splenomegaly, or symptoms, or anemia, or thrombocytopenia, or progression to acute leukemia. I'd say 1 that had been really the biggest unmet need up to this point really had been improvement in anemia. We have 3 other approved JAK inhibitors or medications overall for myelofibrosis. Ruxolitinib and fedratinib, whose benefit is significant but has been primarily in splenomegaly and symptoms, but without really improvement in anemia. In fact, both can potentially worsen anemia. Pacritinib, that may have some benefit in anemia but whose sweet spot in addition to reducing splenomegaly and symptoms is being able to use safely in individuals despite very low platelet counts. Momelotinib is really distinct in that group in being able to improve anemia while keeping those other key parameters of benefit of splenomegaly and symptoms. So, in many ways, it is 1 of the most comprehensive therapies we've had to date for these individuals. It can be used even in the setting of platelets as low as 25,000 based on patients accrued in the studies. So, I think as we speak, it'll impact patients that either 1, have anemia in the frontline setting—you come in, you're newly diagnosed, you have a hemoglobin of 7—momelotinib is a very significant frontline consideration, or 2, an individual who's on another JAK inhibitor and has significant anemia. A change to momelotinib certainly is a consideration depending upon the patient's circumstance.

Pharmacy Times: How do you work with oncology pharmacists as a part of the care team for patients with myelofibrosis?

Mesa: Oncology pharmacists are really a critical element to any team. Here at our Comprehensive Cancer Center, Atrium Health, Wake Forest Baptist Comprehensive Cancer Center…they are a key part of the team. I think for many reasons…for the safety profile for the agent, any drug-drug interactions for patients, helping us keep track of those things making sure we don't have a drug interaction, it's a critical part of the equation. These days it’s just too difficult to know all of these things are off of the top of your mind and they play really a critical role in that piece. Second is really in terms of interacting with the patient as well, in terms of helping sort information about the medication, patient education around the use of the medication as well as helping to monitor for any drug interactions or other toxicities.

Pharmacy Times: What is your perspective on the role of oncology pharmacists in treatment decisions for patients with myelofibrosis?

Mesa: I think they can be very helpful, particularly as we start to think about both the patient's baseline comorbidities and whether there's any concerns around the patient's health that we need to be mindful of. Each of these drugs has a slightly different toxicity profile, there are certain black box warnings we need to be mindful of, such as with fedratinib in the monitoring of thiamin and for Wernicke’s encephalopathy, as well as really being mindful of the profile of other medications that they're on. They will have slightly different drug-drug interactions, and again, some of those may be important as we have individuals that may have a range of different potential options that might sway in the frontline setting. Now, one might consider ruxolitinib for granted or momelotinib depending upon the clinical situation and input from the oncology pharmacist might be important in terms of [determining] which drug might be important or the most appropriate for that individual patient.