Momelotinib Could Represent Pivotal New Treatment Option in Myelofibrosis

The benefits in symptom burden, spleen size, and transfusion dependence demonstrated by treatment momelotinib in patients with myelofibrosis represent a potential key advance for this treatment paradigm, according to Aaron T. Gerds, MD, PhD.

A new drug application (NDA) seeking the approval of momelotinib as a potential therapeutic option in patients with myelofibrosis is currently under review by the FDA, and the review period was extended to a target action date of September 16, 2023.¹

The NDA is supported by data from the phase 3 MOMENTUM trial (NCT04173494), which evaluated the agent in patients with symptomatic and anemic myelofibrosis who received a prior JAK inhibitor. Data showed that 25% of patients treated with momelotinib (n = 130) experienced a reduction in tumor symptom score of at least 50% at week 24 compared with 9% of patients treated with danazol (n = 65; proportion difference, 16%; 95% CI, 6%-26%; P = .0095).²

Additionally, 39% of patients in the momelotinib arm achieved a spleen volume reduction of at least 25% from baseline to week 24 vs 6% in the danazol arm (P < .0001); moreover, 22% and 3% of patients, respectively, experienced a reduction of 35% or more (P = .0011). At week 24, the rates of transfusion independence were 30% (95% CI, 22%-39%) for momelotinib and 20% (95% CI, 11%-32%) for danazol (noninferiority difference, 14%; 95% CI, 2%-25%; 1-sided P = .0016).

“The potential approval of momelotinib is incredibly important for patients. Having additional agents to treat myelofibrosis would be welcomed. As little as a couple of years ago, we only had 1 approved therapy to treat myelofibrosis,” Gerds said in an interview with OncLive®. Gerds is an assistant professor in the Department of Medicine, a member of the Developmental Therapeutics Program, and medical director of the Case Comprehensive Cancer Center in Cleveland, Ohio.

In the interview, Gerds expanded on the potential role of momelotinib in the treatment of patients with myelofibrosis who present with anemia, detailed the data from MOMENTUM, and explained what FDA approval of momelotinib could mean for the treatment of this patient population. Gerds also serves as an associate professor of Medicine in the Department of Hematology and Medical Oncology at the Cleveland Clinic Taussig Cancer Institute.

OncLive: How could the potential approval of momelotinib affect current and future practice patterns for patients with myelofibrosis?

Gerds: The [potential] approval of momelotinib could be another pivotal moment in the care of patients with myelofibrosis. I would argue that the first pivotal moment was the discovery of recurrent JAK2 mutations, followed several years later by the approval of ruxolitinib [Jakafi], the first JAK inhibitor.

Momelotinib provides an extra opportunity for patients, specifically patients who have anemia along with enlarged spleens and significant symptom burden. This drug promises to try to hit all 3 of those key elements of care in patients with myelofibrosis with a single pill.

What unmet needs exist for patients with myelofibrosis and anemia?

Anemia itself in these patients is a key unmet need. Roughly 40% of patients will be anemic at the time of diagnosis. It is common diagnostic and prognostic criteria that is used to predict who may have aggressive disease. Anemia will also develop in patients within the first year after diagnosis, and at some point, every patient will develop anemia as the [bone] marrow begins to fail. Therefore, anemia is something that is incredibly common and difficult to treat.

We can give red blood cell transfusions to combat anemia, but that comes with adverse effects, such as iron overload, transfusion reactions, and the development of alloantibodies. Moreover, blood is a valuable and somewhat scarce resource. The Red Cross is constantly trying to get us to donate more blood because it is a scarce commodity, and it is also expensive to do red blood cell transfusions. In general, it's one of the biggest costs in delivering health care for patients with hematologic malignancies. For all these reasons, treating anemia is incredibly important.

Treatments for anemia are somewhat limited. I mentioned transfusions already, and there are also erythropoiesis stimulating agents [ESAs] that can be given. Another drug, luspatercept-aamt [Reblozyl], is already approved to treat anemia in patients with myelodysplastic syndrome and beta thalassemia. It is used off-label to treat anemia in patients with myelofibrosis. danazol is also commonly used.

We already have these 3 agents; however, none of them are perfect or work 100% of the time, and there are still many patients who suffer from anemia who have [myelofibrosis]. Any new agent that is coming along that can potentially treat anemia in a different mechanism of action is always welcome.

What is the mechanism of action of momelotinib, and what prompted this agent’s examination in patients with myelofibrosis?

Momelotinib, in terms of treating anemia, works very differently than ESAs, luspatercept, and danazol. It works by inhibiting ACVR1, also known as ALK2, which is a regulator of hepcidin. Hepcidin is a key piece in what we think about in hematology in iron regulation and red blood cell production. It is a hot topic in myeloproliferative neoplasms right now, and it has been in the world of hematology for some time.

Hepcidin is a master iron regulator that helps regulate the shuttling of iron out of the iron stores, making it available for the body to use, for example, to make red blood cells. In patients with myelofibrosis, they have anemia or an inflammatory block, meaning that hepcidin levels are very high and can shut a lot of those iron stores. By lowering the levels of hepcidin by blocking ACVR1, we can restore effective erythropoiesis by dropping that anemia or inflammatory block. That component of a patient's anemia can be reversed, potentially by this medication.

What were some of the key efficacy data from MOMENTUM?

The MOMENTUM study pitted momelotinib vs danazol, looking at a couple of key end points. The first was symptom burden reduction, and we also looked at spleen volume reduction—traditional end points for measuring response with JAK inhibitors in patients with myelofibrosis. Another key end point was transfusion independence, and that was the proportion of patients who were transfusion independent at weeks 24 and 48.

We saw that momelotinib outperformed danazol in terms of spleen volume reduction, as well as symptom burden reduction. Momelotinib was also statistically not inferior—this was a non-inferiority analysis—for transfusion independence at week 24 compared with danazol.

What does the safety profile look like for momelotinib in this population?

With respect to safety, one of the early concerns during the development of momelotinib was an increased risk of peripheral neuropathy. This was seen in some earlier studies. However, in subsequent investigations, such as the SIMPLIFY trials [NCT01969838; NCT02101268] and the MOMENTUM study, we did not see excess neuropathy in patients treated on momelotinib compared with best available therapy or danazol, respectively. The rates of peripheral neuropathy were similar in the 2 groups. That was a key take-home point in terms of safety data from the MOMENTUM study.

Certainly, some patients did develop cytopenias while on momelotinib, as well as danazol. There weren't excess gastrointestinal toxicities, as we see with some of the other JAK inhibitors. There was no signal toward increased risk of non-melanoma skin cancers or bile reactivations. However, we certainly watch for those things whenever we're treating a patient with a JAK inhibitor.

If it is approved, where do you see momelotinib fitting into the current treatment paradigm for this population?

With the potential approval of momelotinib, we will see what the uptake looks like in everyday practice. That will be a big part of what happens with this medication: how organically it is picked up by different oncologists and hematologists out there in the community. Clearly, it has efficacy in patients with anemia, so it would be right at home in the treatment of a patient who has myelofibrosis who needs spleen volume reduction and symptom control, and has anemia.

If we look closely at the MOMENTUM inclusion criteria, those patients did have prior exposure to a JAK inhibitor for at least one month, and they all had hemoglobin [levels] less than 10g/dL; that is where this drug tends to shine. However, the amount of JAK inhibition given to those patients prior to going on MOMENTUM was limited. We also do have up-front data in patients previously untreated [with a JAK inhibitor] from the SIMPLIFY trials. You could say that if a patient with myelofibrosis and is borderline anemic, they could also benefit from momelotinib, not just in the second line, but potentially in the frontline setting as well.

References

1. Verstovsek S, Gerds AT, Vannuchi AM, et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. Lancet. 2023;401(10373):269-280. doi:10.1016/S0140-6736(22)02036-0
2. GSK announces extension of FDA review period of momelotinib. News release. GlaxoSmithKline. June 16, 2023. Accessed August 31, 2023. https://www.gsk.com/en-gb/media/press-releases/gsk-announces-extension-of-fda-review-period-for-momelotinib/