Momelotinib Shows Promising JAK and ALK2 Inhibition in Myelofibrosis With Anemia

Srdan Verstovsek, MD, PhD

Momelotinib is an investigational JAK inhibitor that has shown unique efficacy in improving red blood cell counts in patients with myelofibrosis and disease-related anemia, according to Srdan Verstovsek, MD, PhD.

The current standard of care for myelofibrosis is ruxolitinib (Jakafi)-based therapy, which improves some myelofibrosis symptoms through JAK inhibition but worsens anemia. Many patients who have anemia become dependent on blood transfusions, which decreases their quality of life and increases the potential for iron overload issues.

“Momelotinib looks promising for patients with myelofibrosis and anemia” Verstovsek, a professor of medicine and chief of the Section for Myeloproliferative Neoplasms in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, said. “In the near future, I hope momelotinib will be positioned as the anemia drug for people who require improvement in red blood cells, spleen, and symptoms. The distinct characteristics of the different JAK inhibitors are applicable to different subgroups of myelofibrosis.”

Momelotinib is unique from other JAK inhibitors in that, along with JAK1 and JAK2 inhibition, it also inhibits ALK2, a receptor that increases hepcidin levels, which are inversely related to the degree of myelofibrosis and anemia. The phase 3 MOMENTUM study (NCT04173494) aims to shift the treatment paradigm toward momelotinib, a drug that appears to lower hepcidin levels in addition to improving other facets of myelofibrosis.

In an interview with OncLive^®, Verstovsek, who is also the director of the Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasms at The University of Texas MD Anderson Cancer Center, discussed the paper, “Momelotinib: an Emerging Treatment for Myelofibrosis Patients With Anemia,” which he wrote in collaboration with Helen T. Chifotides, PhD, ELS, and Prithviraj Bose, MD, both of The University of MD Anderson Cancer Center. Verstovsek also highlighted the preliminary results of the MOMENTUM study and the potential for ALK2 inhibitor success in the larger anemia treatment landscape.

OncLive^®: What served as the impetus for the paper? What was the focus of the piece?

Verstovsek: Momelotinib is a new JAK inhibitor in late-stage development. The phase 3, randomized MOMENTUM study that will possibly lead to its FDA approval is under way, and some preliminary results have already been announced.

Throughout this study, we learned much about how momelotinib is different from other JAK inhibitors. When we say JAK inhibitors, we talk about inhibition of the JAK [signal transducer and activator of transcription (STAT)] pathway, through inhibition of JAK1, JAK2, or any of the 4 enzymes within the JAK family.

We know momelotinib inhibits JAK1 and JAK2, which would mean anti-proliferative and anti-inflammatory activities. But it also it seems likely that it inhibits another protein called ALK2, which is the receptor on the surface of hepatocytes and other reticuloendothelial systems in the body, like the lining of the [gastrointestinal (GI)] tract or the spleen.

That has much to do with iron metabolism. Importantly, through ALK2 inhibition, hepcidin, a protein in blood, which is the master iron metabolism in the body, is decreased. Hepcidin is very high in patients with myelofibrosis, and it’s inversely related to the degree of anemia and overall survival [OS] of patients.

By decreasing hepcidin through ALK2 inhibition, momelotinib appears to improve red blood cell counts in anemia, and people become transfusion independent. Therefore, in addition to being a JAK-STAT pathway inhibitor, momelotinib also inhibits hepcidin levels. [In other words,] it improves red blood cell counts, which is not normal for other JAK inhibitors.

In this paper, we wanted to relay the differentiating factor between momelotinib and other JAK inhibitors and highlight that momelotinib functions as an anemia drug; it makes people transfusion independent through its iron metabolism modifications.

That [effect] is reflected in the preliminary results of the MOMENTUM study. That study is looking at patients with myelofibrosis who are anemic and not feeling well who were previously treated with ruxolitinib, another JAK inhibitor, which is the standard first-line JAK inhibitor for most patients with myelofibrosis.

Ruxolitinib improves the spleen [volume] and symptoms, but it worsens anemia. Anemia drugs do not exist, and anemia is the leading cause for stopping ruxolitinib.

Once you stop [administering ruxolitinib], anemic patients are not feeling well, and they may have big spleens and low platelets. What do you do? In this setting, momelotinib was tested in the MOMENTUM study and was compared with danazol.

Danazol is an anabolic steroid, a standard therapy for patients with anemia who don’t feel well. It’s not approved though. Danazol may help, but it doesn’t help many patients and doesn’t help for long. However, it’s a valid comparator because we’re trying to help our patients.

In the MOMENTUM study, red blood cell count control, transfusion independence, symptom control, and spleen control were all better with momelotinib than danazol in preliminary results presented to us in March 2022. There is significant potential for momelotinib to be approved as a therapy for patients who have myelofibrosis with anemia and are not feeling well. It may be used widely, particularly in patients who have stopped ruxolitinib, are very anemic, not feeling well, and have big spleens.

[Additionally, in February 2022,] pacritinib [Vonjo], another JAK inhibitor, was approved. Pacritinib is a non-myelosuppressive JAK inhibitor that improves the spleen [volume] and symptoms in patients with platelets below 50,000. This is a small patient subset, and these patients with low platelets did not have many treatment options, because ruxolitinib and fedratinib [Inrebic], the standard JAK inhibitors, are not supposed to be given to people with low platelets. Certainly, there is a bright future for diversifying our armamentarium among JAK inhibitors, depending on patient characteristics.

Could you elaborate on some of the risks associated with anemia and red blood cell dependence in myelofibrosis?

In myelofibrosis, anemia, which is defined as a hemoglobin level of less than 10, is present at the time of diagnosis in approximately 40% to 50% of patients. Some of these patients require blood transfusions. Patients who need transfusions make up approximately 20% of all newly diagnosed patients with myelofibrosis and anemia. A smaller proportion, about 5% to 10%, require a high number of transfusions at the beginning. These are transfusion-dependent patients.

Red blood cell transfusion dependence [may not seem like a huge problem. In this setting, we tend to focus on treating] patients with the JAK inhibitors ruxolitinib and fedratinib for the prevailing problems, which are bad symptoms and bad spleens. However, there is roughly a 50/50 chance that the anemia will worsen with ruxolitinib or fedratinib therapy and as the disease evolves over time.

At the time of stopping frontline therapy with ruxolitinib, almost 70% to 80% of patients are anemic. Almost half of them require transfusions, and about a quarter are transfusion dependent, requiring 2 transfusions monthly for 3 months.

[Transfusions create bad quality of life.] Imagine: you don’t feel well, you don’t have enough red blood cells, you experience shortness of breath, fatigue, and weakness. You also spend much time in the hospital, getting that blood. This may lead to problems with iron overload through those transfusions, because iron is not secreted from the body.

Not only is patient quality of life affected quite a bit, but there is potential for harm from the blood that is given, [which affects any future transplant success.] In addition, overall life expectancy in people who are transfusion-requiring or dependent is very short. [Anemia presents many problems that complicate ideas surrounding simply giving blood.] Once you dig in and start talking about this, you see how cumbersome and problematic it is for patients on multiple levels.

Are there any other unique elements of momelotinib that distinguish it from other JAK inhibitors?

The uniqueness is related to its mode of action, which is JAK1 and JAK2 inhibition, which provides antiproliferative and anti-inflammatory potential, and ALK2 inhibition, which provides anti-anemia potential. [Current treatment development highlights that anti-anemia aspect.] Momelotinib is as anemia drug that makes people feel well and controls the spleen [volume].

The other unique element is that there is not much known hematological toxicity. [Momelotinib does not appear to cause anemia, thrombocytopenia, or neutropenia, making it relatively safe.] That’s important to note because it’s very simple to give momelotinib as a stable dose. Dose intensity during the therapy stays consistent all the time, so there is not much need for adjustments.

With this safety factor comes simplicity; you don’t need to worry about the patients who receive this treatment. Efficacy, safety, and simplicity all come together as positive indicators for the success of momelotinib as a future therapy for patients with myelofibrosis.

Is there anything else you’d like to highlight or any forward-looking research with JAK inhibitors you’d like to touch on?

With the advent of momelotinib as an anemia drug that works in part through ALK2 inhibition, we can affect patient hepcidin levels and resolve functional iron deficiencies, which are when patients have too much hepcidin that their iron is not readily available for erythropoiesis. If that is an active component of how momelotinib works, which we strongly believe and which is described in our paper, then the question is: Can we do even better? Yes.

We can develop specific ALK2 inhibitors that could be more potent than momelotinib. We hope there will be major benefits in the future from specific ALK2 inhibitors or similar drugs that affect hepcidin and iron homeostasis and affect anemia. [Some of this work is currently underway.] Other sponsors and companies will try to develop more specific, more potent ALK2 inhibitors and additional drugs to resolve anemia to an even greater extent.

Therefore, in the near future, [perhaps over the next 3 to 5 years,] we may have highly effective and safe anemia-specific drugs that, if developed, will be proper combination partners with other myelosuppressive JAK inhibitors like ruxolitinib, fedratinib, or even pacritinib. [Understanding how momelotinib works] opens a new chapter for ALK2/hepcidin inhibitors to be the new classes of anemia drugs.