Momelotinib Continues to Prove Itself as a Potential Treatment for Myelofibrosis

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In an interview with Targeted Oncology, Srdan Verstovsek, MD, discussed the potential use of momelotinib as a treatment for patients with myelofibrosis if approved by the FDA in June 2023.

Srdan Verstovsek, MD

Srdan Verstovsek, MD

As updated findings from the MOMENTUM trial (NCT04173494) continue to demonstrate positive results, momelotinib continues to prove its potential as a future treatment option for patients with anemic myelofibrosis.

Momelotinib is an investigational oral treatment for patients with myelofibrosis. The JAK1 and JAK2 inhibitor recently showed benefit in patients with myelofibrosis as momelotinib induced durable symptoms, transfusion independence, and splenic responses through 48 weeks of treatment.

The findings come from the phase 3 open-label, crossover phase of the MOMENTUM study (NCT04173494) which were presented at the American Society of Hematology (ASH) 2022 Annual Meeting.

In this trial, patients were either administered momelotinib or crossed over from danazol to receive momelotinib. Week 24 symptom responses continued through week 48 of treatment in 97% of patients on the momelotinib-to-momelotinib arm compared with 100% in the danazol-to-momelotinib arm.

Further, 29% of patients who crossed over to momelotinib at week 24 and did not have a Total Symptom Score (TSS) response to danazol and achieved TSS responses at week 48. Among patients, 20% who continued momelotinib in this phase of the trial were also new responders at week 48.

According to Srdan Verstovsek, MD, these findings from the MOMENTUM study confirm what have previously been reported in other phase 3 studies, including Simplify 1 study (NCT01969838) and SIMPLIFY 2 study (NCT02101268).

“Improvements in the spleen symptoms and anemia were seen significantly better than danazol. Now we know that these are long lasting benefits, the therapy does not need to be changed, the dose not need to be modified, it is very safe over a prolonged period, it works for a long period of time, and there is a strong suggestion that there may even be a survival benefit in some groups of patients in this setting where life is typically short. I would expect based on this blinded, randomized study that the momelotinib would be approved in United States next June,” stated Verstovsek, MD, associate professor of medicine in the Leukemia department at the University of Texas MD Anderson Cancer Center, in an interview with Targeted OncologyTM.

In the interview, Verstovsek discussed the potential use of momelotinib as a treatment for patients with myelofibrosis if approved by the FDA in June 2023.

Targeted Oncology: Can you discuss the mechanism of action of momelotinib?

Verstovsek: Momelotinib is an interesting medication that inhibits JAK1 and JAK2, which is something that we would expect to benefit patients with the myeloproliferative neoplasms, particularly myelofibrosis, in inhibiting proliferation and inflammation and leading to some clinical benefits like improving quality-of-life, and the reduction in the spleen. It also uniquely improves anemia and that is because it's an ACVR1 inhibitor. ACVR1 is also called ALK-2, [which is] a receptor on the liver where inhibition of that receptor would alter the iron metabolism. It decreases hepcidin, a master regulator of iron metabolism, and allows more iron to be available for erythropoiesis, the blood making process. Therefore, this medication would inhibit more than what you would expect with the JAK inhibitor and lead to clinical benefits on all 3 fronts: The spleen, the symptoms, and the anemia benefits.

Can you discuss the MOMENTUM study of momelotinib in patients with symptomatic and anemic myelofibrosis?

At this age, we have learned a lot from the MOMENTUM study. This is the 1 that finally confirmed what we have seen earlier on in 2 other phase 3 studies. The study is the phase 3 randomized study, blinded, between 2 therapies, momelotinib and danazol in the second-line setting. The standard practice frontline therapy is ruxolitinib [Jakafi], a JAK inhibitor that improves the spleen and symptoms but can worsen anemia. Anemia is the leading cause of why you stop ruxolitinib. Many patients, most of them are anemic when they get to the second-line, so that would be the setting for the development of a new drug like momelotinib. This is where the phase 3 study was done.

Improvements in the spleen symptoms and anemia were seen significantly better than danazol. Now we know that these are long lasting benefits, the therapy does not need to be changed, the dose not need to be modified, it is very safe over a prolonged period, it works for a long period of time, and there is a strong suggestion that there may even be a survival benefit in some groups of patients in this setting where life is typically short. I would expect based on this blinded, randomized study that the momelotinib would be approved in the United States next June.

What studies complement the MOMENTUM trial?

There is a study called the Simplify 1 study which was a frontline study comparing momelotinib with ruxolitinib where momelotinib was as effective as ruxolitinib in controlling the spleen. It was also better than ruxolitinib in the control of anemia, so anemia benefit was already seen in the past. The Simplify 2 study is a phase 3, randomized study in people who had the hematological toxicities from ruxolitinib. They were randomized between momelotinib or best radiotherapy. In that setting as well, there were anemia benefits and symptomatic improvements. There are multiple sources, several phase 3 studies, when you put them together to tell us that this drug is unique [and has the] ability to help a good proportion of patients on anemia, on the spleen, and on the symptoms.

What are some of the data from the studies? What sets them apart from one another?

Transfusion independence is a hallmark of a drug that we seek, in a good way, because anemia may be of a different degree. We talk of anemia, loosely described, as a hemoglobin less than 10. There are patients that have hemoglobin less than 10 but are not symptomatic and don't need intervention. When you start transfusions, you become transfusion-requiring or even transfusion-dependent [where you need] 2 transfusions monthly for a few months, and that is the different ballgame. Here, we talk about the therapy that would prevent transfusions to happen or eliminate the need for transfusions in about a third of the patients in a second-line setting. Similar happened earlier in studies of momelotinib, the Simplify 1 or Simplify 2 studies, in frontline or intolerant patients. Therefore, we have plenty of evidence of the uniqueness of this medication. We will account for its use in a wider group of patients when it comes, and hopefully it will become available for us in community settings.

What are the next steps for this research?

[The next step is looking at] how to optimize the therapy amount further. If we have on 1 hand the ruxolitinib medication as a frontline choice to control the spleen symptoms and for the second setting, we have momelotinib in addition to pacritinib and fedratinib [Inrebic], where else can we see improvements? Well, combination studies with the novel agents may complement what the JAK inhibitors do further. Further improvement in anemia, further improvement in spleen, and the symptoms. Finally, [looking at] potential combinations with the non-JAK inhibitors. Clinical studies of combinations are underway [and evaluating] what would set them apart, not only enhancement of these 3 benefits, but your ability of a control the disease signs and symptoms to say hey, with this combination, maybe with a momelotinib-based combination with another agent, we are going to enhance the control of anemia, spleen, and symptoms, but it will last much longer where overall survival is prolonged. This is where we are heading.

What other ongoing research in the MPN space seems exciting to you?

Momelotinb is the 1 that will be practice changing as it comes available next summer. In a plenary session [at ASH], there was a clinical presentation of something that may have a significant impact on the subgroup of patients with myelofibrosis or MPN in general. I'm talking about the development of the antibody that would target mutated calreticulin. Now, what is muted calreticulin? We know that everybody has hyperactivity over the JAK/STAT pathway, an intracellular signaling pathway, that drives this process. We also know that about a third of the patients have a mutation in a gene called calreticulin, it makes muted calreticulin that comes outside the cell and binds to the receptors from outside the cells in the bone marrow and makes the cells grow without control. That is the case in about a third of the patients. Developing the antibody that would attach itself to the mutated calreticulin and destroy that malignant cell is a desirable next step in the development of our medications. Targeting a genetically identifiable group of people with the marker that you can then utilize for the elimination of malignant cells.

This is where we all aspire to go. To start to talk about the molecular response. Not only control the signs and symptoms, but elimination of the disease and molecular response. So it was very exciting for a plenary session and hopefully within a few years, we will have a study with the calreticulin antibody.

In this past year, what would you say has been the most impactful research in the MPN space?

Understanding the preclinical complexity of the disease over the last 5-10 years led to the development of many different drugs that have nothing to do with the hyperactivity of the JAK/STAT pathway which is present in every case. We now potentially have 4 different JAK inhibitors. But understanding the 4 as I mentioned, the ACVR1 contribution to anemia, contribution of the epigenetic modifications or BCL-xl enhancement, or telomerase role in the disease process, these types of discoveries led to clinical studies with these specific medications for the different molecular or biological abnormalities in myelofibrosis cells. Understanding the biology better leads to clinical development of new drugs and that on its own is exciting. We have about 7 or 8 phase 3 randomized studies underway in myelofibrosis for the development of new drugs with medications that are not JAK2 inhibitors.

How do you foresee this research on momelotinib potentially impacting clinical practice?

As June of [this] year comes, we are expected to get the decision by FDA to approve or not approve momelotinib. I hope it will because the study was well done and clearly shows the benefit of the anemia symptoms and spleen. Right away we would find its place in the management of our patients with myelofibrosis, particularly where the phase 3 randomized study was done in the second-line setting where we struggle. We don't have any therapies for anemia, people may have low platelets, and this drug can be given to people with lower platelets. Of course, it can control the spleen. The spleen has major problems, so I would say that these drugs may become the number 1 choice as a therapy in a secondary setting in myelofibrosis in the near future.

REFERENCE:
Gerds AT, Mesa RA, Vannucchi AM, et al. Updated results from the Momentum phase 3 study of momelotinib (MMB) versus danazol (DAN) in sympatomatic and anemic myelofibrosis (MF) patients previously treated with a JAK inhibitor. Presented at: 2022 ASH Annual Meeting; December 10-13, 2022; New Orleans, LA. Abstract 627
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