FDA Approval of Momelotinib May Establish New SOC for Myelofibrosis With Anemia

The JAK1/JAK2 and ACVR1 inhibitor momelotinib (Ojjaara) not only provides spleen volume and constitutional symptom benefits in patients with anemic symptomatic myelofibrosis that is noninferior to that achieved with available JAK inhibitors, but may meaningfully reduce disease-related anemia symptoms that standard-of-care agents or danazol do not address, according to Andrew T. Kuykendall, MD. He added that the agent’s recent approval in this population requires re-evaluation of current approaches for managing these aspects of the disease.

On September 15, 2023, the FDA approved momelotinib for the treatment of patients with intermediate- or high-risk myelofibrosis, including primary or secondary myelofibrosis, and disease-related anemia.1,2 Findings from the phase 3 MOMENTUM trial (NCT04173494), as well as data from a subpopulation of adult patients with anemia from the phase 3 SIMPLIFY-1 trial (NCT01969838), supported the regulatory decision.

Twenty-five percent of patients with symptomatic and anemic myelofibrosis who were previously exposed to a JAK inhibitor experienced at least a 50% reduction in tumor symptom score (TSS) with momelotinib vs 9% of patients treated with danazol, which translated to a treatment difference of 16% (95% CI, 6%-26%; P < .01). Additionally, 30% of patients in the momelotinib arm achieved transfusion independence (TI) vs 20% of those in the danazol arm, which translated to a noninferiority treatment difference of 14% (95% CI, 2%-25%; P = .023). Spleen volume reduction and a decrease in anemia-related symptoms were also observed with momelotinib.³

“[With momelotinib], we’re extending the benefits of JAK inhibition to more people and we’re potentially helping [to ameliorate] anemia, which has been an area of unmet need for a long time for patients with myelofibrosis,” said Kuykendall, who is an assistant member of the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida.

In an interview with OncLive^®, Kuykendall discussed the importance of this approval for treating patients with anemic symptomatic myelofibrosis in clinical practice, key efficacy and safety data from the MOMENTUM trial that supported the decision, and unanswered questions regarding the agent’s potential role in other subsets within this population.

OncLive: What is the significance of the recent FDA approval of momelotinib for patients with myelofibrosis and anemia?

Kuykendall: This decision represents our further advancement in the perpetual story of [managing patients with] myelofibrosis [over] the past decade. On one hand, [we’re] trying to bring JAK inhibition to as many patients with myelofibrosis as possible. Ruxolitinib [Jakafi] really changed the game in myelofibrosis by allowing patients to [experience] profound improvement of splenomegaly and disease-related symptoms; it is also associated with a modest survival benefit. However, we continue to run into issues with patients who have anemia, which is most patients with myelofibrosis. [These patients, as well as those] who have low platelets, can’t experience the full benefit of JAK inhibition. The accelerated approval of pacritinib [Vonjo] helped with some aspects of that.

Now, momelotinib [provides] a full dose of a potent JAK inhibitor for patients who are anemic and may even be able to help with that anemia, as well. On the flip side, it looks like it can help with patients [who have] low platelets, as well. [The MOMENTUM trial] enrolled [patients] [with a] platelet count [of more than 25 x 10⁹ cells/L].

What is unique about the mechanism of action of momelotinib compared with other JAK inhibitors?

All of the main approved agents in myelofibrosis are JAK2 inhibitors. However, their kinase inhibition profiles serve as differentiating factors. Momelotinib is a bit different in the sense that, like ruxolitinib, it [targets] JAK1 and JAK2. Pacritinib, and to a lesser extent, fedratinib [Inrebic], are more selective for JAK2. [Momelotinib] also inhibits ACVR1, which we believe plays a key role in modulating hepcidin and improving anemia. This potentially distinguishes momelotinib from ruxolitinib.

Now, instead of worsening anemia, which we often see happen with ruxolitinib or fedratinib, we’re able to get those symptom and spleen benefits [that come with] JAK1/JAK2 inhibition, and at the very least, mitigate some of the anemia we saw with ruxolitinib. [Momelotinib could] potentially lead to an overall improvement in anemia and fewer transfusions for patients.

Could you expand on the design of the MOMENTUM trial, and the patient population enrolled?

The MOMENTUM trial was the third phase 3 trial of momelotinib. Ultimately, the trial enrolled patients who had previously been exposed to ruxolitinib, were anemic, had some degree of myelofibrosis-related symptoms, and had splenomegaly. Patients didn’t have to be [treated with] ruxolitinib for a long time. They could have been on it for just about a month, [during which] they had some anemia. Those patients were randomly assigned 2:1 to either momelotinib or danazol, which we know is a control. This means that we use the agent for patients who are anemic.

What key efficacy findings were reported?

The primary end point of the trial was symptom improvement and aimed for a 50% reduction in TSS. Overall, we expected to see improvement with momelotinib over danazol, [However], we know that symptoms can be related not just to inflammatory cytokines or to splenomegaly but can also occur due to anemia. We expected danazol to help with some of those [symptoms]. Some key secondary end points [included] some improvement in splenomegaly reduction compared with danazol. Although the results didn’t meet the criteria for superiority, TI rate [with momelotinib] was nominally better than the rate [observed with danazol]. More patients on the momelotinib arm were TI after 24 weeks vs [those in] the danazol arm with essentially an equal number [transfusion dependent between groups] at baseline.

Spleen response rates [with momelotinib] are similar to what you might expect to see with ruxolitinib or another JAK inhibitor. However, momelotinib has been directly compared with ruxolitinib in the SIMPLIFY-1 trial, where treatment-naive patients were randomly assigned to momelotinib or ruxolitinib. In that trial, momelotinib was noninferior to ruxolitinib in terms of spleen responses. Therefore, we know it is a potent JAK inhibitor in terms of inducing spleen responses. It was exciting to see results play out like that in this pivotal trial.

What should be known about the safety profile of momelotinib?

[The toxicities associated with momelotinib] are relatively benign. When we think about JAK inhibitors, we consider the safety profiles. In general, these are palliative medications that we’re using to make people feel better and improve quality of life and functionality. If our ultimate goal is for people to feel better, we need these agents to be well tolerated. When one of our key findings is symptoms improving, you can see that these are well-tolerated medications. In the short term, patients are reporting that they feel better than they did previously after going on these medications.

In terms of things to watch out for, there’s a mild increase in gastrointestinal [GI] toxicity vs what was seen with danazol. Still, these rates are relatively low for those experiencing nausea, which is also usually low grade. This is probably lower than what we have seen in other trials with pacritinib and fedratinib that inhibit FLT3, as anything that inhibits FLT3 is associated with some degree of GI toxicity.

In previous trials, there was some concern for peripheral neuropathy, which wasn’t really seen in the MOMENTUM study. There were relatively low rates of anemia and thrombocytopenia. In fact, this agent is likely to improve, or at least stabilize, anemia and was leveraged safely in patients with a quite low platelet count. Overall, there’s not too much to be concerned about [regarding] hematologic adverse effects. [Additionally,] momelotinib actually had fewer adverse effects on the kidneys than danazol did.

With this approval, where do you see momelotinib fitting into the treatment paradigm in myelofibrosis?

The clearest answer is [that it will be used for] patients who are quite anemic and have struggled to continue treatment with ruxolitinib at adequate doses without needing transfusions or developing symptomatic anemia. That’s the ideal population. Certainly, you could think about using it outside of those bounds, as well. Anyone with anemia and some degree of splenomegaly symptoms could be afforded momelotinib as an option, given the concern that ruxolitinib or fedratinib treatment might drop hemoglobin [levels], pushing people into transfusion dependency.

In that anemic population, there are outstanding questions: What about patients who don’t have symptomatic splenomegaly and don’t have a ton of disease-related symptoms, but are anemic? Is this now going to be our treatment of choice for this cytopenic population? Momelotinib was nominally better than danazol [at reducing transfusion dependence], so are we going to now choose this over danazol in a patient without too many splenic symptoms? That’s tough to say right now, but you could make an argument for momelotinib in that space.

In patients who are not anemic and are being treated with ruxolitinib but need to move to a second-line agent, is [momelotinib an option] that you’re going to leverage, knowing that anemia is part of the natural history of this disease over time and that it may be reasonable to start this type of an agent earlier rather than later? There are many different areas where this could be a beneficial agent, but [its potential role in] the anemic population is very clear.

What is your main message for colleagues regarding this approval?

Momelotinib is another tool in the toolbox. [It’s approval] is another reason to differentiate and understand when and why you would use different JAK inhibitors since we now have 4 [available]. You have to understand why and when to use one agent over the other, when you’re going to switch from one to the other, when you’re going to dose modify, and which agents are best [for each case]. This is a good time to think about those questions and have a clear plan in mind. It’s great to have different options for patients, but knowing when to use them is going to ensure that we’re using them in the right way.

References

1. Ojjaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia. News release. GlaxoSmithKline. September 15, 2023. Accessed October 4, 2023. https://www.gsk.com/en-gb/media/press-releases/ojjaara-momelotinib-approved-in-the-us-as-the-first-and-only-treatment-indicated-for-myelofibrosis-patients-with-anaemia
2. Momelotinib (Ojjaara) Prescribing information. GlaxoSmithKline; 2023. Accessed November 2, 2023. https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Ojjaara/pdf/OJJAARA-PI-PIL.PDF
3. 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