Behind the FDA Approval: Momelotinib for Myelofibrosis and Anemia

Aaron T. Gerds, MD, MS

The FDA approval of momelotinib (Ojjaara) has provided a potentially new standard-of-care treatment option for patients with myelofibrosis who have anemia, and according to Aaron T. Gerds, MD, MS, findings from the phase 3 MOMENTUM trial (NCT04173494) serve as the basis of this approval.

In the international, randomized, double-blind, controlled study, all the primary and secondary end points were met, including there being a total symptom score (TSS) response rate of 35% among those treated with momelotinib vs 9% for patients given danazol (P =.0095).

In terms of transfusion independence, momelotinib was found to be non-inferior to danazol with a rate of 32% in the momelotinib arm vs 20% in the danazol arm. Splenic response rates of at least 25%, were 40% with momelotinib compared with 6% with danazol (P <.0001).

Additionally, there was a superior absolute TSS change from baseline in the momelotinib arm at –11.5 vs –3.9 in the danazol arm (P =.0014). For splenic response rate (≥35% reduction), momelotinib demonstrated superiority as 23% of patients given momelotinib had a splenic response rate of 35% or more while only 3% of the danazol arm did (P = .0006). At week 24, the rate of zero transfusion was 35% with momelotinib arm and 17% with danazol (P =.0002).

Regarding safety, the most common any-grade adverse events (AEs) seen with momelotinib vs danazol included diarrhea (22% v 9%), nausea (16% v 9%), asthenia (13% v 9%), and pruritus (11% v 11%). In the danazol arm, AEs more frequently appeared to be grade 3 or higher compared with the momelotinib arm. Further, the hematologic AEs that were observed with momelotinib vs danazol were anemia (99% v 100%), thrombocytopenia (76% v 62%), and neutropenia (29% v 26%).

“Based on the most recent trials, including MOMENTUM, this will be a key therapy for patients who have anemia and who have been previously treated with a JAK inhibitor,” Gerds, assistant professor in medicine (Hematology and Medical Oncology) at the Cleveland Clinic, told Targeted Oncology^TM, in an interview.

In the interview, Gerds delves further into the background of momelotinib, how to manage toxicities with the agent, and its role in clinical practice moving forward.

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

Gerds: Momelotinib is a JAK inhibitor, like the other Jak inhibitors that have been tested and approved. The main mechanism of action is inhibition of these JAK molecules, which are a key piece of the JAK/STAT pathway, which is the main dysregulated pathway in MPNs. CHEK2 mutations occur, MPL mutations occur, CALR mutations occur, and they all cause constitutive JAK/STAT activation, so it makes sense to have drugs that target that pathway.

In the past, JAK inhibitors have been shown as a class to reduce spleen volumes and improve symptom burdens. That's pretty much universal with this class of medicine. Now that we have multiple JAK inhibitors approved, the key is parsing out how they are all different from each other, not how they're the same. What sets momelotinib apart is its inhibition of a molecule called ACR1, also known as ALK-2. It's a master regulator of hepcidin. We know that inflammation is a key part of this disease, and you can develop anemia as a reformation. It's a picture of these patients, not the entirety, but a large part of it. By reducing unmodulated hepcidin levels, we could potentially improve anemia, or at least the part of the anemia that's due to that inflammatory block. That is what sets momelotinib apart and the angle it's been taking over the last 5-6 years.

What background can you provide on the MOMENTUM trial?

The MOMENTUM trial isn't the first randomized phase 3 trial done with momelotinib. There was the SIMPLIFY-1 and -2 trials that preceded it. The challenge with SIMPLIFY-1 was that we were asking the right questions, but maybe not trying to answer them in the correct way. The trials were largely positive when you look at the top-line results, but didn't reach the statistically significant outcomes, so the results were mixed from that point of view. That occurred at roughly the same time there was a deepening interest in this ACVR1 inhibition and modulation of hepcidin, so MOMENTUM was designed to be a straightforward, classic phase 3 trial which asked the question of [can we] perhaps improve anemia in patients with myelofibrosis?

What were the key findings from MOMENTUM which led to the FDA approval of the agent?

In the MOMENTUM study, danazol was chosen as the control arm because it is an active agent at ameliorating anemia in patients with myelofibrosis, again being the main angle of momelotinib, it made sense to choose that as a comparator. Key top-line results were presented at the [2022] ASCO meeting and showed that momelotinib was not inferior to danazol in terms of transfusion independence in the patients enrolled on MOMENTUM, but certainly superior in terms of spleen volume response and symptom burden response. These are patients who were previously exposed to a JAK inhibitor, who were anemic, and who had a significant symptom burden. so kind of a pretty typical patient that we see in the clinic every day.

The data presented at the end was subsequently published in The Lancet. There was an update for week 48 given at the ASH Annual Meeting in December of 2022. In the open-label continuation of that study, we saw that responses with momelotinib were maintained when looking at both anemia response, symptom, and spleens. Patients who crossed over from danazol to momelotinib benefited, and a key point that was a bit of a surprise to us was that patients who weren't initially responders on momelotinib ultimately responded with extended therapy. But most importantly, from that extended analysis was the fact that no new safety signals were seen. With the early development of momelotinib, there was a lot of concern over peripheral neuropathies. In the phase 2 trials that were done leading into the MOMENTUM study, as well as MOMENTUM itself, the rates of peripheral neuropathy were incredibly low and similar between the 2 studies.

With the toxicities that have been seen, how will this affect the use of momelotinib in clinical practice?

If someone has peripheral neuropathy or a setup for peripheral neuropathy, you want to be careful using momelotinib because that history is still there. You want to monitor that going forward when someone starts therapy. With all JAK inhibitors, there is warning for major adverse cardiac events, and that's true for JAK inhibitors used to treat MPNs as well as rheumatologic disorders.

As with any JAK inhibitor, although we do see improvements in anemia in patients with myelofibrosis and these trials with momelotinib includes patients with platelet counts as low as 25,000, we do want to make sure that patients aren't acquiring additional or deepening cytopenias, and we may need to adjust based on that as well. Also, in consideration for the class effect of JAK inhibitors, it would be worth keeping an eye out for nonmelanoma skin cancers and viral reactivations. Again, excess nonmelanoma skin cancers and viral reactivations have not been seen and seen with momelotinib but have certainly been seen with other JAK inhibitors. I think it would be wise just to keep your eye out for those things.

How do you foresee this approval impacting the myelofibrosis treatment landscape?

Certainly, there will be a shifting of the sands with this approval of momelotinib because there you have to make room for a fourth agent. The key is the label indications and what the label indication will be. We need to know what exactly the label says because that largely determines what payers will pay for. Fortunately, the way medicine is in the year 2023 is you have to consider insurance companies and what they will and will not cover. Also, we'll have to see how momelotinib is incorporated in guidelines because guidelines help guide care, at least here in North America, as well as you know gives basis for authorization through those pairs.

Based on the most recent trials, including MOMENTUM, this will be a key therapy for patients who have anemia and who have been previously treated with a JAK inhibitor. I think the bigger question remains, what will be the uptake in the upfront setting and in patients with thrombocytopenia.

What advice do you have for community oncologists moving forward with the use of momelotinib?

In the MOMENTUM study, as well as in the SIMPLIFY studies, momelotinib is a highly effective and highly active agent in treating spleen volumes and symptom burdens, as well as a potential anemia benefit. Certainly, this drug is very valuable in the space and toxicities were not excessive and were on par with what we expect normally with the JAK inhibitor. I would have little reservation using it in everyday practice, but of course, myelofibrosis is a very uncommon disease. I would encourage any practicing hematologist or oncologist to [partner with a] specialist to help manage their patients.

Again, I can’t imagine anyone keeping up on everything all the time, and it is just so hard. There are a lot of nuances in the care of patients with myelofibrosis and for myeloproliferative neoplasms, and certainly partnering with someone who spends a vast majority of their time dealing with these things could be a benefit.

REFERENCE:

Verstovsek S, Gerds AT, Vannucchi 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.