Data Support Momelotinib as a Differentiated Approach to Treating Myelofibrosis

January 22, 2021
Jean-Jacques Kiladjian, MD, PhD

JAK inhibitors designed for the treatment of myelofibrosis address the splenic response and constitutional symptoms associated with the disease, but the agents are inherently myelosuppressive and can exacerbate anemia and thrombocytopenia.

JAK inhibitors (JAKi) designed for the treatment of myelofibrosis (MF) address the splenic response and constitutional symptoms associated with the disease, but the agents are inherently myelosuppressive and can exacerbate anemia and thrombocytopenia. Anemia is a common concern at presentation, and it generally progresses over time. In fact, dose reductions are common, and some patients never receive a JAKi, due to low platelet counts or severe anemia. Severe anemia can significantly impact a patient's quality of life and is typically managed with repeated blood transfusions.1

Hepcidin levels, a hormone that controls iron homeostasis, play an important role in the anemia of myelofibrosis. High levels of hepcidin restrict iron availability, suppressing the body's ability to make new red blood cells.2 Data show that both anemia and elevated hepcidin levels are strong prognostic indicators of survival in myelofibrosis.3,4

Momelotinib is an investigational therapy that may address anemia as well as the splenomegaly and constitutional systems through a unique mechanism of action.5 Similar to other currently approved treatments, momelotinib inhibits JAK1 and JAK2, but also inhibits ACVR1. Inhibition of ACVR1 leads to a decrease in hepcidin levels, potentially improving anemia and transfusion requirements.2

In multiple late-stage clinical trials momelotinib has been evaluated and is currently under investigation in the phase 3 MOMENTUM study (NCT04173494). The prior SIMPLIFY-1 trial (NCT01969838) was designed to evaluate momelotinib's potential in JAKi-naïve patients compared to ruxolitinib (Jakafi) and SIMPLIFY-2 (NCT02101268) explored its potential in patients who were previously treated with JAKis compared to best available therapy.6,7 Both previously completed studies had a 24-week randomized treatment phase and a long-term extension of open-label momelotinib. The primary endpoint for both studies was splenic response; secondary endpoints were total symptom score and transfusion independence.

Retrospective analyses of the SIMPLIFY-1 and SIMPLIFY-2 studies were recently presented at the 2020 American Society of Hematology (ASH) Annual Meeting and Exposition. One analysis sought to understand the effects of baseline platelet count and momelotinib efficacy. A second long-term follow-up analysis was conducted to understand the potential overall survival benefit in patients who remained on momelotinib following the initial 24-week trial period. 

Baseline Platelet Count May Not Impact Momelotinib Activity

In this retrospective analysis, patients were stratified into three groups: patients with baseline platelets ≤150 × 109/L, between 150-300 × 109/L and >300 × 109/L.

In SIMPLIFY-1, patients whose baseline platelet counts were below ≤150 × 109/L, momelotinib achieved substantially higher transfusion independence rates (62% vs. 42%) and splenic response rates (23% vs. 4%) and showed a similar symptomatic response (28% vs. 33%) relative to ruxolitinib. Patients with platelet counts between 150-300 × 109/L showed a similar splenic (35% vs. 32%) and symptom response rates (33% vs. 41%) and a higher transfusion independence rate (72% vs. 54%). In patients with platelet counts >300 × 109/L, ruxolitinib achieved higher splenic (44% vs. 19%) and symptom response rates (46% vs. 23%) at week 24. However, the final transfusion independence remained higher with momelotinib (63% vs. 51%).8

In SIMPLIFY-2, momelotinib's response rates for the three response parameters remain consistent with the overall intent-to-treat response rates in patients whose baseline platelets were ≤150 × 109 /L. Additionally, momelotinib's symptomatic and anemia benefit were also preserved in patients whose baseline platelet counts were <50 and >50-100 x 109/L. In both studies, rates of treatment-emergent adverse events on momelotinib were generally similar.8 

This retrospective analysis of the data from the two phase 3 SIMPLIFY studies demonstrate that momelotinib's safety and activity profile do not appear to be affected by baseline platelet counts. Ruxolitinib's activity declined in patients with lower baseline platelet counts. Therefore, the relative benefit-risk profile of momelotinib and ruxolitinib may be influenced by baseline platelet count and is generally comparable or favorable in JAKi-naïve patients with baseline platelet counts ≤ 300 x 109 /L. These retrospectiveefficacy analyses complement previous findings highlighting the ability to initiate and maintain near-maximal momelotinib dose intensity irrespective of baseline platelet count, suggesting that this durable dosing contributes to the compound's efficacy profile.

Robust Overall Survival Benefits With Momelotinib

In addition to this retrospective analysis, a long-term study of the SIMPLIFY-1 and SIMPLIFY-2 trials found robust overall survival (OS) benefits in both patients initially treated with, as well as those who crossed over to, momelotinib. In SIMPLIFY-1, the median OS was 53 months in patients who crossed over from ruxolitinib to momelotinib and has not been reached in patients initially treated with momelotinib (HR, 0.99, P =.97). In SIMPLIFY-2, the median OS was 34.3 months in patients initially treated with momelotinib and 37.5 months in the patients that crossed over from the best available therapy to momelotinib (HR, 0.96, P =.86).9

This analysis demonstrates a robust OS benefit for momelotinib in both JAK inhibitor-naïve and patients who were previously treated with ruxolitinib. In particular, the median OS of 34.3 and 37.5 months, observed in the two treatment arms of SIMPLIFY-2, compare favorably with OS previously reported in patients who have received JAK inhibitors in earlier lines of treatment.

Future Potential for Momelotinib

Cumulatively, these studies provide strong support for the potential of momelotinib as a new treatment option for patients with myelofibrosis. Its activity profile could allow patients and physicians to individualize treatment decisions based on factors such as anemia or pretreatment platelet counts and ultimately improve treatment outcomes.Moreover, the OS data demonstrate momelotinib’s potential as a long-term, sustainable treatment option. 

References:
1.  Tefferi A. Essential thrombocythemia, polycythemia vera, and myelofibrosis: Current management and the prospect of targeted therapy. Am J Hematol. 2008;83(6):491-497. doi:10.1002/ajh.21183
2. Oh ST, Talpaz M, Gerds AT, et al. ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial. Blood Adv. 2020;4(18):4282-4291. doi:10.1182/BLOODADVANCES.2020002662
3. Nicolosi M, Mudireddy M, Lasho TL, et al. Sex and degree of severity influence the prognostic impact of anemia in primary myelofibrosis: Analysis based on 1109 consecutive patients. Leukemia. 2018;32(5):1254-1258. doi:10.1038/s41375-018-0028-x
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6. Mesa RA, Kiladjian J-J, Catalano J V., et al. SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor–Naïve Patients With Myelofibrosis. J Clin Oncol. 2017;35(34):3844. doi:10.1200/JCO.2017.73.4418
7. Harrison CN, Schaap N, Vannucchi AM, et al. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematol. 2017;4(7):e317-e324. doi:10.1016/S2352-3026(17)30088-1
8. Kiladjian JJ. Momelotinib’s spleen, symptom and anemia efficacy is maintained in intermediate/high risk myelofibrosis patients with thrombocytopenia. December 2020.
9. Verstovsek S, Egyed M, Lech-Marańda E, et al. Robust overall survival and sustained efficacy outcomes during long term exposure to momelotinib in jak inhibitor naïve and previously jak inhibitor treated intermediate/high risk myelofibrosis patients. Blood. 2020;136(Suppl 1):51-52. doi:10.1182/BLOOD-2020-135872