MPN-149: Long-Term Safety of Momelotinib in JAK Inhibitor-Naïve and Previously JAK Inhibitor-Treated Intermediate-/High-Risk Myelofibrosis Patients

Background: Momelotinib (MMB) is a potent, orally bioavailable, small-molecule inhibitor of JAK1, JAK2, and ACVR1 with demonstrable clinical activity against the three hallmark features of myelofibrosis (MF), namely anemia, constitutional symptoms, and splenomegaly, across the continuum of intermediate-/high-risk MF patients whether JAKi-naïve or previously JAKi-treated. Objective: To characterize the long-term safety of MMB in comparison to ruxolitinib (RUX). Methods: SIMPLIFY-1 was a double-blind, randomized, study of MMB vs RUX in intermediate-/high-risk JAKi-naïve patients with MF (n=215 MMB, 217 RUX). SIMPLIFY-2 (S2) was a randomized study of MMB vs best available therapy (BAT; RUX in 88% of patients) in prior RUX-treated patients with hematological toxicity (n=104 MMB, 52 BAT). Randomized treatment (RT) for 24 weeks was followed by open-label MMB extended treatment in both studies. Data from RT were compared, and further long-term data were analyzed from 550 subjects receiving MMB, including 336 subjects on MMB for ≥48 weeks and 148 for ≥144 weeks. Results: Despite treatment duration exceeding 3.5 years for >90 subjects, the incidence of grade 3/4 hematological toxicity was very low. During the S1 RT period, grade 3/4 anemia occurred in only 6.1% of MMB subjects compared with -4-fold higher rate (22.7%) for RUX. Dose reductions due to thrombocytopenia were also 4-fold higher for RUX (24.5%) than MMB (6.1%). Subjects randomized to MMB in S1 experienced a rapid, sustained increase in hemoglobin, in contrast to significant hemoglobin decrease on RUX. Following crossover to MMB from RUX, hemoglobin increased rapidly to above baseline. Platelet values were also significantly higher compared to RUX. Similarly, in S2, hemoglobin and platelet values were maintained or improved on MMB. Importantly, no new safety signals and no cumulative toxicity were observed during extended MMB dosing. Rates of peripheral neuropathy remained low. Conclusions: MMB displays very favorable long-term tolerability, including an absence of significant rates of high-grade hematological and other toxicities or evidence of cumulative toxicity, consistent with its differentiated pharmacological and clinical profile. Notably, subjects switching from RUX also experienced favorable tolerability, despite their previous therapy. Momelotinib (MMB) is a potent, orally bioavailable, small-molecule inhibitor of JAK1, JAK2, and ACVR1 with demonstrable clinical activity against the three hallmark features of myelofibrosis (MF), namely anemia, constitutional symptoms, and splenomegaly, across the continuum of intermediate-/high-risk MF patients whether JAKi-naïve or previously JAKi-treated. To characterize the long-term safety of MMB in comparison to ruxolitinib (RUX). SIMPLIFY-1 was a double-blind, randomized, study of MMB vs RUX in intermediate-/high-risk JAKi-naïve patients with MF (n=215 MMB, 217 RUX). SIMPLIFY-2 (S2) was a randomized study of MMB vs best available therapy (BAT; RUX in 88% of patients) in prior RUX-treated patients with hematological toxicity (n=104 MMB, 52 BAT). Randomized treatment (RT) for 24 weeks was followed by open-label MMB extended treatment in both studies. Data from RT were compared, and further long-term data were analyzed from 550 subjects receiving MMB, including 336 subjects on MMB for ≥48 weeks and 148 for ≥144 weeks. Despite treatment duration exceeding 3.5 years for >90 subjects, the incidence of grade 3/4 hematological toxicity was very low. During the S1 RT period, grade 3/4 anemia occurred in only 6.1% of MMB subjects compared with -4-fold higher rate (22.7%) for RUX. Dose reductions due to thrombocytopenia were also 4-fold higher for RUX (24.5%) than MMB (6.1%). Subjects randomized to MMB in S1 experienced a rapid, sustained increase in hemoglobin, in contrast to significant hemoglobin decrease on RUX. Following crossover to MMB from RUX, hemoglobin increased rapidly to above baseline. Platelet values were also significantly higher compared to RUX. Similarly, in S2, hemoglobin and platelet values were maintained or improved on MMB. Importantly, no new safety signals and no cumulative toxicity were observed during extended MMB dosing. Rates of peripheral neuropathy remained low. MMB displays very favorable long-term tolerability, including an absence of significant rates of high-grade hematological and other toxicities or evidence of cumulative toxicity, consistent with its differentiated pharmacological and clinical profile. Notably, subjects switching from RUX also experienced favorable tolerability, despite their previous therapy.