MPN-148: Momelotinib Dose-Intensity is Maintained in JAK Inhibitor-Naïve and Previously JAK Inhibitor-Treated Intermediate-/High-Risk Myelofibrosis Patients

Abstract

Background: Progressive dose reduction due to myelosuppression is common with ruxolitinib (RUX) treatment in myelofibrosis (MF) patients. Literature reports indicate that decreased RUX dose intensity (DI) is associated with loss of efficacy. Momelotinib (MMB) is a potent, orally bioavailable, inhibitor of JAK1, JAK2, and ACVR1 with differentiated anemia benefit and a favorable hematological safety profile. Objective: To characterize MMB DI vs RUX in the SIMPLIFY-1 (S1) and SIMPLIFY-2 (S2) Phase 3 studies. Methods: S1 was a double-blind, randomized, study of MMB vs RUX in intermediate-/high-risk JAKi-naive patients with MF (n=215 MMB, 217 RUX). S2 was a randomized study of MMB vs best available therapy (BAT; 88% RUX) in prior RUX-treated patients with hematological toxicity (n=104 MMB, 52 BAT). Mean daily doses of both agents were calculated over the 24-week randomized treatment (RT) periods and subsequent 24-week open-label (OL) periods. Results: In both studies, nearly all subjects commenced randomized MMB treatment at the full 200 mg QD dose and ∼85% continued at that dose throughout the RT period. In contrast, only ∼59% of RUX-randomized subjects in S1 started at the full 20 mg BID dose due to RUX's platelet-dictated dose schema. Furthermore, progressive RUX dose-reductions were observed in S1 with only ∼37% receiving the 20 mg or higher BID dose by the end of RT. Despite the preponderance of RUX dose reductions, subjects who switched to OL MMB in S1 achieved high MMB DI with ∼89% receiving full dose in the first week. Similarly, high MMB DI was noted in S2. Conclusions: These analyses demonstrate that MMB's differentiated anemia benefit and favorable hematological toxicity profile facilitate sustained DI and prolonged efficacy across the continuum of JAKi-naive and previously JAKi-treated intermediate/high risk patients, in contrast to progressive myelosuppression-induced dose reduction for RUX. Specifically, dose reductions or interruptions due to thrombocytopenia were 4-fold more frequent for RUX than MMB. Subjects who switched from RUX to MMB, including those receiving markedly reduced RUX doses, nearly always went on to receive full-dose MMB over an extended period, confirming the ability to maintain high DI MMB therapy in patients with RUX-induced or exacerbated hematological toxicity.