Science

Pipeline

Sierra is currently recruiting for its pivotal Phase 3 clinical study, MOMENTUM, a randomized double-blind trial for myelofibrosis patients who are symptomatic and anemic, and who have been treated previously with a JAK inhibitor.

Momelotinib Overview

Momelotinib is a novel, orally bioavailable inhibitor of JAK1, JAK2, and ACVR1. This combined profile is unique amongst currently approved and emerging JAK inhibitor-based therapeutics. Momelotinib is an investigational agent that has not been approved by any regulatory agency.

Data from worldwide clinical trials involving more than 800 patients with MF—across the continuum of intermediate/high risk patients including JAKi-naïve and previously JAKi-treated subjects—suggest that momelotinib has the potential to improve constitutional symptoms and splenomegaly while also addressing the chronic anemia and transfusion dependency associated with the disease. The most commonly reported grade 3 or 4 adverse events observed in randomized Phase 3 trials with momelotinib include thrombocytopenia, anemia, diarrhea and neutropenia.

It is hypothesized that momelotinib’s anemia impact may be achieved through direct inhibition of ACVR1, leading to a decrease in circulating hepcidin. Hepcidin is often markedly elevated in MF and contributes to iron restricted anemia. By lowering hepcidin, a corresponding increase in available serum iron occurs with consequent clinically relevant increases in hemoglobin and red blood cells.15

15 Asshoff M, Petzer V, Warr M, et al. 2017. Blood. 129(13):1823-1830.
Oh S, Talpaz M, Gerds A, et al. 2020. Blood Advances. 4(18):4282-4291.

Publications

More than 820 patients with myelofibrosis have received momelotinib during its development, including a number of patients who remain on treatment since the start of the original Phase 2 studies initiated a decade ago. The data presented at EHA 2020 and ASH 2020 draw from more than 550 patients across the two previously conducted SIMPLIFY Phase 3 studies and their subsequent ongoing extended treatment periods, and further demonstrate the potential anemia benefits and favorable hematological safety profile and long-term term tolerability of momelotinib.

 

Professor Claire Harrison Presents Momelotinib Safety Data

Consistent with prior data, and reflecting momelotinib’s differentiated pharmacological profile, our new long-term safety analyses continue to show a rapid and sustained increase in hemoglobin levels during momelotinib therapy, in contrast to the significant decrease in hemoglobin for patients receiving ruxolitinib. Patients treated with momelotinib also experienced significantly higher mean platelet counts compared to those receiving ruxolitinib. Importantly, patients who switched from ruxolitinib to momelotinib also achieved a sustained improvement in both hemoglobin and platelets. In addition to an absence of significant rates of high-grade hematological toxicities, long-term tolerability was favorable with no new safety signals or evidence of cumulative toxicity. Notably, this was achieved with most patients receiving full-dose momelotinib.” Prof. Claire Harrison, Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom.

 

Dr. Vikas Gupta Presents Momelotinib Dose-Intensity Data

“Momelotinib’s safety profile and durable anemia benefits facilitated sustained dose intensity across the continuum of JAK inhibitor naïve and previously JAK inhibitor treated myelofibrosis patients. While the starting doses for ruxolitinib were often attenuated due to low platelets, further reductions in dose intensity were also commonly required for ruxolitinib. In contrast, momelotinib was initiated at full dose for all subjects enrolled to the SIMPLIFY studies and high dose intensity was maintained in the majority over extended durations. The ability to safely dose momelotinib sustainably at high dose intensity likely facilitates its ability to durably control the cardinal features of myelofibrosis, namely anemia, constitutional symptoms, and splenomegaly. Furthermore, patients who switch from ruxolitinib to momelotinib saw an immediate and sustained improvement in dose intensity, suggesting a link to the corresponding improvements in hemoglobin and platelets noted by Prof. Harrison. These data suggest that momelotinib may be an optimal therapy in myelofibrosis patients, in particular those experiencing hematological toxicity and disease-related myelosuppression, which are significant unmet needs in this disease.”