Momelotinib is a novel, orally bioavailable inhibitor of three key signaling pathways: JAK1, JAK2, and ACVR1/ALK2. This combined profile is unique amongst currently approved and emerging JAK inhibitor-based therapeutics. By inhibiting ACVR1/ALK2 as well as JAK1 and JAK2, we believe that momelotinib has the potential to improve anemia as well as improving constitutional symptoms and splenomegaly while preserving platelet count. Momelotinib is an investigational agent and 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 and high-risk patients, including those who are JAKi-naïve and previously JAKi-treated 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/ALK2, 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.
SRA515 (formerly AZD5153) is a selective BRD4 BET inhibitor with a novel bivalent binding mode that inhibits both protein bromodomains. Preclinical and early clinical data suggest SRA515 is a differentiated BET inhibitor through its high potency, selectivity, and bivalent binding, which may offer more complete target inhibition relative to monovalent binders.
1 Asshoff M, Petzer V, Warr M, et al. 2017. Blood. 129(13):1823-1830.
The combination of JAK inhibition plus BET inhibition has been identified as a promising emergent approach for the treatment of myelofibrosis. Evidence suggests that inhibition of both JAK and BET pathways can result in the synergistic reduction of disease and overall improvement in the prognosis of myelofibrosis. However, currently available JAK inhibitors are myelosuppressive, leaving a critical unmet need for patients with anemia or those at risk of developing treatment-emergent anemia.
Unlike currently approved JAK inhibitors, momelotinib is not myelosuppressive, therefore we believe the combination of momelotinib and SRA515 may provide an efficacy and safety advantage over other JAK inhibitor plus BET inhibitor combinations. Specifically, the combination may have the potential to deepen and prolong improvements in anemia, symptoms and splenomegaly as well as reduce bone marrow fibrosis and clonal proliferation. There also could be synergistic NF-kB inhibition with the combination.
Initiation of a Phase 2 clinical trial evaluating the combination of momelotinib and SRA515 is planned for the first half of 2022. The trial will be designed to provide preliminary proof of concept for a future confirmatory study and support potential additional studies of momelotinib with other novel agents in development for myelofibrosis.
Clinical Relevance of BET Inhibition
Inhibitors of the Bromodomain and Extra-terminal Domain (BET) protein family consisting of BRD2, BRD3, BRD4 and BRDT) can modify a range of pathological cellular processes, including the initiation and continuation of transcription and cell cycle control. BET inhibition can lead to decreased inflammatory cytokine release, anti-fibrotic activity and reduced mutant cell proliferation, all of which are indicative of disease-modifying effects in myelofibrosis.
Several BET inhibitors are under clinical investigation in multiple solid tumor and hematologic indications, including myelofibrosis.
Sources: Rhyasen et al, Molecular Cancer Ther., 15(11) 2563-74; Rhyasen et al, Plos ONE, July 2018; and Wang et al, Abstract 3085, ASCO 2018.
More than 820 patients with myelofibrosis have received momelotinib during its development, including a number of patients who remain on treatment for more than ten years since the start of the original Phase 2 studies. The data presented at EHA 2020, ASH 2020 and EHA 2021 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, favorable hematological safety profile and long-term term tolerability of momelotinib.
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.
“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.”