<p>Evaluating the Safety, Efficacy, and Therapeutic Potential of Momelotinib in the Treatment of Intermediate/High-Risk Myelofibrosis: Evidence to Date</p>

Abstract

Myelofibrosis is a heterogeneous disorder with regard to both molecular pathogenesis and clinical phenotype, ranging from an initial fairly indolent condition in some through to an aggressive and debilitating scenario with profound constitutional symptoms, cytopenia frequently requiring transfusional support, and massive splenomegaly. Many advances have been made within the therapeutic arena, and an increasing array of novel agents are now available for disease management. Within this review, we focus on the current and predicted role of the JAK inhibitor momelotinib (Sierra Oncology) in myelofibrosis, with an emphasis on clinical trial evaluation, drug efficacyand safety, and discuss the suggested place in the therapeutic paradigm of myelofibrosis in 2020 and beyond.

Deferasirox in the management of iron overload in patients with myelofibrosis treated with ruxolitinib: The multicentre retrospective RUX‐IOL study

“…The anaemia benefits were observed in conjunction with decreased plasma hepcidin and improved iron homeostasis likely contributing to increased erythropoiesis, consistent with the action mechanism of the drug. However, MMB did not appear to be superior to RUX with regards to improving splenomegaly and constitutional symptoms and hence the drug remains unlicensed at present 42–44 . Therefore, we may hypothesize that RUX will continue to be widely used in patients with significant splenomegaly or systemic symptoms, regardless of the presence of anaemia.…”

Next Generation Therapeutics for the Treatment of Myelofibrosis

“…However, there are novel JAKi in development which may be useful in these challenging scenarios. Momelotinib is a selective inhibitor of JAK1, JAK2, and ACVR1 which is being developed in anemic MF patients [ 20 ]. In preclinical models, inhibition of ACVR1 by momelotinib leads to decreased hepcidin production, which mobilizes sequestered iron and improves erythropoiesis [ 21 ].…”

Momelotinib: an emerging treatment for myelofibrosis patients with anemia

“…Indeed, the median duration of transfusion-independence was not reached after more than 3 years in patients who achieved transfusion-independence in SIMPLIFY-1, and the median duration of transfusion-independence on momelotinib was more than one year in SIMPLIFY-2. As detailed above, momelotinib may also have overall survival benefits in frontline and second-line MF patients; however, no statistically significant difference was found between the two arms of SIMPLIFY-1 (momelotinib versus ruxolitinib) with respect to leukemic transformation [ 103 ].…”

“…Besides the benefits of momelotinib with respect to anemia/transfusion-dependence and its ability to also effectively address the other two hallmarks of MF (splenomegaly and constitutional symptoms) [ 103 ], momelotinib conferred notable survival outcomes in both JAK inhibitor-naïve and ruxolitinib-pretreated patients. In particular, in the SIMPLIFY-1 trial, patients who were treated with ruxolitinib during the initial randomization period and crossed over to momelotinib thereafter had a median OS of 53.1 months, whereas the median OS had not been reached for the patients originally randomized to momelotinib (HR = 0.99, P = 0.97) [ 91 ].…”