Momelotinib – a tale of trials, tribulations, transfusion independence, and triumph

Momelotinib is a small molecule inhibitor of JAK1, JAK2, and ACVR1 that is approved by the FDA and EMA for adults patients with intermediate/high risk myelofibrosis (MF) and anemia. Inhibition of the JAK-STAT pathway has a well-established role in MF therapy, producing reductions in MF-related symptoms and spleen size. Inhibition of ACVR1 downregulates hepcidin production and improves anemia. The mechanism of action of momelotinib addresses three critical aspects of morbidity in MF, ith both spleen and symptom-directed therapy for both cytopenic and proliferative MF patients. Key milestones in the development of momelotinib and its regulatory approvals are reviewed here. Additionally, the efficacy, safety, and tolerability of momelotinib are discussed. The literature review is based on a comprehensive search of English language, peer-reviewed articles using PubMed and clinical trial information is taken from w ww. ClinicalTrials.gov. Studies from 1 January 2000, through 31 January 2025, were included. The development of momelotinib represents an important breakthrough in MF therapy with spleen and symptom directed therapy with improvements in anemia and limited myelosuppression, facilitating dose intensity. Current and future research efforts for MF therapy are directed at development of newer, anemia-directed therapies including combinations with momelotinib.