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While currently approved Janus kinase (JAK) inhibitors (ruxolitinib, fedratinib) improve splenomegaly and symptoms, most can exacerbate myelofibrosis\u2010related anemia, a negative prognostic factor for survival. Momelotinib is a novel JAK1\/JAK2\/activin A receptor type 1 (ACVR1) inhibitor approved in the US, European Union, and the UK and is the first JAK inhibitor indicated specifically for patients with myelofibrosis with anemia. Momelotinib not only addresses the splenomegaly and symptoms associated with myelofibrosis by suppressing the hyperactive JAK\u2013STAT (signal transducer and activator of transcription) pathway but also improves anemia and reduces transfusion dependency through ACVR1 inhibition. The recommended dose of momelotinib is 200\u2009mg orally once daily, which was established after review of safety, efficacy, pharmacokinetic, and pharmacodynamic data. Momelotinib is metabolized primarily by CYP3A4 and excreted as metabolites in feces and urine. Steady\u2010state maximum concentration is 479\u2009ng\/mL (CV%, 61%), with a mean AUC<jats:sub>tau<\/jats:sub> of 3288\u2009ng.h\/mL (CV%, 60%); its major metabolite, M21, is active (\u224840% of pharmacological activity of parent), with a metabolite\u2010to\u2010parent AUC ratio of 1.4\u20132.1. This review describes momelotinib's mechanism of action, detailing how the JAK\u2013STAT pathway is involved in myelofibrosis pathogenesis and ACVR1 inhibition decreases hepcidin, leading to improved erythropoiesis. Additionally, it summarizes the pivotal studies and data that informed the recommended dosage and risk\/benefit assessment.<\/jats:p>","DOI":"10.1111\/cts.70018","type":"journal-article","created":{"date-parts":[[2024,8,27]],"date-time":"2024-08-27T13:38:48Z","timestamp":1724765928000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Momelotinib: Mechanism of action, clinical, and translational science"],"prefix":"10.1111","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7390-9712","authenticated-orcid":false,"given":"Georgios","family":"Vlasakakis","sequence":"first","affiliation":[{"name":"GSK  Collegeville Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5715-9563","authenticated-orcid":false,"given":"Michael T.","family":"McCabe","sequence":"additional","affiliation":[{"name":"GSK  Collegeville Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0074-1938","authenticated-orcid":false,"given":"Yu Liu","family":"Ho","sequence":"additional","affiliation":[{"name":"GSK  Collegeville Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5703-8315","authenticated-orcid":false,"given":"Geraldine","family":"Ferron\u2010Brady","sequence":"additional","affiliation":[{"name":"GSK  Collegeville Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2598-4520","authenticated-orcid":false,"given":"Paul","family":"Martin","sequence":"additional","affiliation":[{"name":"Certara Drug Development Solutions  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2136-9264","authenticated-orcid":false,"given":"Darren","family":"Bentley","sequence":"additional","affiliation":[{"name":"Certara Drug Development Solutions  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7635-7846","authenticated-orcid":false,"given":"Catherine","family":"Ellis","sequence":"additional","affiliation":[{"name":"GSK  Collegeville Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Antonysamy","sequence":"additional","affiliation":[{"name":"GSK  Collegeville Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2186-7195","authenticated-orcid":false,"given":"Sandra A. 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