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Momelotinib: Mechanism of action, clinical, and translational science
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Journal Article
Momelotinib: Mechanism of action, clinical, and translational science
2024
Overview
Myelofibrosis is a chronic myeloproliferative disorder characterized by bone marrow fibrosis, splenomegaly, anemia, and constitutional symptoms, with a median survival of ≈6 years from diagnosis. While currently approved Janus kinase (JAK) inhibitors (ruxolitinib, fedratinib) improve splenomegaly and symptoms, most can exacerbate myelofibrosis‐related 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–STAT (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 mg 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‐state maximum concentration is 479 ng/mL (CV%, 61%), with a mean AUCtau of 3288 ng.h/mL (CV%, 60%); its major metabolite, M21, is active (≈40% of pharmacological activity of parent), with a metabolite‐to‐parent AUC ratio of 1.4–2.1. This review describes momelotinib's mechanism of action, detailing how the JAK–STAT 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.
Publisher
John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
Subject
/ Anemia
/ Animals
/ Benzamides - adverse effects
/ Benzamides - pharmacokinetics
/ Enzymes
/ Fibrosis
/ Hepcidin
/ Humans
/ Iron
/ Janus Kinase 1 - antagonists & inhibitors
/ Janus Kinase 2 - antagonists & inhibitors
/ Kinases
/ Mutation
/ Plasma
/ Primary Myelofibrosis - drug therapy
/ Primary Myelofibrosis - metabolism
/ Protein Kinase Inhibitors - administration & dosage
/ Protein Kinase Inhibitors - adverse effects
/ Protein Kinase Inhibitors - pharmacokinetics
/ Protein Kinase Inhibitors - pharmacology
/ Protein Kinase Inhibitors - therapeutic use
/ Pyrimidines - administration & dosage
/ Pyrimidines - adverse effects
/ Pyrimidines - pharmacokinetics
/ Pyrimidines - therapeutic use
/ Signal Transduction - drug effects
/ Survival
