Momelotinib for the treatment of myelofibrosis in patients with moderate-to-severe anemia: a drug safety evaluation

INTRODUCTION: Momelotinib is an oral inhibitor of Janus kinase 1 and 2 (JAK1/JAK2) and of activin A receptor type 1 (ACVR1). Its key distinguishing feature is the suppression of hepcidin through ACVR1 inhibition, which mitigates the iron-restricted anemia observed in myelofibrosis (MF) due to the hyperinflammatory state. It is the first agent approved for intermediate- or high-risk MF with potential to treat anemia and reduce transfusion dependence. AREAS COVERED: We review the pharmacology, efficacy, and principally, the safety profile of momelotinib in MF patients with moderate-to-severe anemia. We integrate the controlled safety data of SIMPLIFY-1, SIMPLIFY-2 and MOMENTUM with the rapidly expanding post-marketing real-world evidence (>700 patients across five independent cohorts) and place the profile in the context of the alternative second-line JAK inhibitors fedratinib and pacritinib. EXPERT OPINION: Momelotinib reshapes the therapeutic algorithm for the anemic myelofibrosis patient, an unmet need that other JAK inhibitors aggravate rather than relieve. The trial-derived haematological profile is favorable, but real-world monitoring has surfaced two signals - treatment-emergent nephropathy and peripheral neuropathy - that were not fully detected in the registration program and now warrant active monitoring. Outstanding questions concern long-term renal and neurological safety, optimal sequencing, and survival benefit.