ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial.

Journal Article (Journal Article)

Momelotinib (MMB) is a JAK1/2 and ACVR1 inhibitor with demonstrated clinical activity in all 3 hallmarks of myelofibrosis (MF): anemia, constitutional symptoms, and splenomegaly. In this phase 2 open-label translational biology study (NCT02515630) of 41 transfusion-dependent patients with MF, we explored mechanisms underlying the favorable activity of MMB on MF-associated iron-restricted anemia, including its impact on serum hepcidin levels, and markers of iron storage and availability, erythropoiesis, and inflammation. A transfusion-independent response (TI-R), defined as red blood cell transfusion independence (TI) ≥12 weeks at any time on study, occurred in 17 patients (41%; 95% confidence interval [CI], 26%-58%), including 14 patients (34%; 95% CI, 20%-51%) who achieved TI-R by week 24. In addition, 78% of TI nonresponse (TI-NR) patients achieved a ≥50% decrease in transfusion requirement for ≥8 weeks. Adverse events (AEs) were consistent with previous studies of MMB in MF, with cough, diarrhea, and nausea as the most common. Twenty-one patients experienced grade ≥3 AEs, most commonly anemia and neutropenia. Consistent with preclinical data, daily MMB treatment led to an acute and persistent decrease in blood hepcidin associated with increased iron availability and markers of erythropoiesis. Baseline characteristics associated with TI-R were lower inflammation and hepcidin as well as increased markers of erythropoiesis and bone marrow function. Overall, the study demonstrates that MMB treatment decreases hepcidin in conjunction with improving iron metabolism and erythropoiesis, suggesting a mechanistic explanation for the reduced transfusion dependency observed in transfusion-dependent MF patients treated with MMB, thereby addressing the key unmet medical need in the MF population.

Full Text

Duke Authors

Cited Authors

  • Oh, ST; Talpaz, M; Gerds, AT; Gupta, V; Verstovsek, S; Mesa, R; Miller, CB; Rivera, CE; Fleischman, AG; Goel, S; Heaney, ML; O'Connell, C; Arcasoy, MO; Zhang, Y; Kawashima, J; Ganz, T; Kowalski, M; Brachmann, CB

Published Date

  • September 22, 2020

Published In

  • Blood Adv

Volume / Issue

  • 4 / 18

Start / End Page

  • 4282 - 4291

PubMed ID

  • 32915978

Pubmed Central ID

  • PMC7509854

Electronic International Standard Serial Number (EISSN)

  • 2473-9537

Digital Object Identifier (DOI)

  • 10.1182/bloodadvances.2020002662


  • eng

Conference Location

  • United States