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

ABSTRACT: 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.

SUBMITTER: Oh ST

PROVIDER: S-EPMC7509854 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Oh Stephen T ST Talpaz Moshe M Gerds Aaron T AT Gupta Vikas V Verstovsek Srdan S Mesa Ruben R Miller Carole B CB Rivera Candido E CE Fleischman Angela G AG Goel Swati S Heaney Mark L ML O'Connell Casey C Arcasoy Murat O MO Zhang Yafeng Y Kawashima Jun J Ganz Tomas T Kowalski Mark M Brachmann Carrie Baker CB

Blood advances 20200901 18

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, erythrop ...[more]

PMID: 32915978

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Project description:Myelofibrosis is a Philadelphia chromosome–negative myeloproliferative neoplasm associated with cytopenias, splenomegaly, poor quality of life, and shortened survival. About half of patients with myelofibrosis carry a gain-of-function mutation in the Janus kinase 2 gene (JAK2 V617F) that contributes to the pathophysiology of the disease. INCB018424 is a potent and selective Janus kinase 1 (JAK1) and JAK2 inhibitor.We conducted a phase 1?2 trial of INCB018424 in patients with JAK2 V617F?positive or JAK2 V617F?negative primary myelofibrosis, post–essential thrombocythemia myelofibrosis, or post–polycythemia vera myelofibrosis.A total of 153 patients received INCB018424 for a median duration of more than 14.7 months. The initial dose-escalation phase established 25 mg twice daily or 100 mg once daily as maximum tolerated doses, on the basis of reversible thrombocytopenia. A dose-dependent suppression of phosphorylated signal transducer and activator of transcription 3 (STAT3), a marker of JAK signaling, was demonstrated in patients with wild-type JAK2 and in patients with the JAK2 V617F mutation. We studied additional doses and established that a 15-mg twice-daily starting dose, followed by individualized dose titration, was the most effective and safest dosing regimen. At this dose, 17 of 33 patients (52%) had a rapid objective response (?50% reduction of splenomegaly) lasting for 12 months or more, and this therapy was associated with grade 3 or grade 4 adverse events (mainly myelosuppression) in less than 10% of patients. Patients with debilitating symptoms, including weight loss, fatigue, night sweats, and pruritus, had rapid improvement. Clinical benefits were associated with a marked diminution of levels of circulating inflammatory cytokines that are commonly elevated in myelofibrosis.INCB018424 was associated with marked and durable clinical benefits in patients with myelofibrosis for whom no approved therapies existed. (Funded by Incyte; ClinicalTrials.gov number, NCT00509899.)

Dataset Information

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

Publications

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

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