TY - JOUR
T1 - ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial
AU - Oh, Stephen T.
AU - Talpaz, Moshe
AU - Gerds, Aaron T.
AU - Gupta, Vikas
AU - Verstovsek, Srdan
AU - Mesa, Ruben
AU - Miller, Carole B.
AU - Rivera, Candido E.
AU - Fleischman, Angela G.
AU - Goel, Swati
AU - Heaney, Mark L.
AU - Connell, Casey O.
AU - Arcasoy, Murat O.
AU - Zhang, Yafeng
AU - Kawashima, Jun
AU - Ganz, Tomas
AU - Kowalski, Mark
AU - Brachmann, Carrie Baker
N1 - Funding Information:
This work was supported by Gilead Sciences, Inc. Writing support was provided by Impact Communication Partners and funded by Gilead Sciences, Inc.
Funding Information:
Conflict-of-interest disclosure: S.T.O. has served as a consultant for Incyte, Gilead Sciences, Novartis, Celgene/Bristol Myers Squibb, Blueprint Medicines, Kartos Therapeutics, Disc Medicine, and CTI BioPharma. M.T. has received clinical research funding from AbbVie, Novartis, CTI BioPharma, Constellation Pharmaceuticals, Celgene, and NS Pharma. A.T.G. has served as a consultant for CTI BioPharma, Celgene, Kartos Therapeutics, Promedior, and Pfizer. V.G. has served as a consultant for Novartis, Celgene, Sierra Oncology, and Pfizer and has received research funding from Novartis and Incyte. S.V. has received research support for conduct of clinical studies from Incyte, Roche, NS Pharma, Celgene, Gilead Sciences, Promedior, CTI BioPharma, Genentech, Blueprint Medicines, Novartis, Sierra Oncology, Pharma Essentia, AstraZeneca, Ital Pharma, Protagonist Therapeutics, Constellation Pharmaceuticals, Kartos Therapeutics, Prelude Therapeutics, AbbVie, and Telios Pharmaceuticals and has received consulting fees from Constellation Pharmaceuticals, Sierra Oncology, Incyte, Novartis, and Celgene. R.M. has served as a consultant for Novartis, Sierra Oncology, and La Jolla Pharmaceutical and has received research funding from Incyte, CTI BioPharma, Celgene, and Genentech. C.B.M. has served as a consultant for Incyte, Verastem Oncology, and CTI BioPharma. A.G.F. serves on the speaker’s bureau for
Funding Information:
Incyte. M.L.H. has served as a consultant for Blueprint Medicines, Roche, Shire, and Partner Therapeutics and has received research funding from Blueprint Medicine, Bristol Myers Squibb, Constellation Pharmaceuticals, CTI BioPharma, Deciphera Pharmaceuticals, Gilead Sciences, Incyte, Janssen, Novartis, Onconova Therapeutics, and Roche. C.O. has served on an advisory board for AbbVie . M.O.A. has received research funding from Gilead Sciences, Incyte, Janssen, CTI BioPharma, and Samus Therapeutics. T.G. has served as a consultant for Sierra Oncology, Keryx/Akebia, Ionis, Vifor Pharma, American Regent, Silarus Therapeutics, Gossamer Bio, and Disc Medicine; has received research funding from Sierra
Publisher Copyright:
© 2020 by The American Society of Hematology
PY - 2020/9
Y1 - 2020/9
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85091538560&partnerID=8YFLogxK
U2 - 10.1182/BLOODADVANCES.2020002662
DO - 10.1182/BLOODADVANCES.2020002662
M3 - Article
C2 - 32915978
AN - SCOPUS:85091538560
VL - 4
SP - 4282
EP - 4291
JO - Blood advances
JF - Blood advances
SN - 2473-9529
IS - 18
ER -