A phase 3 trial of luspatercept in patients with transfusion-dependent β-thalassemia

BACKGROUND Patients with transfusion-dependent ?-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor ? superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients. METHODS In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent ?-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies. RESULTS A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P
Abbott Laboratories Novartis Alexion Pharmaceuticals Terumo BCT Celgene FibroGen: 7,988,973, 8,007,809, 8,895,016 Novartis Pharma Acceleron Vifor Pharma
Supported by Celgene in collaboration with Acceleron Pharma. Dr. Cappellini reports receiving grant support, paid to her institution, and advisory board fees from Celgene; Dr. Viprakasit, receiving consulting fees from Celgene; Dr. Taher, receiving research funding and consulting fees from Celgene; Dr. Georgiev, receiving grant support from Celgene; Dr. Kuo, receiving advisory board fees from Agios Pharmaceuticals, Apellis Pharmaceuticals, and Celgene, lecture fees and advisory board fees from Alexion Pharmaceuticals, fees for serving on a data and safety monitoring board from Bioverativ Therapeutics, consulting fees from Bluebird Bio, lecture fees and consulting fees from Novartis, and grant support and consulting fees from Pfizer; Dr. Coates, receiving advisory board fees from Agios Pharmaceuticals and Celgene and advisory board fees and consulting fees from ApoPharma; Dr. Liew, receiving grant support, paid to his institution, from Celgene; Dr. Forni, receiving advisory board fees from Bluebird Bio, Celgene, and Novartis Pharma; Dr. Lal, receiving grant support, paid to his institution, from Bluebird Bio, Insight Magnetics, La Jolla Pharmaceutical Company, Novartis, Protagonist Therapeutics, and Terumo BCT, and grant support, paid to his institution, and advisory board fees from Celgene; Dr. Kattamis, receiving advisory board fees, fees for serving on a steering committee, and travel support from Celgene, grant support, paid to his institution, and advisory board fees from Novartis, fees for serving on a trial steering committee from Vertex Pharmaceuticals, and advisory board fees from Vifor Pharma; Dr. Origa, receiving grant support from Celgene; Dr. Aydinok, receiving grant support, paid to Ege University Hospital, from Celgene; Dr. Shah, receiving advisory board fees from Bluebird Bio and Roche, advisory board fees, lecture fees, and fees for serving on a steering committee from Celgene, advisory board fees and lecture fees from Novartis, and lecture fees from Sobi; Dr. Neufeld, receiving fees for serving on a data and safety monitoring board and consulting fees from Acceleron Pharma, fees for serving on a data and safety monitoring board from ApoPharma, advisory board fees and fees for serving on a steering committee from Celgene, and advisory board fees and consulting fees from Novartis Pharma; Dr. Thompson, receiving grant support, paid to her institution, from Baxalta and BioMarin Pharmaceuticals, and grant support, paid to her institution, and consulting fees from Bluebird Bio, Celgene, and Novartis Pharma; Dr. Shetty, being employed by Celgene; Dr. Zhang, being employed by and owning stock and stock options in Celgene; Dr. Miteva, being employed by Celgene; Dr. Zinger, being employed by and owning stock options in Celgene; Dr. Linde, being employed by and owning stock in Acceleron Pharma and owning stock in Abbott Laboratories and FibroGen; Dr. Sherman, being employed by and receiving consulting fees from Acceleron Pharma and Deciphera Pharmaceuticals, receiving consulting fees from Fusion Pharma and Mersana Therapeutics and fees for serving as a board member from Newlink Genetics, Pieris Pharmaceuticals, and Pulmatrix, and holding patents 10,093,707, 8,007,809, 8,895,016, and 7,988,973 on antagonists of activin-ActRIIA and uses for increasing red-cell levels, licensed to Acceleron Pharma; Dr. Hermine, receiving grant support from Alexion Pharmaceuticals, Celgene, and Takeda California; Dr. Porter, receiving lecture fees and advisory board fees from Agios Pharmaceuticals, advisory board fees and presentation fees from Bluebird Bio, advisory board fees from Celgene, and fees for serving on a steering committee from Vifor Pharma; and Dr. Piga, receiving grant support, paid to his institution, from Acceleron and grant support, paid to his institution, and advisory fees from Celgene. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. A data sharing statement provided by the authors is available with the full text of this article at NEJM.org. We thank the patients and families who participated in the BELIEVE trial; the investigators who collaborated in the trial; personnel at Acceleron Pharma, including Kenneth M. Attie, Xiaosha Zhang, Carolyn J. Barron, Joseph G. Reynolds, John Oram, and Tad Akers; and Daria I. Grisanzio of Excerpta Medica and Khaled Musallam and Hannah Wills of AMICULUM for writing assistance with an earlier version of the manuscript.