[en] Spinal muscular atrophy (SMA) is a rare, genetic neurodegenerative disorder caused by insufficient production of survival motor neuron (SMN) protein. Diminished SMN protein levels lead to motor neuron loss, causing muscle atrophy and weakness that impairs daily functioning and reduces quality of life. SMN upregulators offer clinical improvements and increased survival in SMA patients, although significant unmet needs remain. Myostatin, a TGF-β superfamily signaling molecule that binds to the activin II receptor, negatively regulates muscle growth; myostatin inhibition is a promising therapeutic strategy for enhancing muscle. Combining myostatin inhibition with SMN upregulation, a comprehensive therapeutic strategy targeting the whole motor unit, offers promise in SMA. Taldefgrobep alfa is a novel, fully human recombinant protein that selectively binds to myostatin and competitively inhibits other ligands that signal through the activin II receptor. Given a robust scientific and clinical rationale and the favorable safety profile of taldefgrobep in patients with neuromuscular disease, the RESILIENT phase 3, randomized, placebo-controlled trial is investigating taldefgrobep as an adjunct to SMN upregulators in SMA (NCT05337553). This manuscript reviews the role of myostatin in muscle, explores the preclinical and clinical development of taldefgrobep and introduces the phase 3 RESILIENT trial of taldefgrobep in SMA.
Disciplines :
Pediatrics
Author, co-author :
Servais, Laurent ; Université de Liège - ULiège > Département des sciences cliniques ; Department of Pediatrics, University of Oxford, Oxford OX3 9DU, UK
Lair, Lindsey Lee ; Biohaven Pharmaceuticals Inc., New Haven, CT 06510, USA
Connolly, Anne M; Nationwide Children's Hospital, Columbus, OH 43205, USA
Byrne, Barry J; Department of Pediatrics, University of Florida, Gainesville, FL 32611, USA
Chen, Karen S; Spinal Muscular Atrophy Foundation, 970 W Broadway STE E, PMB 140, Jackson, WY 83001, USA
Coric, Vlad; Biohaven Pharmaceuticals Inc., New Haven, CT 06510, USA
Qureshi, Irfan; Biohaven Pharmaceuticals Inc., New Haven, CT 06510, USA
Durham, Susan; Biohaven Pharmaceuticals Inc., New Haven, CT 06510, USA
Campbell, Daniel J; Biohaven Pharmaceuticals Inc., New Haven, CT 06510, USA
Maclaine, Grant; Biohaven Pharmaceuticals Inc., New Haven, CT 06510, USA
Marin, Jackie; Biohaven Pharmaceuticals Inc., New Haven, CT 06510, USA
Bechtold, Clifford; Biohaven Pharmaceuticals Inc., New Haven, CT 06510, USA
Language :
English
Title :
Taldefgrobep Alfa and the Phase 3 RESILIENT Trial in Spinal Muscular Atrophy.
Publication date :
24 September 2024
Journal title :
International Journal of Molecular Sciences
ISSN :
1661-6596
eISSN :
1422-0067
Publisher :
Multidisciplinary Digital Publishing Institute (MDPI), Switzerland
The authors thank the patients and their families who generously participated in the studies mentioned in this manuscript; the SMA Foundation, Cure SMA and SMA Europe for their commitment to serving as champions for the SMA community; and Eubio for providing editorial support funded by Biohaven, Ltd. This article is a revised and expanded version of a papers entitled Preclinical and Clinical Data Supporting the Phase 3 RESILIENT Study in Spinal Muscular Atrophy, which was presented at The 4th Scientific International Congress on Spinal Muscular Atrophy, Ghent, Belgium, 14\u201316 March 2024. The Phase 3 RESILIENT Study in Spinal Muscular Atrophy, which was presented at the 9th Congress of the European Academy of Neurology, Budapest, Hungary, 14 July 2023. The Phase 3 RESILIENT Study: Taldefgrobep Alfa in Spinal Muscular Atrophy, which was presented at the American Academy of Neurology, Denver, Colorado, USA, 13 April 2024. Taldefgrobep Alfa: Preclinical and Clinical Data Supporting the Phase 3 RESILIENT Study in Spinal Muscular Atrophy, which was presented at the 28th Annual Congress of the World Muscle Society. Charleston, South Carolina, USA, 3\u20137 October 2023.The RESILIENT phase 3 trial is funded by Biohaven Pharmaceuticals, Inc.
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