NYMC Faculty Publications

Taldefgrobep Alfa and the Phase 3 RESILIENT Trial in Spinal Muscular Atrophy

Author Type(s)

Faculty

DOI

10.3390/ijms251910273

Journal Title

International Journal of Molecular Sciences

First Page

10273

Document Type

Review Article

Publication Date

9-24-2024

Department

Neurology

Keywords

Humans, Myostatin, Muscular Atrophy, Spinal, Clinical Trials, Phase III as Topic, Activin Receptors, Type II, Animals, Recombinant Proteins

Disciplines

Medicine and Health Sciences

Abstract

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.

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