Emerging therapies for Duchenne muscular dystrophy.

Duchenne muscular dystrophy is an X-linked disease caused by the absence of functional dystrophin in the muscle cells. Major advances have led to the development of gene therapies, tools that induce exon skipping, and other therapeutic approaches, including treatments targeting molecular pathways downstream of the absence of functional dystrophin. However, glucocorticoids remain the only treatment unequivocally shown to slow disease progression, despite the adverse effects associated with their long-term use. Besides glucocorticoids, which are standard care, five compounds have received regulatory approval in some but not all jurisdictions, with further efficacy results being awaited. Several compounds with promising results in early-phase clinical trials have not met their efficacy endpoints in late-phase trials, but the clinical development of many other compounds is ongoing. The current landscape is complicated by the number of compounds in various stages of development, their various mechanisms of action, and their genotype-specific applicability. The difficulties of clinical development that arise from both the rarity and variability of Duchenne muscular dystrophy might be overcome in the future by use of sensitive biomarkers, natural history data, and ameliorated trial designs.

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Declaration of interests TM is an Onassis Foundation Scholar (Scholarship ID: F ZQ 040-1/2020-2021). MO serves as a methodologist for the American Academy of Neurology and a volunteer member of the Medical and Scientific Advisory Board for Muscular Dystrophy Canada; and is a clinical research scholar supported by the Fonds de recherche du Québec Santé. MAF received grant support from the National Health and Medical Research Council of Australia (APP1194940). NG has participated on data safety monitoring or advisory boards of Pfizer, Wave Life Sciences, Sarepta Therapeutics, Pliant Therapeutics, and Santhera Pharmaceuticals. LS has participated on data safety monitoring or advisory boards of FibroGen, Santhera Pharmaceuticals, RegenexBio, and Catabasis Pharmaceuticals, and is supported by a grant from Muscular Dystrophy UK. TD has received payment for lectures from Sarepta Therapeutics. NG has received payment for lectures from Sarepta Therapeutics and Santhera Pharmaceuticals. TD has received consulting fees from Pfizer, Edgewise Therapeutics, Dyne Therapeutics, Solid Biosciences, and ATOM International. MAF has received consulting fees from Pfizer. LS has received consulting fees from Sarepta, Pfizer, and F Hoffmann La Roche. TD is a member of TreatNMD Advisory Committee for Therapeutics (TACT), Treat-NMD Duchenne muscular dystrophy database committee, CureDuchenne, and Parent Project Muscular Dystrophy. LS is executive secretary of the World Muscle Society.