AAV gene therapy for Duchenne muscular dystrophy: the EMBARK phase 3 randomized trial

Duchenne muscular dystrophy (DMD) is a rare, X-linked neuromuscular disease caused by pathogenic variants in the DMD gene that result in the absence of functional dystrophin, beginning at birth and leading to progressive impaired motor function, loss of ambulation and life-threatening cardiorespiratory complications. Delandistrogene moxeparvovec, an adeno-associated rh74-viral vector-based gene therapy, addresses absent functional dystrophin in DMD. Here the phase 3 EMBARK study aimed to assess the efficacy and safety of delandistrogene moxeparvovec in patients with DMD. Ambulatory males with DMD, ≥4 years to <8 years of age, were randomized and stratified by age group and North Star Ambulatory Assessment (NSAA) score to single-administration intravenous delandistrogene moxeparvovec (1.33 × 10<sup>14</sup> vector genomes per kilogram; n = 63) or placebo (n = 62). At week 52, the primary endpoint, change from baseline in NSAA score, was not met (least squares mean 2.57 (delandistrogene moxeparvovec) versus 1.92 (placebo) points; between-group difference, 0.65; 95% confidence interval (CI), -0.45, 1.74; P = 0.2441). Secondary efficacy endpoints included mean micro-dystrophin expression at week 12: 34.29% (treated) versus 0.00% (placebo). Other secondary efficacy endpoints at week 52 (between-group differences (95% CI)) included: Time to Rise (-0.64 (-1.06, -0.23)), 10-meter Walk/Run (-0.42 (-0.71, -0.13)), stride velocity 95th centile (0.10 (0.00, 0.19)), 100-meter Walk/Run (-3.29 (-8.28, 1.70)), time to ascend 4 steps (-0.36 (-0.71, -0.01)), PROMIS Mobility and Upper Extremity (0.05 (-0.08, 0.19); -0.04 (-0.24, 0.17)) and number of NSAA skills gained/improved (0.19 (-0.67, 1.06)). In total, 674 adverse events were recorded with delandistrogene moxeparvovec and 514 with placebo. There were no deaths, discontinuations or clinically significant complement-mediated adverse events; 7 patients (11.1%) experienced 10 treatment-related serious adverse events. Delandistrogene moxeparvovec did not lead to a significant improvement in NSAA score at week 52. Some of the secondary endpoints numerically favored treatment, although no statistical significance can be claimed. Safety was manageable and consistent with previous delandistrogene moxeparvovec trials. ClinicalTrials.gov: NCT05096221.

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Publication Details

Journal
Nature Medicine
Published
2024-10-09
DOI
https://doi.org/10.1038/s41591-024-03304-z
Citations
128
Primary Topic
Muscle Physiology and Disorders
Type
article
Field-Weighted Citation Impact
29.93

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article

AAV gene therapy for Duchenne muscular dystrophy: the EMBARK phase 3 randomized trial

Alexander P. Murphy, Louise R. Rodino‐Klapac, Craig M. Zaidman, Christoph Wandel et al.
128 citations
Nature Medicine
Muscle Physiology and Disorders
29.93
article

AAV gene therapy for Duchenne muscular dystrophy: the EMBARK phase 3 randomized trial

Alexander P. Murphy, Louise R. Rodino‐Klapac, Craig M. Zaidman, Christoph Wandel, Eddie Darton, Carol Reid, Rachael A. Potter, Stefanie Mason, Ulrike Schara‐Schmidt, Eugenio Maria Mercuri, Emma Ciafaloni, Paulo Fontoura, Teji Singh, A. Nascimento, Aravindhan Veerapandiyan, Crystal M. Proud, Damon R. Asher, Hirofumi Komaki, Craig M. McDonald, Carmen Leon‐Astudillo, Maitea Guridi, Francesco Muntoni, Wenfei Zhang, Jerry R. Mendell, Jacob Elkins
article en
128 citations

Abstract

Duchenne muscular dystrophy (DMD) is a rare, X-linked neuromuscular disease caused by pathogenic variants in the DMD gene that result in the absence of functional dystrophin, beginning at birth and leading to progressive impaired motor function, loss of ambulation and life-threatening cardiorespiratory complications. Delandistrogene moxeparvovec, an adeno-associated rh74-viral vector-based gene therapy, addresses absent functional dystrophin in DMD. Here the phase 3 EMBARK study aimed to assess the efficacy and safety of delandistrogene moxeparvovec in patients with DMD. Ambulatory males with DMD, ≥4 years to <8 years of age, were randomized and stratified by age group and North Star Ambulatory Assessment (NSAA) score to single-administration intravenous delandistrogene moxeparvovec (1.33 × 10<sup>14</sup> vector genomes per kilogram; n = 63) or placebo (n = 62). At week 52, the primary endpoint, change from baseline in NSAA score, was not met (least squares mean 2.57 (delandistrogene moxeparvovec) versus 1.92 (placebo) points; between-group difference, 0.65; 95% confidence interval (CI), -0.45, 1.74; P = 0.2441). Secondary efficacy endpoints included mean micro-dystrophin expression at week 12: 34.29% (treated) versus 0.00% (placebo). Other secondary efficacy endpoints at week 52 (between-group differences (95% CI)) included: Time to Rise (-0.64 (-1.06, -0.23)), 10-meter Walk/Run (-0.42 (-0.71, -0.13)), stride velocity 95th centile (0.10 (0.00, 0.19)), 100-meter Walk/Run (-3.29 (-8.28, 1.70)), time to ascend 4 steps (-0.36 (-0.71, -0.01)), PROMIS Mobility and Upper Extremity (0.05 (-0.08, 0.19); -0.04 (-0.24, 0.17)) and number of NSAA skills gained/improved (0.19 (-0.67, 1.06)). In total, 674 adverse events were recorded with delandistrogene moxeparvovec and 514 with placebo. There were no deaths, discontinuations or clinically significant complement-mediated adverse events; 7 patients (11.1%) experienced 10 treatment-related serious adverse events. Delandistrogene moxeparvovec did not lead to a significant improvement in NSAA score at week 52. Some of the secondary endpoints numerically favored treatment, although no statistical significance can be claimed. Safety was manageable and consistent with previous delandistrogene moxeparvovec trials. ClinicalTrials.gov: NCT05096221.

Nature MedicineVol. 31(1)
Roche (Switzerland) (CH), Arkansas Children's Hospital (US), Hospital Sant Joan de Déu Barcelona (ES), Nationwide Children's Hospital (US), Washington University in St. Louis (US), Great Ormond Street Hospital (GB), Instituto de Salud Carlos III (ES), University of Rochester Medical Center (US), University of Florida (US), National Center of Neurology and Psychiatry (JP), Centre for Biomedical Network Research on Rare Diseases (ES), Centro Clinico Nemo (IT), Roche (United Kingdom) (GB), Sant Joan de Déu Research Foundation (ES), Children's Hospital of The King's Daughters (US), Sarepta Therapeutics (United States) (US), Istituti di Ricovero e Cura a Carattere Scientifico (IT), UC Davis Health (US), University College London (GB), The Ohio State University (US), University of Duisburg-Essen (DE), University of Arkansas for Medical Sciences (US)
Pfizer, Roche, Muscular Dystrophy Association, Biogen, Parent Project Muscular Dystrophy, FibroGen, F. Hoffmann-La Roche, Nationwide Children's Hospital, CSL Behring, Taiho Pharmaceutical, PTC Therapeutics, AveXis, Sarepta Therapeutics, Nippon Shinyaku, Astellas Pharma, Italfarmaco, Genentech, Chugai Pharmaceutical, UCB Pharma
Openalex Percentile: Top 0%
Muscle Physiology and Disorders
29.93
DOIOpen Access PDFOpenAlex
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