Long-Term Safety and Efficacy Data of Golodirsen in Ambulatory Patients with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping: A First-in-human, Multicenter, Two-Part, Open-Label, Phase 1/2 Trial
Laurent Servais, Eugenio Mercuri, Volker Straub, Michela Guglieri, Andreea Seferian, Mariacristina Scoto, Daniela Leone, E. Koenig, Navid Khan, A. Dugar, Xiaodong Wang, Baoguang Han, Dan Wang, Francesco Muntoni, on behalf of the SKIP-NMD Study Group, Chiara Brusa, Laura Antonaci, Claudia Brogna, Laura Merli, Mauro Monforte, Giulia Norcia, Marika Pane, Gloria Ferrantini, George Dickson, Jennifer E. Morgan, Valentina Sardone, Cody Akana, Jay S. Charleston, Cody A. Desjardins, Saleh El-Husayni, Diane E. Frank, Frederick J. Schnell
Abstract
The aim of this Phase 1/2, 2-part, multicenter trial was to report clinical safety and efficacy of long-term golodirsen treatment among ambulatory patients with exon 53 skip-amenable Duchenne muscular dystrophy (DMD). Part 1 was a 12-week, randomized, double-blind, placebo-controlled, dose-titration study followed by 9-week safety review. Part 2 was a 168-week, open-label evaluation of golodirsen 30 mg/kg. Part 1 primary endpoint was safety. Part 2 primary endpoints were dystrophin protein expression and 6-minute walk test (6MWT); secondary endpoints were percent predicted forced vital capacity (FVC%p) and safety. Post hoc ambulation analyses used mutation-matched external natural history controls. All patients from Part 1 (golodirsen, n = 8; placebo, n = 4) plus 13 additional patients entered Part 2; 23 completed the study. Adverse events were generally mild, nonserious, and unrelated to golodirsen, with no safety-related discontinuations or deaths. Golodirsen increased dystrophin protein (16.0-fold; P < 0.001) and exon skipping (28.9-fold; P < 0.001). At 3 years, 6MWT change from baseline was −99.0 m for golodirsen-treated patients versus −181.4 m for external controls ( P = 0.067), and loss of ambulation occurred in 9% versus 26% ( P = 0.21). FVC%p declined 8.4% over 3 years in golodirsen-treated patients, comparing favorably with literature-reported rates. This study provides evidence for golodirsen biologic activity and long-term safety in a declining DMD population and suggests functional benefit versus external controls. Clinical Trial Registration number: NCT02310906.