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Updated: Oct 13, 2025
Characterizing Exon Skipping Efficiency in DMD Patient Samples in Clinical Trials of Antisense Oligonucleotides
Published on: May 7, 2020
Long-Term Safety and Efficacy Data of Golodirsen in Ambulatory Patients with Duchenne Muscular Dystrophy Amenable to
Laurent Servais1,2,3, Eugenio Mercuri4,5, Volker Straub6
1I-Motion Institute, Hôpital Armand Trousseau, Paris, France.
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.
Insights
Long-term golodirsen treatment demonstrated safety and efficacy in Duchenne muscular dystrophy (DMD) patients. The drug increased dystrophin protein and showed potential functional benefits compared to natural history controls.
Area of Science:
- Neurology
- Genetics
- Clinical Pharmacology
Background:
- Duchenne muscular dystrophy (DMD) is a progressive genetic disorder.
- Exon 53 skipping amenable mutations represent a specific target for therapeutic intervention.
- Long-term safety and efficacy data for novel DMD treatments are crucial.
Purpose of the Study:
- To evaluate the long-term clinical safety and efficacy of golodirsen in ambulatory patients with exon 53 skip-amenable Duchenne muscular dystrophy.
- To assess golodirsen's impact on dystrophin protein expression, ambulation, and respiratory function over 168 weeks.
- To compare functional outcomes with external natural history controls.
Main Methods:
- Phase 1/2, 2-part, multicenter trial including a 12-week randomized, double-blind, placebo-controlled period and a 168-week open-label golodirsen treatment period.
- Primary endpoints included safety, dystrophin protein expression, and the 6-minute walk test (6MWT).
- Secondary endpoints included percent predicted forced vital capacity (FVC%p); post hoc analyses utilized mutation-matched external natural history controls.
Main Results:
- Golodirsen significantly increased dystrophin protein expression (16.0-fold, P < 0.001) and exon skipping (28.9-fold, P < 0.001).
- Over 3 years, golodirsen-treated patients showed a trend towards better 6MWT outcomes (-99.0m vs. -181.4m for controls, P=0.067) and a lower rate of ambulation loss (9% vs. 26%).
- Forced vital capacity decline was 8.4% over 3 years, comparing favorably to literature rates. Adverse events were mild and unrelated to treatment.
Conclusions:
- Golodirsen exhibits significant biological activity, increasing dystrophin protein and promoting exon skipping in DMD patients.
- Long-term golodirsen treatment appears safe and suggests potential functional benefits in ambulation and respiratory function compared to natural history.
- These findings support golodirsen's role in managing ambulatory patients with specific Duchenne muscular dystrophy mutations.
