Novel AAV-based gene therapy for Duchenne muscular dystrophy

rAAVrh74.MHCK7.micro-dystrophin (SRP-9001) is a novel adeno-associated virus (AAV)-based gene transfer therapy for the treatment of Duchenne muscular dystrophy (DMD). Findings of the first part of a placebo-controlled trial reinforced a favourable benefit-risk profile. Treatment was well tolerated and appeared to improve muscle function.

The novel gene therapy was subjected to the randomised, double-blind, placebo-controlled trial SRP-9001-102 (NCT03769116) that evaluated safety, efficacy, and tolerability of a single intravenous dose of SRP-9001 in boys with DMD gene mutation (exons 18–58) aged 4–7 years [1]. This phase 2 trial has 3 parts: two 48-week randomised, double-blind, placebo-controlled periods with crossover design (part 1 and 2) and an open-label follow-up period of up to 212 weeks (part 3). Results from the 41 randomised patients in part 1 were communicated.

There were 1.6 copies of the transgene DNA per nucleus at week 12. Micro-dystrophin expression at week 12 was achieved (28.1% of normal), and the percentage of dystrophin-positive fibres was 33% of normal. Functional outcomes were measured in terms of North Star Ambulatory Assessment (NSAA). In the 6- and 7-year-olds, a large imbalance in baseline NSAA was present; this is why the results (not reaching statistical significance; P=0.37) are hard to interpret. In 4- and 5-year-olds, baseline function was well matched. Change in NSAA in this subgroup was significantly higher in the experimental group than in the placebo group (4.3 vs 1.9; P=0.0172). Treatment was generally well tolerated, with treatment-emergent adverse events in the SRP-9001 and placebo group being reported in 85% and 43%. The most common treatment-emergent adverse event was vomiting (60% vs 19%).

1. Mendell J, et al. A Multicenter Randomized, Double-Blind, Placebo-Controlled, Gene-Delivery Clinical Trial of rAAVrh74.MHCK7.micro-dystrophin for Duchenne Muscular Dystrophy. S32.004, AAN 2021 Virtual Congress, 17-22 April.

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Posted on 16 June 2021