Gene Therapy for Duchenne Muscular Dystrophy Fails Key Trials, Review Finds

Two flagship phase 3 programs of AAV-based shortened dystrophin gene therapy for Duchenne muscular dystrophy failed to demonstrate benefit on their primary functional endpoints, according to a systematic review published in the European Journal of Medical Research. The review, which applied the GRADE framework to rate the certainty of evidence separately for each viral construct, concluded that current evidence supports biological target engagement but does not establish consistent one-year functional efficacy.

Duchenne muscular dystrophy (DMD) has driven the development of adeno-associated virus (AAV)-based shortened dystrophin gene therapies. Two such therapies dominate the clinical landscape: delandistrogene moxeparvovec, which has received approval, and fordadistrogene movaparvovec, which has been discontinued. The authors of the review noted that a synthesis incorporating both the EMBARK and CIFFREO trials, with construct-specific certainty assessment, had been lacking.

The review was registered with PROSPERO (CRD420261346035) and searched PubMed, Scopus, Embase, and the Cochrane Central Register of Controlled Trials through 24 March 2026. Eligible studies evaluated AAV-based shortened dystrophin constructs in DMD. The researchers deliberately synthesized evidence separately by construct and did not pool results across different viral vectors. An exploratory random-effects meta-analysis was restricted to comparable randomized data on delandistrogene moxeparvovec.

In total, twelve reports were included, representing seven clinical trial datasets and five companion reports. The headline result came from the EMBARK trial of delandistrogene moxeparvovec, which did not meet its primary endpoint on the North Star Ambulatory Assessment (NSAA), a standardized measure of ambulatory function in DMD. The between-group difference was 0.65 points, with a 95 percent confidence interval of −0.45 to 1.74 and a p-value of 0.2441 — a result statistically indistinguishable from no effect.

The CIFFREO trial, testing fordadistrogene movaparvovec, was similarly negative on the NSAA, with a difference of just 0.09 points (95 percent CI −1.46 to 1.64; p = 0.91).

The exploratory pooling of delandistrogene data offered only a modest and uncertain positive signal. For Time to Rise, a timed functional test, the pooled mean difference was −0.65 seconds (95 percent CI −1.06 to −0.24) with no heterogeneity between studies (I² = 0.0 percent). However, the authors rated this signal as low certainty under GRADE criteria. Pooled NSAA results were not statistically significant, and estimates for the 10-Meter Walk/Run and 100-Meter Walk/Run tests were heterogeneous, meaning the studies disagreed with one another rather than converging on a consistent effect.

Safety findings extended beyond trial adverse events. Post-authorization cases of fatal liver failure prompted the U.S. Food and Drug Administration to issue a boxed warning for delandistrogene moxeparvovec and to restrict its approved indication. The review treats these regulatory actions as part of the evidence base, underscoring that the safety profile of AAV-based dystrophin gene therapy remains an active concern even after marketing authorization.

Across construct-specific randomized outcomes, GRADE certainty ranged from moderate to very low.

The authors conclude that both phase 3 programs failed to demonstrate benefit on their primary functional endpoint, and they call for construct-specific interpretation of results, longer follow-up of treated patients, standardized functional assessment across trials, and continued safety surveillance. For a field that has invested heavily in AAV-mediated microdystrophin delivery, the review is a sobering accounting: the biology of target engagement appears to be working, but translating that into measurable, durable functional benefit for patients with Duchenne muscular dystrophy remains unproven at the one-year mark.

Subject of Research: Systematic review of the efficacy and safety of AAV-based shortened dystrophin gene therapy in Duchenne muscular dystrophy

Article Title: Efficacy, safety, and certainty of AAV-based shortened dystrophin gene therapy in duchenne muscular dystrophy: a construct-specific systematic review and GRADE appraisal

Article References: Murugadoss, H., Ayyasamy, L., Sananthya, K., Gunasekaran, J. P., & Haridoss, M. (2026). Efficacy, safety, and certainty of AAV-based shortened dystrophin gene therapy in duchenne muscular dystrophy: a construct-specific systematic review and GRADE appraisal. European Journal of Medical Research. https://doi.org/10.1186/s40001-026-05379-5

Image Credits: AI Generated

DOI: 10.1186/s40001-026-05379-5

Keywords: Duchenne muscular dystrophy, gene therapy, AAV vectors, dystrophin, delandistrogene moxeparvovec, fordadistrogene movaparvovec, EMBARK trial, CIFFREO trial, GRADE certainty, systematic review, FDA boxed warning, liver failure