DMD-ELEVIDYS-MA
(2026)Objective
Quantify the 1-year efficacy of delandistrogene moxeparvovec (SRP-9001, Elevidys) gene therapy vs standard treatment on functional motor outcomes and dystrophin expression in ambulatory boys aged 4 to <8 years with Duchenne muscular dystrophy (DMD).
Study Summary
• Time to rise from floor: MD −0.85 s (95% CI −1.23 to −0.47, I²=96.4%, p<0.01) favoring gene therapy.
• Safety: ≥1 AE in 95–100%; SAEs rare (liver injury 1–5%, rhabdomyolysis 1–10%, myocarditis); ≥3 US and 1 Brazilian post-marketing fatal acute liver failure deaths.
Intervention
Single IV infusion of delandistrogene moxeparvovec (AAVrh74-based microdystrophin gene therapy; 1.33 × 10¹⁴ vg/kg in EMBARK & ENDEAVOR, 2.0 × 10¹⁴ vg/kg in Studies 101 & 102) vs placebo or propensity-matched external natural-history cohorts; all patients on ≥12 wk stable oral corticosteroids.
Inclusion Criteria
Male at birth, 4 to <8 y, molecularly confirmed DMD (exons 18–79), on stable oral corticosteroids ≥12 wk, follow-up ≥48 wk, ambulatory, reporting NSAA, 10MWR, TTR, or dystrophin expression.
Study Design
Arms: Delandistrogene moxeparvovec (single IV) vs standard treatment (placebo in RCTs or propensity-matched external natural-history cohort)
Patients per Arm: Delandistrogene 107 vs standard treatment 195 (total 302; from 4 studies)
Outcome
• NSAA (RCTs-only LSMD): +0.70 (0.48 to 0.92, p<0.01, I²=0%).
• TTR: MD −0.85 s (−1.23 to −0.47, p<0.01).
• 10MWR: overall MD −0.28 s (p=0.56, NS); LSMD-only −0.71 s (p=0.02).
• Dystrophin expression: +28.39% of normal (15.39–41.39, p<0.01, I²=0%).
• Safety: AEs 95–100%; most common vomiting (54–64%), decreased appetite (14–45%), nausea (7–40%), elevated liver enzymes (20–40%); SAEs rare (liver injury 1–5%, rhabdomyolysis 1–10%, isolated myocarditis).
Clinical Question
In ambulatory boys aged 4 to <8 years with Duchenne muscular dystrophy on stable corticosteroids, does single-dose delandistrogene moxeparvovec gene therapy improve functional motor outcomes (NSAA, time to rise, 10-meter walk/run) and dystrophin expression at 1 year compared with placebo or matched external natural-history controls?
Bottom Line
Pooled 1-year data from 4 studies (302 boys) show that delandistrogene moxeparvovec produces small but statistically significant improvements in NSAA, time to rise, and dystrophin expression versus standard treatment — with a modest ~0.7-point NSAA benefit in the RCT-only subset — accompanied by frequent gastrointestinal and hepatic adverse events and rare but serious hepatotoxicity, myocarditis, and post-marketing fatal acute liver failure.
Major Points
- Systematic review/meta-analysis (PROSPERO CRD42025635605) of PubMed/Embase/Cochrane through Jan 2025; included 4 studies (2 RCTs: EMBARK, Study 102; 2 non-randomized: ENDEAVOR, Study 101) enrolling 302 ambulatory boys aged 4 to <8 y with confirmed DMD on ≥12 wk oral corticosteroids.
- Primary NSAA analysis (all data): MD +2.48 points (95% CI 0.15 to 4.81; I²=98.9%; p=0.04) favoring gene therapy; LSMD-only sensitivity +1.52 (−0.04 to 3.08; p=0.06) tended toward but did not meet significance; RCT-only LSMD +0.70 (0.48 to 0.92; I²=0%; p<0.01) is the most robust estimate.
- Time to rise from supine improved with therapy: MD −0.85 s (95% CI −1.23 to −0.47; I²=96.4%; p<0.01) overall, and LSMD-only −0.90 s (−1.4 to −0.40; p<0.01).
- 10-meter walk/run overall not significant (MD −0.28 s; 95% CI −1.23 to 0.66; p=0.56) but LSMD-only leave-one-out sensitivity showed significant reduction of −0.71 s (−1.29 to −0.14; p=0.02).
- Muscle dystrophin content by Western blot at 12 weeks increased by 28.39% of normal (95% CI 15.39 to 41.39; I²=0%; p<0.01) versus baseline/controls.
- Non-randomized studies (ENDEAVOR, Study 101) reported larger treatment effects than RCTs (EMBARK, Study 102), likely reflecting external-cohort selection and reduced blinding; heterogeneity was very high (I² ≈96–99%) for most outcomes.
- Safety was manageable in trials (95–100% AEs, mostly mild GI or transaminase elevations; rare rhabdomyolysis, myocarditis, hepatotoxicity), but post-marketing surveillance has reported at least 3 US deaths from acute liver failure within 2 months of treatment and 1 fatal case in Brazil, prompting ongoing FDA safety review of AAVrh74-platform therapies.
- Delandistrogene is contraindicated with DMD exon 8/9 deletions (immune-mediated myositis risk); pre-treatment anti-AAVrh74 antibody testing is required, and post-treatment antibody development may preclude future AAV-based gene therapies.
Study Design
- Study Type
- Systematic Review and Random-Effects Meta-Analysis
- Randomization
- No
- Blinding
- N/A (meta-analysis; included studies: 2 double-blind RCTs and 2 open-label non-randomized cohorts)
- Sample Size
- 302
- Follow-up
- 48–52 weeks (standardized to 1 year); ENDEAVOR 1 y, EMBARK 2 y, Study 101 5 y, Study 102 2 y
- Centers
- Multiple (across 4 included studies)
- Countries
- United States, Europe, Asia (multinational EMBARK)
Primary Outcome
Definition: Change from baseline in North Star Ambulatory Assessment (NSAA) total score at 1 year — RCT-only LSMD analysis (most robust)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Standard treatment (placebo in RCTs) | Delandistrogene moxeparvovec | - (0.48 to 0.92) | <0.01 |
Limitations & Criticisms
- Very small evidence base — only 4 studies and 302 boys, with just 107 treated; limits precision and generalizability.
- Extreme statistical heterogeneity (I² ≈96–99%) for NSAA, TTR, and 10MWR pooled analyses, reflecting differences in design, controls, and dosing.
- Two of 4 studies used external natural-history or historical controls rather than concurrent placebo, introducing confounding and inflating apparent benefit; nonrandomized cohorts (ENDEAVOR, Study 101) drove much of the positive signal.
- Individual RCTs (EMBARK, Study 102) were NOT independently statistically significant for NSAA at 52 weeks; pooled significance depends on inclusion of nonrandomized data.
- Mixed use of least-squares mean difference vs mean difference across studies required multiple sensitivity analyses; results moved in and out of significance depending on which studies were included.
- 1-year follow-up is short for a disease with a decades-long trajectory; long-term durability, respiratory/cardiac/QoL outcomes, and effects on loss of ambulation were not assessed.
- Safety could not be quantitatively meta-analyzed (only qualitative synthesis); post-marketing fatal acute liver failure signal is not captured in the trials pooled.
- Excluded ongoing pivotal trials (SRP-9001-302 ENVOL, SRP-9001-303 ENVISION) because published results were not available at search date.
- Population overlap possible across external cohorts drawn from Nationwide Children's Hospital.
- Restricted to ambulatory boys aged 4 to <8 y; findings do not apply to non-ambulatory, older, or younger patients or to those with exon 8/9 deletions (contraindicated).
Citation
Neurol Genet. 2026 Jul;12(4):e200408.