Delandistrogene DMD Meta-Analysis
Duchenne Muscular Dystrophy and Delandistrogene Moxeparvovec Gene Therapy in Children: A Systematic Review and Meta-Analysis
Bottom Line
In a pooled analysis of 4 studies (2 RCTs, 2 nonrandomized cohorts; 302 boys), delandistrogene moxeparvovec produced small but statistically significant improvements in NSAA (MD 2.48, p=0.04; RCT-only LSMD 0.7, p<0.01), time-to-rise (MD −0.85 s, p<0.01), and muscle microdystrophin content (+28.39%, p<0.01), with an 10MWR benefit only in the LSM-sensitivity analysis (LSMD −0.71 s, p=0.02); adverse events were common (95–100%, mostly GI and transaminase elevations) but serious events were rare within trials, though post-marketing acute liver failure deaths have been reported.
Major Points
- Meta-analysis of the 4 published delandistrogene moxeparvovec studies in DMD boys 4-<8 y: EMBARK RCT (n=125), Study 102 RCT part 1 (n=41), ENDEAVOR nonrandomized (n=111), Study 101 nonrandomized (n=25); total 107 treated vs 195 controls.
- NSAA change from baseline at 1 year: MD 2.48 (95% CI 0.15–4.81, I²=98.9%, p=0.04); LSM-only sensitivity LSMD 1.52 (p=0.06, ns); RCT-only LSM (EMBARK + Study 101) LSMD 0.7 (95% CI 0.48–0.92, I²=0%, p<0.01).
- Time-to-rise from supine improved: MD −0.85 s (95% CI −1.23 to −0.47, I²=96.4%, p<0.01); LSM-only LSMD −0.9 s (p<0.01).
- 10-meter walk/run: full pooled analysis non-significant (MD −0.28 s, p=0.56); statistically significant only in LSM-only sensitivity (LSMD −0.71 s, 95% CI −1.29 to −0.14, p=0.02).
- Muscle microdystrophin expression on Western blot at 12 weeks (2 studies) rose 28.39% of normal (95% CI 15.39–41.39, I²=0%, p<0.01), the strongest and most consistent finding.
- Adverse events were near-universal (95–100% of treated patients); the most common TEAEs were GI (vomiting 54–64%) and transaminase elevations (20–40%). Serious treatment-related events (rhabdomyolysis 1–10%, liver injury 1–5%, myocarditis, hepatotoxicity 1–2%) were uncommon within trials.
- Post-marketing acute liver failure deaths have been reported outside these clinical trials (3 in the United States and 1 in Brazil linked to Anvisa reports), and the FDA is investigating hepatotoxicity risk with rAAVrh74-based gene therapies.
- Heterogeneity was very high (I² 96–99%) for the pooled NSAA, TTR, and 10MWR analyses, driven by mixing RCTs with external-control cohorts and mixing LSM vs mean change metrics; the RCT-only NSAA subanalysis had I²=0%.
- The authors highlight that nonrandomized studies reported larger benefits than RCTs; the true effect is likely modest but clinically meaningful.
- Study was prospectively registered on PROSPERO (CRD42025635605) and followed PRISMA guidelines.
Design
Study Type: Systematic Review and Meta-Analysis
Randomization:
Blinding: Not applicable (meta-analysis); 2 included studies were placebo-controlled double-blind RCTs, 2 were open-label nonrandomized cohorts with external comparators
Enrollment Period: Databases searched from inception through January 2025
Follow-up Duration: 48 weeks to 5 years across included studies; results standardized to 1-year outcomes
Countries: United States, Europe, Asia
Sample Size: 302
Analysis: Random-effects inverse-variance meta-analysis (R meta package, restricted maximum likelihood for T²); mean difference (MD) with 95% CI; heterogeneity assessed by I² and Cochran Q; predefined sensitivity analyses (LSM-only, RCT-only) and leave-one-out analyses; risk of bias assessed with Cochrane RoB 2 (RCTs) and ROBINS-I (nonrandomized); registered PROSPERO CRD42025635605; PRISMA-compliant.
Inclusion Criteria
- Randomized controlled trials or nonrandomized cohort studies (predefined intervention-exposed cohort with longitudinal follow-up)
- Comparator arm: placebo or propensity-matched external cohort (natural-history or historical controls)
- Male patients ≥4 years to <8 years old with genetically confirmed Duchenne muscular dystrophy (DMD gene variants between exons 18 and 79)
- On a stable dose of oral corticosteroids for ≥12 weeks prior to treatment
- Follow-up of at least 48 weeks
- Reported at least one predefined clinical outcome (NSAA score, 10-meter walk/run, time to rise from floor, or dystrophin expression)
Exclusion Criteria
- Reviews, case reports, case series, case-control studies, and preclinical research
- Ongoing studies and abstracts without published results at the time of the search
- For Study 102, only randomized part 1 was included; part 2 patients and external-cohort comparisons were excluded to avoid population overlap and bias
- Patients with DMD deletions in exons 8 and/or 9 (contraindication to delandistrogene moxeparvovec because of immune-mediated myositis risk) — excluded by original trial protocols
- Nonambulatory patients or patients outside the 4-<8 year age band — excluded by original trial protocols
- Patients not on stable corticosteroid therapy
Arms
| Field | Delandistrogene moxeparvovec | Control |
|---|---|---|
| Intervention | Single IV infusion of delandistrogene moxeparvovec (SRP-9001), a recombinant AAVrh74 vector encoding microdystrophin. Dose 1.33×10¹⁴ vg/kg (ENDEAVOR, EMBARK) or 2.0×10¹⁴ vg/kg by supercoiled qPCR (Study 101, Study 102; later established as bioequivalent to 1.33×10¹⁴ vg/kg by linear qPCR). | Placebo IV infusion in the RCT arms (EMBARK, Study 102 part 1), or propensity-score-matched external/natural-history cohort in the nonrandomized studies (ENDEAVOR ENHC and Study 101 EC). All patients received background oral corticosteroids. |
| Duration | One-time IV infusion with subsequent follow-up; results standardized to 1 year | Concurrent with active-arm follow-up (standardized to 1 year) |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Change from baseline in North Star Ambulatory Assessment (NSAA) total score at 1 year (17-item, 0–34 scale; higher = better motor function). Pooled across all 4 studies (3 LSM + 1 mean change). | Primary | Pooled standard-treatment change from baseline (see figure 2 forest plot) | Pooled delandistrogene moxeparvovec change from baseline (see figure 2) | 2.48 (all-data primary); LSMD 1.52 (LSM-only sensitivity); LSMD 0.7 (RCT-only LSM) | 0.04 (all data); 0.06 (LSM only); <0.01 (RCT only) |
| Time to rise from floor (TTR, seconds) — change from baseline at 1 year (all-data primary) | Secondary | −0.85 s | <0.01 | ||
| Time to rise from floor — LSM-only leave-one-out sensitivity analysis | Secondary | <0.01 | |||
| 10-meter walk/run (10MWR, seconds) — full pooled analysis | Secondary | −0.28 s | 0.56 (non-significant) | ||
| 10-meter walk/run — LSM-only sensitivity analysis | Secondary | 0.02 | |||
| Muscle dystrophin content (% of normal, Western blot at 12 weeks; 2 studies) | Secondary | +28.39% of normal | <0.01 | ||
| Any adverse event (per treated patient) | Adverse | 95–100% across the 4 studies (ENDEAVOR 95%, EMBARK 98.4%, Study 101 100%, Study 102 100%) | |||
| Vomiting (TEAE) | Adverse | 54–64% (ENDEAVOR 55%, EMBARK 54%, Study 101 64.2%, Study 102 60%) | |||
| Decreased appetite | Adverse | 14–45% (ENDEAVOR 45%, EMBARK 27%, Study 101 14.3%, Study 102 30%) | |||
| Nausea | Adverse | 7–40% (ENDEAVOR 40%, EMBARK 31.7%, Study 101 7.1%, Study 102 30%) | |||
| GLDH/transaminase elevations | Adverse | 20–40% (ENDEAVOR GLDH 40% + transaminases 20%; EMBARK GLDH 23.8%) | |||
| Pyrexia | Adverse | ≈16% (EMBARK 15.9%) | |||
| Abdominal pain (upper) | Adverse | 13–15% (EMBARK 12.7%, Study 102 15%) | |||
| Constipation | Adverse | 25% (ENDEAVOR) | |||
| Thrombocytopenia | Adverse | 15% (ENDEAVOR) | |||
| Treatment-related SAEs | Adverse | Rare overall. Rhabdomyolysis 1–10% (Study 102 10%, EMBARK 1.58%); liver injury / transient liver enzyme elevations 1–5% (EMBARK 4.75%, Study 102 5%, ENDEAVOR 5%); myocarditis, hepatotoxicity, pyrexia ≤1–2% (isolated cases in EMBARK) | |||
| Deaths in included clinical trials | Adverse | None reported across the 4 included studies | |||
| Deaths in post-marketing / real-world use (context, not pooled) | Adverse | 3 US deaths from acute liver failure within 2 months post-treatment; 3 adverse event reports in Brazil (Anvisa), 1 fatal (attributed by Anvisa to severe influenza A rather than the therapy); FDA is investigating acute liver failure risk with rAAVrh74 platform gene therapies | |||
| Boxed-warning-relevant class effects | Adverse | Infusion-related hypersensitivity/anaphylaxis; acute serious liver injury (peak ~8 weeks post-infusion, prophylactic corticosteroids + weekly LFTs required); immune-mediated myositis (contraindicated for exon 8/9 deletions); myocarditis; anti-AAVrh74 antibodies develop in all treated patients and may preclude future AAV gene therapy | |||
Subgroup Analysis
Prespecified sensitivity analyses by statistical method (LSM-only vs mixed LSM/mean) and by design (RCT-only). RCT-only LSM NSAA analysis (EMBARK + Study 102 part 1) was the most robust: LSMD 0.7 (95% CI 0.48–0.92, I²=0%, p<0.01). Nonrandomized studies generally reported larger effect estimates than RCTs; pooled estimates likely fall between the two design types.
Criticisms
- Very high statistical heterogeneity (I² 96–99%) in the primary NSAA, TTR, and 10MWR analyses; the authors acknowledge that pooled point estimates should be interpreted with caution.
- Only 4 studies and 302 patients total (107 actively treated) — sample size and event counts are small, especially for the nonrandomized studies (Study 101 had only 4 treated patients).
- Two of four studies are nonrandomized open-label with external / propensity-matched historical controls, which are known to inflate treatment effect estimates in rare-disease gene therapy.
- Different studies used different SRP-9001 dose designations (1.33×10¹⁴ vs 2.0×10¹⁴ vg/kg by different qPCR methods), and different statistical metrics (LSM vs mean change), forcing sensitivity analyses that changed the conclusions for 10MWR.
- Individual-study RCTs (EMBARK, Study 102) did not meet their prespecified NSAA endpoints at 52 weeks; the meta-analytic significance arises largely from pooling with nonrandomized cohorts.
- The safety analysis was qualitative (no meta-analysis of AE rates) because comparable placebo/external-control AE data were not available.
- Real-world post-marketing acute liver failure deaths (US and Brazil) are not captured in the trial dataset; the meta-analysis therefore likely understates hepatotoxicity risk.
- 1-year follow-up only — durability of microdystrophin expression and functional benefit, and long-term cardiac / respiratory effects, cannot be judged from this analysis.
- Two published trials known to be ongoing at the time of the search (SRP-9001-302 ENVOL and SRP-9001-303 ENVISION) were excluded because peer-reviewed results were not yet available, limiting current evidence base.
- Excluded population subgroups — nonambulatory boys, patients <4 or >8 y, and patients with exon 8/9 deletions — mean these findings do not generalize outside the ambulatory 4-<8 y cohort.
Funding
The authors report no targeted funding. Article Processing Charge was funded by the authors themselves. The authors report no relevant disclosures.
Based on: Delandistrogene DMD Meta-Analysis (Neurology Genetics, 2026)
Authors: Antonello BB, Cargnelutti Fontoura F, Braga Albuquerque AL, ..., Zattar Ribeiro PV.
Citation: Antonello BB, et al. Neurol Genet 2026;12(4):e200408. DOI: 10.1212/NXG.0000000000200408. PMID 42396397. PMCID PMC13326780.
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