EMBARK
Two-Year Outcomes Following Delandistrogene Moxeparvovec Treatment in Ambulatory Patients with Duchenne Muscular Dystrophy: Phase 3 EMBARK Trial
Clinical Question
Does a single IV dose of delandistrogene moxeparvovec slow disease progression over 2 years in ambulatory boys with DMD?
Study Overview
Objective
To evaluate the efficacy and safety of delandistrogene moxeparvovec gene therapy over 2 years in ambulatory boys with DMD aged 4 to <8 years
Study Summary
- Primary endpoint of NSAA change at 52 weeks did not reach statistical significance vs placebo
- 2-year data showed significant benefit vs propensity-score-weighted external control with disease stabilization
Intervention
Delandistrogene moxeparvovec 1.33 x 10^14 vg/kg IV single dose vs placebo
Patients per Arm
64 treated in Part 1; 125 total; 143 external controls for 2-year analysis
Bottom Line
Primary endpoint (NSAA at 52 weeks vs placebo) not met, but 2-year data showed significant stabilization vs external control with maintained micro-dystrophin expression and manageable safety.
Major Points
- Casimersen (exon 45 skipping ASO) for Duchenne muscular dystrophy: increased dystrophin to 5.7% of normal at 96 weeks (P<0.001 vs baseline).
- North Star Ambulatory Assessment (NSAA): -0.1 (casimersen) vs -3.5 (external comparator) at 96 weeks.
- 43 patients (ages 7-13) with DMD amenable to exon 45 skipping. Open-label with external control.
- Casimersen 30 mg/kg/week IV. Sarepta Therapeutics.
- FDA accelerated approval 2021 based on dystrophin increase as surrogate endpoint.
- Western blot: dystrophin 0.93% → 5.74% of normal at 96 weeks.
- Functional outcomes supportive but from external comparison (not randomized).
- Third exon-skipping therapy approved for DMD (after eteplirsen [exon 51] and golodirsen [exon 53]).
- Part of broader DMD precision medicine approach — specific mutation-targeted therapy.
- Confirmatory trial ongoing. Accelerated approval pathway.
Design
Study Type: Phase 3 randomized controlled trial (two-part crossover)
Randomization: 1
Blinding: Placebo-controlled
Follow-up Duration: 104 weeks (2 years)
Countries: USA, UK, Italy, Japan, Spain, Germany
Sample Size: 125
Analysis: MMRM; propensity-score-weighted external control for 2-year analysis
Inclusion Criteria
- Ambulatory males aged 4 to <8 years
- Duchenne muscular dystrophy diagnosis
Arms
| Field | Delandistrogene moxeparvovec | Control |
|---|---|---|
| Intervention | Single IV dose 1.33 x 10^14 vg/kg | Placebo (Part 1) / External control (2-year analysis, n=143) |
| Duration | 2 years | 2 years |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Change in NSAA total score at 52 weeks vs placebo | Primary | Not significant | |||
| NSAA at 2 years vs external control | Secondary | Statistically significant benefit | |||
| Treatment-related deaths | Adverse | 0 |
Criticisms
- Primary endpoint not met at 52 weeks
- 2-year comparison used external control rather than randomized placebo
- P values nominal and not adjusted for multiplicity
- Significant COI (Sarepta employees/co-inventors)
Funding
Sarepta Therapeutics, Inc.
Based on: EMBARK (Neurology and Therapy, 2026)
Authors: Mendell JR, Rodino-Klapac LR, et al.
Citation: Neurol Ther. 2026 Apr;15(2):545-559
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