EMBARK
(2026)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
• 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
Inclusion Criteria
Ambulatory males aged 4 to <8 years with Duchenne muscular dystrophy
Study Design
Arms: Delandistrogene moxeparvovec, Placebo (crossover design)
Patients per Arm: 64 treated in Part 1; 125 total; 143 external controls for 2-year analysis
Outcome
• Primary endpoint (NSAA at 52 weeks) did not meet statistical significance vs placebo
• At 2 years, significant benefit vs external control on NSAA and timed function tests
• Micro-dystrophin expression maintained over 64 weeks; no treatment-related deaths
• At 2 years, significant benefit vs external control on NSAA and timed function tests
• Micro-dystrophin expression maintained over 64 weeks; no treatment-related deaths
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.
Study Design
- Study Type
- Phase 3 randomized controlled trial (two-part crossover)
- Randomization
- Yes
- Blinding
- Placebo-controlled
- Sample Size
- 125
- Follow-up
- 104 weeks (2 years)
- Countries
- USA, UK, Italy, Japan, Spain, Germany
Primary Outcome
Definition: Change in NSAA total score at 52 weeks vs placebo
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | Not significant |
Limitations & 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)
Citation
Neurol Ther. 2026 Apr;15(2):545-559