CIFFREO
(2026)Objective
To assess the safety and efficacy of fordadistrogene movaparvovec, an rAAV9-based mini-dystrophin gene therapy, in slowing functional decline in ambulatory boys with Duchenne muscular dystrophy
Study Summary
• Significant safety signal: AEs in 99% vs 77%, vomiting 76% vs 14%, pyrexia 62% vs 9%, SAEs 32% vs 14%; Pfizer discontinued further development of fordadistrogene movaparvovec
Intervention
Fordadistrogene movaparvovec (rAAV9-based mini-dystrophin gene therapy) 2×10^14 vg/kg IV vs placebo
Inclusion Criteria
Male, ambulatory, aged 4 to <8 years, genetic diagnosis of DMD
Study Design
Arms: Fordadistrogene movaparvovec 2×10^14 vg/kg IV vs Matching Placebo
Patients per Arm: Fordadistrogene: 81 randomized (64 analyzed), Placebo: 41 randomized (28 analyzed)
Outcome
• AEs: 99% vs 77%; vomiting 76% vs 14%, pyrexia 62% vs 9%, SAEs 32% vs 14%
• No deaths; sponsor discontinued further development
Bottom Line
Fordadistrogene movaparvovec did not improve motor function (NSAA) compared to placebo at 52 weeks in ambulatory boys with DMD, with a substantially higher adverse event burden. Pfizer has discontinued further clinical development of this gene therapy.
Major Points
- Cipaglucosidase alfa (novel recombinant GAA enzyme) + miglustat (ERT enhancer) vs alglucosidase alfa (standard ERT) in late-onset Pompe disease.
- Primary endpoint: 6MWT change at 52 weeks — cipaglucosidase +20.8m vs alglucosidase +7.2m (P=0.07, NS for superiority).
- FVC change: cipaglucosidase -0.8% vs alglucosidase -2.9% (P=0.02 — significant respiratory benefit).
- 199 ERT-experienced patients with LOPD. Phase 3, randomized, double-blind, active-controlled.
- Cipaglucosidase: bis-phosphorylated GAA with higher M6P content → better cellular uptake.
- Miglustat (oral): prevents premature unfolding of cipaglucosidase in blood, enhancing delivery.
- First active-controlled Phase 3 trial in Pompe — compared to existing standard rather than placebo.
- Published NEJM 2023 (Schoser et al.). Amicus Therapeutics.
- FDA approved cipaglucosidase (Pombiliti) + miglustat (Opfolda) for LOPD in 2023.
- Represents next-generation ERT for Pompe — targets both muscle function and respiratory decline.
Study Design
- Study Type
- Phase 3, double-blind, randomized, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Double-blind (participants, investigators, and outcome assessors masked)
- Sample Size
- 122
- Follow-up
- 52 weeks
- Centers
- 45
- Countries
- Australia, Belgium, Canada, France, Germany, Israel, Italy, Japan, Russia, South Korea, Spain, Switzerland, Taiwan, UK, USA
Primary Outcome
Definition: Change from baseline to week 52 in NSAA total score
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| LS mean 1.37 (SE 0.65) | LS mean 1.46 (SE 0.43) | - (−1.46 to 1.64) | 0.91 |
Limitations & Criticisms
- Mini-dystrophin transgene may not provide sufficient functional protein replacement
- High rate of immune-mediated adverse events raises safety concerns for AAV gene therapy in DMD
- Second major negative AAV gene therapy trial for DMD (after EMBARK), questioning the therapeutic approach
- Delayed-start crossover design complicates long-term follow-up interpretation
Citation
Muntoni F et al. Lancet Neurol. 2026;25(3):245-255. DOI: 10.1016/S1474-4422(26)00036-0