STR1VE
(2021)Objective
To evaluate the safety and efficacy of commercial-grade onasemnogene abeparvovec gene therapy in symptomatic SMA Type 1 infants with two SMN2 copies
Study Summary
• Treatment-related SAEs: hepatic aminotransferase elevation (2 patients), hydrocephalus (1 patient); most common AE was pyrexia; confirmed Phase 1 START findings with commercial-grade manufacturing
Intervention
Single IV infusion of onasemnogene abeparvovec 1.1x10^14 vg/kg
Inclusion Criteria
Age <6 months, SMA with biallelic SMN1 mutations (deletion or point mutations), 1 or 2 copies of SMN2
Study Design
Arms: Single arm (onasemnogene abeparvovec); compared to PNCR untreated historical cohort (n=23)
Patients per Arm: Treatment: 22; Historical control (PNCR): 23
Outcome
• Survival free from permanent ventilation at 14 months: 20/22 (91%, 97.5% CI 79-100%) vs 6/23 (26%) untreated (P<0.0001)
• All 22 had AEs (100%); treatment-related SAEs: hepatic aminotransferases (2), hydrocephalus (1); most common: pyrexia, bronchiolitis, pneumonia
Bottom Line
59% achieved independent sitting at 18 months (vs 0% untreated, P<0.0001) and 91% survived free from permanent ventilation at 14 months (vs 26% untreated). Confirmed Phase 1 START findings with commercial-grade product.
Major Points
- Confirmatory Phase 3 trial of commercial-grade onasemnogene abeparvovec in SMA Type 1 -- validated manufacturing scale-up from Phase 1 research-grade product
- 13/22 (59%) achieved functional independent sitting (Bayley-III item 26, >=30 seconds) at 18 months vs 0/23 untreated PNCR controls (P<0.0001)
- 20/22 (91%) survived free from permanent ventilation at 14 months vs 6/23 (26%) in untreated historical cohort (P<0.0001)
- Treatment-related serious adverse events: hepatic aminotransferase elevation (2 patients requiring prolonged prednisolone), hydrocephalus (1 patient)
- Single one-time IV infusion at 12 US centers -- first multicenter demonstration of AAV9 gene therapy feasibility
- All 22 patients (100%) experienced at least one adverse event; most common was pyrexia
- Supported FDA approval of Zolgensma with commercial-grade manufacturing
Study Design
- Study Type
- Phase 3, open-label, single-arm, multicenter trial with prespecified historical comparator
- Randomization
- No
- Blinding
- Open-label
- Sample Size
- 22
- Follow-up
- Until age 18 months or early termination
- Centers
- 12
- Countries
- United States
Primary Outcome
Definition: Functional independent sitting (Bayley-III gross motor item 26, sitting without support >=30 seconds) at 18 months of age
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 0/23 (0%) in PNCR untreated cohort | 13/22 (59%) | - (97.5% CI 36.4% to 100%) | <0.0001 |
Limitations & Criticisms
- Open-label design without blinding introduces potential for assessment bias, particularly in motor milestone evaluation
- Single-arm design with historical comparator rather than concurrent randomized control -- PNCR cohort may not perfectly match treated population in disease severity, supportive care era, or geographic characteristics
- Small sample size (n=22) limits ability to detect rare adverse events and assess subgroup effects
- Limited to US centers only -- may not reflect global treatment patterns or diverse populations
- Anti-AAV9 antibody exclusion (>1:50) eliminates a subset of eligible patients and precludes re-dosing
- Prednisolone co-treatment (started 1 day before infusion) may contribute to motor improvements independently
- 1 death during study from respiratory failure; relationship to disease progression vs treatment contribution difficult to fully disambiguate in open-label setting
- Cost of therapy (~$2.1 million per patient for single infusion) raises significant health economic and access equity concerns
Citation
Lancet Neurol. 2021 Apr;20(4):284-293