CBER-Approved BLA for ZOLGENSMA (onasemnogene abeparvovec-xioi)
On May 24, 2019, the FDA approved AveXis’s ZOLGENSMA® (onasemnogene abeparvovec-xioi), “for the treatment of pediatric patients less than two years of age with a specific type of spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene.” Of note: AveXis was granted Fast Track, Orphan Drug, and Breakthrough Therapy designations as well as a Rare Pediatric Disease Priority Review Voucher. Key findings from the FDA’s Summary Basis for Regulatory Action and the BLA Clinical Review Memorandum: Comparison of the results of the ongoing phase 3 trial, CL-303 (NCT03306277; n=21), to available natural history data of infants with SMA provides primary evidence of the effectiveness of onasemnogene abeparvovec-xioi. Results of the phase 1 trial, CL-101 (NCT02122952; n=15) additionally supported effectiveness. Other potential sources of effectiveness data, such as the U.S. expanded access program, are ongoing and therefore incomplete. Contributions to the safety database include: the phase 1 and 3 trials, other ongoing trials, and patients treated through the U.S. expanded access program. Purpose To support the efficacy outcomes of the phase 3 trial—an open-label, single-arm study—the applicant used available natural history data of infants with SMA to serve as a control. To contribute to the safety database, the applicant submitted information from compassionate use. What was done Natural history data: Natural history data were obtained from the Pediatric Neuromuscular Clinical Research database and the NeuroNEXT database (Finkel 2014; Kolb 2016; Kolb 2017). The two recent studies (n=23) provided detailed characterization of SMA type 1 infants with two copies of SMN2, which provided historical control data for the ongoing phase 3 trial. FDA expanded access program: The applicant submitted information from 46 U.S. patients with infantile-onset SMA who received onasemnogene abeparvovec-xioi under the FDA expanded access program. In all cases, the product was administered by intravenous infusion. Outcome Natural history data: The two primary efficacy endpoints in the ongoing phase 3 trial include:
- The proportion of patients achieving the milestone of sitting without support for at least 30 seconds at 18 months of age (achievement: 67% versus 25%); and,
- Survival at 14 months of age (achievement: 47% versus 0).
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