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:

1. 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,
2. Survival at 14 months of age (achievement: 47% versus 0).

Comparison of two primary efficacy endpoints outcomes to natural-history controls supports the effectiveness of onasemnogene abeparvovec-xioi. On historic subtype classification, the FDA reviewer acknowledged that it can be problematic. The review included SMA type 1, while including different possible genotypes and avoiding the inherent delay of retrospective classification based on motor milestones. FDA expanded access program: The safety database primarily consists of 42 pediatric patients, from open-label clinical trials (CL303; CL-101, with some subjects continuing in an ongoing observational long-term follow-up study; one ongoing phase 3 trial conducted outside of the U.S.). The information from the FDA expanded access program also contributed to the safety database. The applicant will conduct long-term follow-up studies to collect safety and efficacy information on patients who participated in the phase 1 or 3 trials under IND 15699. In addition, the applicant proposed postmarketing measures. Cited Literature ‍ Finkel RS, McDermott MP, Kaufmann P, et al. (2014) Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology 83:810-817. Kolb, SJ, Coffey CS, Yankey JW, et al. (2016) Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study. Ann Clin Transl Neurol 3:132–145. Kolb, SJ, Coffey CS, Yankey JW, et al. (2017) Natural history of infantile-onset spinal muscular atrophy. Ann Neurol 82:883-891. ‍