Zolgensma: what was done before first-in-human, and what came after?

“The completed clinical trial enrolled 15 infants with SMA from one site in the United States.”

“The applicant noted that for phase 1 clinical trials, clinical dose identification was based on 2 criteria identified in animal studies: doubling Delta 7 SMA mouse life span (7.4e+13 vg/kg ) and restoring full life (1.2e+14 vg/kg ) in delta 7 SMA mice.”

“No repeat-dose toxicology studies were performed with AVXS-101 since this will be intended for single IV administration only.”

“The Applicant conducted two 12 weeks and one 24 weeks GLP compliant studies with a single IV Zolgensma administration in neonatal FVB wild type mice as indicated in the table below.”

“In fertility and early embryonic development studies conducted in mice administered onasemnogene abeparvovec, the active ingredient found in ZOLGENSMA, intravenously (IV) at dose levels of 1.1 × 10 13 or 1.1 × 10 14 vector genomes (vg)/kg body weight, onasemnogene abeparvovec DNA was detected in gonadal tissues of both males and females.”

“The target patient population for AVXS-101 with infantile-onset SMA are typically less than 1 year of age and sexually immature.”

“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, carcinogenicity/tumorigenicity of AVXS-101 were not conducted for AVXS-101. These studies were not warranted based on the product characteristics, results from the toxicology studies, and target patient population.”

“No animal studies have been performed to evaluate the effects of ZOLGENSMA on carcinogenesis or mutagenesis.”

“Ongoing clinical trials (under IND #15699) since September 2013 have shown no evidence of tumor formation clinically in any subject administered with AVXS-101.”

“These studies were not warranted based on the product characteristics, results from the toxicology studies, and target patient population.”