Zolgensma

“Single-dose toxicology studies were conducted to evaluate the safety of AVXS-101 following a single IV administration in healthy neonatal FVB/n mice.”

“The Applicant has chosen to use the FVB/n strain in the toxicology studies to be able to directly compare safety data from the SMNΔ7 studies.”

“The subsequent GLP single dose toxicity studies, Study 20122446 and Study 8384031, using GMP test material from the initial Process B manufacturing process revealed dose-dependent, delayed cardiovascular toxicity that was associated with thrombus formation in the atrium of the heart resulting in unscheduled mortality in a significant number of animals.”

“The Applicant has provided a pilot study and three GLP studies in which the safety and biodistribution of IV-administered Zolgensma was tested in neonatal wild-type mice. Furthermore, a pilot IV study in NHP which were dosed at PND90, was provided.”

“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.”

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

“Single-dose toxicology studies were conducted to evaluate the safety of AVXS-101 following a single IV administration in healthy neonatal FVB/n mice.”

“In a 6-month toxicology study conducted in juvenile non-human primates, single IV administration of onasemnogene abeparvovec at the recommended clinical dose level of 1.1 × 10 14 vg/kg, with or without corticosteroid treatment, resulted in microscopic findings in the dorsal root ganglia (DRG), trigeminal ganglia (TG), spinal cord, brainstem, and liver.”

“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.”

“Route of Administration IV via the temporal vein”

“Recent scientific literature supports low random integration frequencies of recombinant AAV (rAAV) vectors1,2 and lack of hepatic genotoxicity in rAAV2/5 genome integration in NHP and human liver samples.”

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

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

“In a 6-month toxicology study conducted in juvenile non-human primates, single IV administration of onasemnogene abeparvovec at the recommended clinical dose level of 1.1 × 10 14 vg/kg, with or without corticosteroid treatment, resulted in microscopic findings in the dorsal root ganglia (DRG), trigeminal ganglia (TG), spinal cord, brainstem, and liver.”

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

“No safety pharmacology studies were performed with AVXS-101.”

“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, carcinogenicity/tumorigenicity of AVXS-101 were not conducted for AVXS-101.”

“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, carcinogenicity/tumorigenicity of AVXS-101 were not conducted for AVXS-101.”

“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, carcinogenicity/tumorigenicity of AVXS-101 were not conducted for AVXS-101.”

“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.”

“No safety pharmacology studies were performed with AVXS-101.”

“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.”

“Based on the lack of similar cardiovascular toxicities resulting in Zolgensma-related mortality, the low dose of 1.5 x 1014 vg/kg was defined as the maximum tolerated dose (MTD).”

“Nevertheless, the NHP raised an antibody titre against both the vector and the transgene, while the mice raised an antibody titre against the vector alone.”

“The biodistribution (BD) and SMN transgene expression profile of AVXS-101 were evaluated in neonatal FVB mice through 12 weeks.”

“Target organ toxicity in the heart and liver was associated with mortality in mice at dose levels of 2.4 × 10 14 vg/kg and above, approximately 2.2-fold higher than the recommended clinical dose level.”

“Nevertheless, the NHP raised an antibody titre against both the vector and the transgene, while the mice raised an antibody titre against the vector alone.”

“In ZOLGENSMA clinical trials, patients were required to have baseline anti-AAV9 antibody titers of ≤ 1:50, measured using an enzyme-linked immunosorbent assay (ELISA). Evidence of prior exposure to AAV9 was uncommon.”

“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.”

“occurrence of tissue lesions (primarily liver and ventricle) already found in doses 0.7- to 1.4-fold the clinical dose and the striking mortality in mice at doses 2-3 the clinical dose required discussion.”

“Based on the lack of similar cardiovascular toxicities resulting in Zolgensma-related mortality, the low dose of 1.5 x 1014 vg/kg was defined as the maximum tolerated dose (MTD).”

“At dose levels of 1.2 x 1013 up to 1.1 x 1014 vg/kg, the single IV administration of the various clinical vector lots of AVXS-101 resulted in a dose-dependent improvement in survival in neonatal SMNdelta7 mice.”

“Ultimately, the therapeutic window in mice is small and there is no clear rationale or justification for clinical dose selection, since underlying data are missing.”

“All studies were performed with pre-process A batch material, except for the two 12-week GLP studies (process B).”

“Zolgensma finished product is a single-dose, preservative-free, sterile, clear to slightly opaque, and colourless to faint white, intravenous infusion of non-replicating, self-complementary AAV9 vector at a target concentration of 2.0 x 1013 vg/mL.”

“The program ended with approval of Zolgensma by the US FDA on 24 May 2019.”