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.”

“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.”

“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.”

“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.”