Zolgensma: which tox species, and why?

“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.”