Exondys 51: what flexibility did regulators accept, and why?

“Carcinogenicity studies have not been conducted for eteplirsen. As agreed to by the division, carcinogenicity studies in two species would be conducted post approval as PMRs.”

“4) DMD is a life-threatening and severely disabling disease for which no satisfactory alternative therapy exists. The sponsor’s justification is acceptable.”

“Because the patient population is primarily male, standard reproductive and developmental studies were not required. To assess male fertility, the sponsor conducted a histopathological evaluation of male reproductive organs in the pivotal toxicity studies,”

“For mdx mouse, the pharmacological activity of the human product cannot be tested because of differences in the dystrophin gene mutation, requiring use of a mouse-specific PMO, exon 23 skipping AON and, therefore, resulting in a different truncated dystrophin.”

“Overall, the nonclinical studies of eteplirsen and the mouse surrogate (AVI-4225) are adequate to support approval of the NDA, with appropriate labeling and PMRs for carcinogenicity studies in two species.”

“Safety margins based on plasma (AVI-4225 or eteplirsen) exposures at the NOAELs in adult animals are low (<1 in mdx mouse, 3.4 in monkey); however, plasma exposures at the highest doses tested, which were associated with minimal-to-slight toxicity (except for moderate dilatation of lateral ventricles), were 17 and 20 times the anticipated human exposure.”