Zepzelca: what flexibility did regulators accept, and why?

“Regarding the interspecies comparison of exposures and safety margins, these are determined based on Maximal Tolerated Doses (MTDs) for general toxicity studies instead of the NOAELs since the NOAELs were determined only in some toxicology studies (and companion toxicokinetics). Exposure margins at MTDs are well below 1 in all of the performed studies and all of the species.”

“In vivo testing was not conducted, but this is acceptable under ICH S2 for strongly cytotoxic compounds targeting rapidly dividing cells.”

“Given its mechanism of action as a genotoxic agent targeting rapidly dividing cells, FDA would not generally request an embryofetal development study, however, the Applicant did conduct a preliminary single dose, single-dose level embryo-fetal development study in rats.”

“However, no further non-clinical concern is raised due to: (i) absence of a full toxicological coverage of both human major metabolites (see discussion above), and (ii) ICH S9 Q&A, stating that no additional studies are required with disproportional metabolites.”