Xdemvy: genotox, carcinogenicity and repro: done or skipped?

“AHC 2224920 was negative for genotoxic potential in a complete battery of genotoxicity GLP studies (i.e., Ames test, in vitro chromosome aberration test in cultured human lymphocytes and in vivo micronuclei assay in rats).”

“As agreed with the Sponsor during their pre-NDA interaction with the Division, carcinogenicity studies were not conducted to support the approval of Lotilaner Ophthalmic Solution, 0.25%, for the treatment of Demodex blepharitis.”

“There was a marked effect on mean fetal weight at 50 mg/kg/day and there was an indication of a developmental delay characterized by an increased number of fetuses with incomplete ossification of individual bones of the skeleton.”

“The central nervous system, respiratory and cardiovascular assessments of Lotilaner were evaluated in GLP studies in vitro (hERG assay) and in vivo in rats and dogs. No clinically relevant adverse effects were noted in any of the studies.”

“Lotilaner was not genotoxic in the following assays: Ames assay for bacterial gene mutation, in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes, and in vivo rat micronucleus test.”

“Lotilaner was not genotoxic in the following assays: Ames assay for bacterial gene mutation, in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes, and in vivo rat micronucleus test.”

“Lotilaner was not genotoxic in the following assays: Ames assay for bacterial gene mutation, in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes, and in vivo rat micronucleus test.”

“Based on the totality of Sponsor’s arguments, this reviewer judged the waiver request for carcinogenicity studies receivable since the weight of evidence indicated no cause for concerns in the animals or humans, nor significant systemic exposure for a long period of time”

“No studies were performed. The Sponsor provided a rationale for not conducting carcinogenicity studies with Lotilaner that was found to be acceptable by this reviewer”

“Lotilaner did not induce any significant block of hERG current at concentrations up to 100 µM (60 µg/mL).”