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

“Lumateperone was positive for mutagenic potential in the Ames test in the presence of metabolic activation in the TA1537 tester strain and the mouse lymphoma test. Lumateperone was negative for clastogenic activity in the in vivo micronucleus assay in rats and was not genotoxic in the in vivo Comet assay in rats”

“Lifetime carcinogenicity studies were conducted in rats and mice, and results showed no carcinogenic potential in either species.”

“Oral administration of lumateperone to male and female rats adversely affected male and female fertility and caused estrus cycle irregularities at doses approximately equal to the MRHD of 42 mg lumateperone on a mg/m2 basis.”

“Lumateperone was positive for mutagenic potential in the Ames test in the presence of metabolic activation in the TA1537 tester strain and the mouse lymphoma test.”

“Lumateperone was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) or the mouse lymphoma test in the absence of metabolic activation. Lumateperone was positive for mutagenic potential in the Ames test in the presence of metabolic activation in the TA1537 tester strain and the mouse lymphoma test.”

“Lumateperone was negative for clastogenic activity in the in vivo micronucleus assay in rats and was not genotoxic in the in vivo Comet assay in rats at doses ~16 times the MRHD of 42 mg on a mg/m2 basis.”

“Lifetime carcinogenicity studies were conducted in rats and mice, and results showed no carcinogenic potential in either species.”

“The nonclinical study reports for the carcinogenicity studies were submitted on April 19, 2018 and April 26, 2018. The Applicant submitted the final portion of the NDA on September 27, 2019.”

“(Q)SAR models for hERG channel inhibition and drug-induced phospholipidosis identified structural alerts for all but the glucuronide metabolite, suggesting that metabolites containing the aniline moiety do not exhibit distinctively different effects at these endpoints.”