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

“Elafibranor was negative in the in vitro bacterial reverse mutation (Ames) assay, the in vivo rat micronucleus assay, and the in vivo comet assay in rats. Elafibranor was positive for mutagenicity in L5178Y tk+/- mouse lymphoma cells.”

“The liver tumors in mice and rats may be attributed to the expected rodent-specific PPARα-related liver toxicity and its related consequences. Therefore, the relevance to humans is uncertain.”

“Treatment of pregnant rats with elafibranor during organogenesis through lactation resulted in stillbirths, reduced survival, decrease in pup body weight, and/or blue/black discoloration of the caudal section of body, which occurred at maternal plasma drug exposures lower than or approximately equal to human exposure at the recommended dose”

“A single dose oral administration of elafibranor at 30 mg/kg had no effect on heart rate, arterial blood pressure, or electrocardiogram (Leads I, II, III, aVL, aVR and aVF) in the in vivo telemetry study in conscious dogs. At the doses of 100, 300, and 1000 mg/kg, elafibranor induced delayed (in terms of duration) and dose-dependent tachycardia.”

“Elafibranor was negative in the in vitro bacterial reverse mutation (Ames) assay, the in vivo rat micronucleus assay, and the in vivo comet assay in rats.”

“Elafibranor was positive for mutagenicity in L5178Y tk+/- mouse lymphoma cells. In the in vitro micronucleus assay in L5178Y tk+/- mouse lymphoma cells, elafibranor induced a weak but reproducible genotoxic effect.”

“Elafibranor was negative in the in vitro bacterial reverse mutation (Ames) assay, the in vivo rat micronucleus assay, and the in vivo comet assay in rats.”

“In the rat carcinogenicity study, elafibranor induced the “tumour triade” (hepatocellular carcinomas/adenomas and pancreatic acinar cell adenomas in both sexes and Leydig cell adenomas in males), as well as increased incidence of preputial gland carcinomas. In the mouse carcinogenicity study, increased incidence of hepatocellular carcinoma, adenoma and adenoblastoma at all dose levels was observed.”

“In a 2-year study in Sprague-Dawley rats, elafibrinor produced hepatocellular adenoma in males and females at a dose of 30 mg/kg/day”

“In vitro human ether-a-go-go (hERG) studies with elafibranor did not reveal potential adverse effects on cardiac function, since elafibranor induced only a 20% inhibition of hERG tail current at a concentration >500-fold higher than the expected plasma Cmax at the therapeutic dose of 80 mg elafibranor.”