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

“Mutagenesis Etrasimod was negative in a battery of in vitro (Ames, chromosomal aberration in human peripheral blood lymphocytes) and in vivo (rat micronucleus) assays.”

“hemangioma/hemangiosarcoma were observed at exposures ≥ 46-fold the exposure at the MRHD (based on AUC comparison). In a two-year carcinogenicity study in rats, no evidence of carcinogenic potential was observed at exposures up to 88- and 198-fold the exposure at the MRHD in males and females, respectively (based on AUC comparison).”

“In animal reproduction studies, administration of etrasimod during organogenesis produced adverse effects on development, including embryolethality and fetal malformations, in both rats and rabbits at maternal exposures 5 and 6 times, respectively, the exposure at the maximum recommended human dose (MRHD).”

“In a standard battery of nonclinical safety pharmacology studies, etrasimod had no significant effects on hERG channel current in vitro, cardiovascular function in dogs, CNS parameters in rats, or respiratory function in rats.”

“Etrasimod was not mutagenic under the tested conditions.”

“Etrasimod did not induce structural aberrations in human peripheral blood lymphocytes under the conditions of the study, with or without metabolic activation.”

“Etrasimod was positive for inducing bone marrow micronuclei in female rats at the highest tested dose of 300 mg/kg/day, a systemically toxic dose; however, this increase was within the historical control range, substantially lower than the positive control, and not observed in males.”

“two-year carcinogenicity studies in mice and rats”

“The NDA submission included the final study reports and corresponding SEND datasets for the 2-year carcinogenicity studies in mice and rats.”

“Etrasimod inhibited hERG signaling in vitro, with a maximal inhibitory effect of 59% at the highest tested dose of 3 µM; a specific IC50 value could not be determined based on the study design but is likely between 1000-3000 nM (460-1370 ng/mL; 4-12 times the steady state Cmax at the MRHD).”