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

“Ritlecitinib was aneugenic in vitro, as determined by an in vitro micronucleus assay in TK6 cells and follow-up in vitro mechanism experiments. However, ritlecitinib was not mutagenic in a reverse mutation assay in bacterial cells.”

“In a 2-year rat carcinogenicity study, ritlecitinib increased the incidence of combined benign and malignant thymomas in female rats, and thyroid follicular adenomas and combined follicular adenomas and carcinomas in male rats at 100 mg/kg/day (29 times the MRHD based on AUC comparison). No ritlecitinib-related tumors were noted at doses up to 30 mg/kg/day (6.3 times the MRHD based on AUC comparison).”

“In an embryo-fetal development study in pregnant rats, oral administration of ritlecitinib from gestation days 6 to 17 decreased fetal body weights and caused fetal skeletal malformations (malformed vertebrae and ribs) and variations (delayed ossification) at doses ≥175 mg/kg/day (49 times the MRHD based on AUC comparison).”

“At clinically relevant concentrations in vitro, ritlecitinib did not inhibit hERG currents (IC50 >300 µM). A single oral dose of ritlecitinib did not produce acute CNS or respiratory effects in male rats (doses: 0, 75, 175, and 400 mg/kg; NOEL: 400 mg/kg).”

“Ritlecitinib was not mutagenic in the in vitro bacterial reverse mutation assay (Ames assay).”

“Ritlecitinib was positive in an in vitro micronucleus assay in TK6 cells. However, mechanistic studies determined that ritlecitinib is aneugenic and does not present a clinically relevant genotoxic concern.”

“Additionally, in an in vivo rat bone marrow micronucleus assay, ritlecitinib was not aneugenic or clastogenic at doses up to 400 mg/kg/day.”

“In a 2-year rat carcinogenicity study, ritlecitinib increased the incidence of combined benign and malignant thymomas in female rats, and thyroid follicular adenomas and combined follicular adenomas and carcinomas in male rats at 100 mg/kg/day (29 times the MRHD based on AUC comparison).”

“The potential for carcinogenicity was assessed in a 6-month study in transgenic rasH2 (tg/wt) mice and a 2-year study in rats in accordance with ICH Guidelines M3(R2), 2009.”

“At clinically relevant concentrations in vitro, ritlecitinib did not inhibit hERG currents (IC50 >300 µM).”