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

“Omidenepag was not mutagenic in the bacterial reverse mutation (Ames) test and the in vivo mouse micronucleus test. Omidenepag isopropyl was positive (mutagenic and clastogenic) without metabolic activation in the in vitro mouse lymphoma forward mutation assay.”

“Lifetime rodent studies have not been performed to evaluate the carcinogenic potential of omidenepag isopropyl or omidenepag. In rats dosed by subcutaneous injection daily for 26 weeks, nephroblastoma and a spermatic cord tumor were found at 0.003 mg/kg/day (33 times the RHOD based on the estimated area under the curve [AUC]).”

“In animal reproduction studies, subcutaneous administration of omidenepag isopropyl to pregnant rabbits throughout the period of organogenesis produced fetal skeletal anomalies at a dose of 24 times the clinical dose, based on estimated plasma C max .”

“For in-life cardiovascular safety pharmacology endpoints, 0.268 mg/kg/day did not have an apparent effect. Doses ≥ 1.02 mg/kg of omidenepag caused increased heart rate, shortened PR interval, decreased blood pressure, and prolonged QTc.”

“Inadequate bacterial reverse mutation test”

“Omidenepag isopropyl was positive (mutagenic and clastogenic) without metabolic activation in the in vitro mouse lymphoma forward mutation assay.”

“The study is wholly inadequate to evaluate potential clastogenicity, because dose selection was too low to adequately characterize potential activity.”

“Lifetime rodent studies have not been performed to evaluate the carcinogenic potential of omidenepag isopropyl or omidenepag. In rats dosed by subcutaneous injection daily for 26 weeks, nephroblastoma and a spermatic cord tumor were found at 0.003 mg/kg/day (33 times the RHOD based on the estimated area under the curve [AUC]).”

“Carcinogenicity testing has not been performed with omidenepag isopropyl or omidenepag.”

“These results are not concerning for topical ocular dosing, based on the systemic exposure margin (approximately 150 x from the low-dose TK means to the clinical PK means for both Cmax and AUC).”