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

“Orforglipron was not mutagenic or clastogenic in a bacterial reverse mutation test, an in vitro micronucleus test in human lymphoblastoid cells, or in an in vivo bone marrow micronucleus study in rats.”

“FDA concurs with the Applicant that orforglipron was not carcinogenic in a lifetime study in rats and a 6-month study in rasH2 transgenic mice.”

“In a rabbit embryofetal development study, orforglipron caused off-target embryofetal effects which included decreased fetal and placental weights and malformations at exposures 14x the MRHD.”

“Orforglipron did not affect respiratory or CNS functions in monkeys. In cardiovascular studies in monkeys, orforglipron produces effects consistent with GLP-1 pharmacology including increases in heart rate and PR interval prolongation.”

“Orforglipron was not mutagenic or clastogenic in a bacterial reverse mutation test, an in vitro micronucleus test in human lymphoblastoid cells, or in an in vivo bone marrow micronucleus study in rats.”

“Orforglipron was not mutagenic or clastogenic in a bacterial reverse mutation test, an in vitro micronucleus test in human lymphoblastoid cells, or in an in vivo bone marrow micronucleus study in rats.”

“Orforglipron was not mutagenic or clastogenic in a bacterial reverse mutation test, an in vitro micronucleus test in human lymphoblastoid cells, or in an in vivo bone marrow micronucleus study in rats.”

“FDA concurs with the Applicant that orforglipron was not carcinogenic in a lifetime study in rats and a 6-month study in rasH2 transgenic mice.”

“Carcinogenicity assessments were conducted in a 26-week study in Tg.RasH2 transgenic mice and a 2-year study in rats.”

“At the highest concentration tested in 2 different hERG assays, an IC50 for orforglipron was not determined (<50% inhibition). The free Cmax exposure multiple in these hERG assays to the estimated exposure at the 36 mg capsule human dose is >1700-fold.”