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

“The genotoxicity of momelotinib was evaluated in a battery of in vitro and in vivo tests (bacterial reverse mutation assay, in vitro mammalian cytogenetic test using human lymphocytes, and in vivo micronucleus assay). Overall, momelotinib was not genotoxic under the test conditions.”

“Oral administration of the top dose of 15 mg/kg/day of momelotinib (17-times the MRHD) for 2 years significantly increased the incidence of testicular Leydig cell tumors in male rats (11/60 versus 2/60 in control males, Table 32).”

“MMB, when administered orally to pregnant rats and rabbits during organogenesis showed evidence of embryo-fetal toxicities, but no teratogenicity.”

“The cardiovascular in vitro studies showed that MMB was a weak inhibitor of hERG channel K+ current (IC50>10 µM), with no clinical relevance.”

“Momelotinib was not mutagenic in a bacterial reverse mutation assay, or clastogenic in an in vitro chromosomal aberration assay with human peripheral blood lymphocytes or in vivo in a rat bone marrow micronucleus assay.”

“Momelotinib was not mutagenic in a bacterial reverse mutation assay, or clastogenic in an in vitro chromosomal aberration assay with human peripheral blood lymphocytes or in vivo in a rat bone marrow micronucleus assay.”

“Momelotinib was not mutagenic in a bacterial reverse mutation assay, or clastogenic in an in vitro chromosomal aberration assay with human peripheral blood lymphocytes or in vivo in a rat bone marrow micronucleus assay.”

“There was no evidence of tumorigenicity in male or female mice that received momelotinib doses up to 100 mg/kg/day for 26 weeks. In a 2‑year oral carcinogenicity study in Sprague‑Dawley rats, momelotinib caused benign Leydig cell tumors at a dose of 15 mg/kg/day (17 times the maximum recommended dose”

“In the 26-week carcinogenicity study in transgenic mice, there were no MMB-related neoplasms in animals administered up to 100 mg/kg/day, although there was a clear carcinogenic response in animals administered the positive control article.”

“The QRS values were unaffected by momelotinib in dogs despite a very weak inhibition of hERG channel potassium (IC50 of >10 µM) observed in the hERG assay. It should be noted that the weak effect observed in the hERG assay was about 8-times the Cmax in dogs (30 mg/kg, Cmax 1174 ng/mL) and 21-times the Cmax (479 ng/mL) in humans at 200 mg dose”