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

“In a standard genotoxicity battery, neither tepotinib nor the major metabolite M506 were positive in either the Ames or the in vitro micronucleus assay regardless of metabolic activation. Tepotinib was also negative in the in vivo micronucleus assay.”

“Dedicated carcinogenicity studies were not conducted with tepotinib, as they are not needed to support the use of a drug intended to treat patients with advanced cancer.”

“At dose levels ≥ 5 mg/kg there was an increased frequency of skeletal abnormalities, including misshapen scapula and clavicle, malpositioned calcaneus and talus, malrotated hind paw, and incomplete ossification of sternebra.”

“Tepotinib (hydrochloride hydrate) inhibited the Kv11.1 (hERG) channel current with an IC50 of 1.2 µM, at a concentration 24-fold higher than the equivalent unbound maximum plasma concentration of the proposed clinical dose of 500 mg.”

“Tepotinib and its major circulating metabolite were not mutagenic in vitro in the bacterial reverse mutation (Ames) assay , or a mouse lymphoma assay.”

“Tepotinib and its major circulating metabolite were not mutagenic in vitro in the bacterial reverse mutation (Ames) assay , or a mouse lymphoma assay.”

“The micronucleus test was negative, although it should be noted that the exposure levels in the rat is estimated to be 3-fold lower than clinical exposure, resulting in an uncertainty.”

“In line with the ICH S9 guideline, no studies have been performed to evaluate the carcinogenic potential of tepotinib”

“Dedicated carcinogenicity studies were not conducted with tepotinib, as they are not needed to support the use of a drug intended to treat patients with advanced cancer.”

“Tepotinib (hydrochloride hydrate) inhibited the Kv11.1 (hERG) channel current with an IC50 of 1.2 µM, at a concentration 24-fold higher than the equivalent unbound maximum plasma concentration of the proposed clinical dose of 500 mg.”