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

“Genotoxicity testing was not performed. The product is a recombinant IgG2 protein of naturally occurring amino acids and is not expected to react with DNA or other chromosomal material.”

“A low incidence of osteosarcoma (2/54) was observed in high dose males at 19x human exposure. However, the lack of statistical significance of this finding and the large exposure multiple suggests that romosozumab is unlikely to increase the human risk of osteosarcoma.”

“Findings in the definitive FEED and EFD studies included reduced ventral processes of the 6th cervical vertebrae at doses of 100 and 300 mg/kg (17-56x human exposure).”

“Safety pharmacology endpoints were evaluated in a single dose neurobehavioral study in rat and in a single dose combined cardiovascular/respiratory study in cynomolgus monkey.”

“Mutagenesis has not been evaluated, as monoclonal antibodies are not expected to alter DNA or chromosomes.”

“Mutagenesis has not been evaluated, as monoclonal antibodies are not expected to alter DNA or chromosomes.”

“Mutagenesis has not been evaluated, as monoclonal antibodies are not expected to alter DNA or chromosomes.”

“In a rat carcinogenicity study, once-weekly romosozumab-aqqg doses of 3, 10 or 50 mg/kg were administered by subcutaneous injection to Sprague-Dawley rats from 8 weeks up to 98 weeks of age, resulting in systemic exposures that were up to 19 times the systemic exposure observed in humans following a monthly subcutaneous dose of 210 mg EVENITY (based on AUC comparison).”

“A carcinogenicity study was conducted in Sprague Dawley rats. The rats were dosed for up to 98 weeks with 0, 3, 10, 50 mg/kg/week, equivalent to 1-19x human exposure.”

“The results of these studies indicate that romosozumab had no effect on cardiovascular (blood pressure, heart rate, ECGs, QT/QTc) functions after subcutaneous dosing with exposure margins exceeding 200-fold to the clinical exposure.”