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

“According to ICH S6(R1), genotoxicity studies were not performed.”

“A thorough weight of evidence evaluation, in combination with data from the repeat dose toxicity studies, which included exposure to concizumab up to 52 weeks, does not suggest that concizumab has carcinogenic potential.”

“In a 26-week toxicity study in sexually mature male and female cynomolgus monkeys with subcutaneous doses up to 9 mg/kg/day (corresponding to 3400-fold the human exposure, based on AUC 0 to 24h ), concizumab-mtci did not affect fertility”

“No effects of concizumab on safety pharmacology endpoints were observed in any of these studies at repeat doses up to 200 mg/kg/once weekly (i.v.) and 50 mg/kg/day (s.c.).”

“Genotoxicity studies were not conducted, as concizumab consists of naturally occurring amino acids (endogenous) and is not anticipated to be genotoxic and there were no mechanistic data that suggested a mutagenic potential for concizumab.”

“Genotoxicity studies were not conducted, as concizumab consists of naturally occurring amino acids (endogenous) and is not anticipated to be genotoxic and there were no mechanistic data that suggested a mutagenic potential for concizumab.”

“Genotoxicity studies were not conducted, as concizumab consists of naturally occurring amino acids (endogenous) and is not anticipated to be genotoxic and there were no mechanistic data that suggested a mutagenic potential for concizumab.”

“Instead, the Applicant conducted a carcinogenicity risk assessment of concizumab using a weight-of-evidence (WOE) approach that considered the mode of action (MOA), a review of relevant literature and an evaluation of the nonclinical and clinical data.”

“The Division determined that no additional nonclinical studies assessing the carcinogenic potential of concizumab were warranted for the indications of hemophilia A and hemophilia B and the CDER Executive Carcinogenicity Assessment Committee (ECAC) concurred with the Division’s recommendation.”

“In addition, QT prolongation was not observed during ECG assessments in cynomolgus monkeys administered repeat doses of concizumab up to 9 mg/kg/day (SC), 4300x MRHD (AUC) and 4400X MRHD (Cmax), for up to 52 weeks.”