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

“Genotoxicity studies with biologics such as garadacimab are not required.”

“Based on the weight of evidence, the Division agreed with the Applicant that a rodent carcinogenicity study was not technically feasible. Further, there appears to be a low or negligible carcinogenic potential based on the results of the 26-week monkey study and review of the published literature regarding chronic inhibition of FXIIa.”

“For the F1 generation, no garadacimab-related effects were observed on mortality, clinical signs, body weight, developmental signs, functional observation battery, eye-blink response, presence of motile sperm, reproductive performance, cesarean section parameters, or preweaning or postweaning macroscopic observations.”

“Safety pharmacology parameters were incorporated into the pivotal repeat-dose 26-week monkey toxicology study. With intravenous (IV) doses up to 100 mg/kg/week and subcutaneous (SC) doses up to 200 mg/kg/week, no treatment-related effects on electrocardiogram, blood pressure, respiration rate, or pulse rate were observed during the 26-week Treatment Period.”

“As per International Council for Harmonisation (ICH) guideline, S6(R1) Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (June 2011), standard in vitro and in vivo genotoxicity studies are not applicable to biologics because these molecules are unlikely to interact directly with DNA or chromosomal material.”

“As per International Council for Harmonisation (ICH) guideline, S6(R1) Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (June 2011), standard in vitro and in vivo genotoxicity studies are not applicable to biologics because these molecules are unlikely to interact directly with DNA or chromosomal material.”

“As per International Council for Harmonisation (ICH) guideline, S6(R1) Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (June 2011), standard in vitro and in vivo genotoxicity studies are not applicable to biologics because these molecules are unlikely to interact directly with DNA or chromosomal material.”

“Based on the weight of evidence, the Division agreed with the Applicant that a rodent carcinogenicity study was not technically feasible.”

“Based on the weight of evidence, the Division agreed with the Applicant that a rodent carcinogenicity study was not technically feasible.”

“With intravenous (IV) doses up to 100 mg/kg/week and subcutaneous (SC) doses up to 200 mg/kg/week, no treatment-related effects on electrocardiogram, blood pressure, respiration rate, or pulse rate were observed during the 26-week Treatment Period.”