Sarclisa: what was done before first-in-human, and what came after?

“Based on the overall data, the recommended starting human dose for the first-in-human study was 0.0001 mg/kg, which is approximately 10% of the predicted CD38 receptor occupancy measured in normal human B and T cells.”

“toxicology studies with isatuximab were limited to a repeat-dose (once weekly for 3 weeks) toxicity study in cynomolgus monkeys (preceded by a small exploratory study)”

“The weekly repeated intravenous administration of isatuximab for 3 weeks to cynomolgus monkeys at doses of 20, 50 or 100 mg/kg/week resulted in no isatuximab-related findings in any parameters and in any groups.”

“Due to the lack of an appropriate pharmacologically relevant animal species for a study assessing the effects of isatuximab on embryo-fetal development, the evaluation of the reproductive and developmental toxicity of isatuximab is based on a weight of evidence (WOE) approach using literature on the involvement of CD38 in reproduction and development.”

“Effects observed in target antigen CD38 knockout animal models include the depletion of fetal CD38 positive immune cells and a decrease in bone density.”

“Prenatal and Postnatal Development The Applicant's Position: No study or assessment conducted. The FDA's Assessment: FDA concurs based on the ICH S9 guidance.”

“No carcinogenicity studies were performed with isatuximab.”

“In line with relevant guidelines no genotoxicity, carcinogenicity and reproductive toxicity studies were conducted (ref. ICH S6, ICH S9; SmPC section 5.3).”

“No fertility and early embryonic development, or carcinogenicity studies have been conducted or are warranted based on the proposed indication.”