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

“Study DS8201-A-J101 was a Phase 1, 2-part, multicenter, nonrandomized, open-label, multiple-dose, FIH study of fam-trastuzumab deruxtecan, with study sites in Japan and the US (see Table 19).”

“The FIH dose of 0.8 mg/kg was selected based on one-twelfth of the human equivalent dose of the highest non-severely toxic dose (HNSTD) in cynomolgus monkeys in toxicology studies and was also estimated to provide trough concentration in humans comparable to the minimum effective concentrations in nonclinical studies.”

“The FIH dose of 0.8 mg/kg was selected based on one-twelfth of the human equivalent dose of the highest non-severely toxic dose (HNSTD) in cynomolgus monkeys in toxicology studies and was also estimated to provide trough concentration in humans comparable to the minimum effective concentrations in nonclinical studies.”

“Intermittent Dose Toxicity Study in Monkeys Treated Intravenously with DS-8201a Once per 3 Weeks for 3 Months Followed by a 3-Month Recovery Period: SBL315-526”

“The Applicant conducted GLP-compliant, repeat-dose general toxicology studies to evaluate the toxicity of DS-8201a, MAAA-1181a, or MAAL-9001 in rats and/or monkeys.”

“As recommended by ICH S9 guidance, embryo-fetal toxicity studies were not conducted based on the justification that these studies are not warranted to support the proposed indication because MAAA-1181a is genotoxic and targets rapidly dividing cells”

“The Applicant did not conduct any reproductive toxicology studies with DS-8201a.”

“In accordance with ICH S9, no studies were conducted to assess fertility and early embryonic development to implantation, effects on pre and postnatal development, including maternal function, or embryo-fetal developmental toxicity.”

“No carcinogenicity studies have been conducted in accordance with ICH S9.”

“Carcinogenicity studies have not been conducted with trastuzumab deruxtecan. This is, according to the ICH S9 guideline, not needed for advanced cancer indications, which the current MAA proposed indication indeed is considered to be.”

“FDA agrees that carcinogenicity studies are not needed to support this BLA submission.”