Enhertu

“DS-8201a and MAAL-9001 bound to cynomolgus monkey HER2 protein but not to mouse or rat HER2 proteins, showing that the cynomolgus monkey is an appropriate species in which to conduct toxicity evaluation with DS-8201a, based on its binding to HER2.”

“In the same assay, DS-8201a and MAAL-9001 bound to cynomolgus monkey HER2-His protein (Kd [ED50] = 7.46 ng/mL and 6.77 ng/mL, respectively) but not to mouse or rat HER2-His proteins.”

“In the studies with trastuzumab deruxtecan, the rodent study and one monkey study were performed with process 1 material, whereas the 2 additional cynomolgus monkey studies were performed with process 2 material.”

“In cynomolgus monkeys, Cmax and AUC0-21d values increased dose-dependently, and there were no accumulation or sex-related differences in toxicokinetic parameters following administration of 3, 10, or 30 mg/kg DS-8201a IV, once every 3 weeks for 3 months.”

“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.”

“The in vivo studies were primarily conducted via intravenous injection in mice, rats, and monkeys, as this is the intended route of administration in humans.”

“MAAA-1181a was clastogenic in both an in vivo rat bone marrow micronucleus assay and an in vitro Chinese hamster lung chromosome aberration assay but was not mutagenic in an in vitro bacterial reverse mutation assay.”

“Carcinogenicity studies are not warranted to support the licensing application of fam-trastuzumab deruxtecan-nxki for the proposed indication.”

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

“In a safety pharmacology study, DS-8201a did not have any significant effects on blood pressure, heart rate, ECG parameters, body temperature, or neurobehavioral function in conscious and unrestrained telemetered male cynomolgus monkeys following a single 78.8 mg/kg dose.”

“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 highest non-severely toxic dose of trastuzumab deruxtecan was established at 197 mg/kg in rats (non-binding species), and 30 mg/kg in cynomolgus monkey”

“In the monkey studies, only pre-dose samples in a few animals in two of the four studies showed detectable ADA (one male in study SBL315-031, 3 animals in Study SBL315-526).”

“After a single administration of 6.4 mg/kg 14C-DS-8201a IV, the highest radioactivity was observed in the large intestinal contents, followed by the blood, lung, adrenal gland, and liver (all tissue-to-blood ratios were less than 1).”

“Nevertheless, the presence of HER2 in parenchymal cells of the lung may have an important role in the processes leading to inflammatory changes and interstitial lung toxicity, however, the precise mechanisms are unclear.”