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.”

“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”

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

“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 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.”

“DXd, was clastogenic in both an in vivo rat bone marrow micronucleus assay and an in vitro Chinese hamster lung chromosome aberration assay and was not mutagenic in an in vitro bacterial reverse mutation assay.”

“DXd, was clastogenic in both an in vivo rat bone marrow micronucleus assay and an in vitro Chinese hamster lung chromosome aberration assay and was not mutagenic in an in vitro bacterial reverse mutation assay.”

“DXd, was clastogenic in both an in vivo rat bone marrow micronucleus assay and an in vitro Chinese hamster lung chromosome aberration assay and was not mutagenic in an in vitro bacterial reverse mutation assay.”

“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.”

“In vitro, MAAA-1181a did not have any effects on the hERG channel current up to 10 µmol/L (IC50 > 10 µM).”

“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.”

“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). No other animals were positive for ADA during the studies.”

“Among patients who received ENHERTU as a single agent over a 6 to 9 month treatment period in 13 clinical trials, anti-fam-trastuzumab deruxtecan-nxki antibodies developed in 2.2% (49/2,231) of patients who received ENHERTU 5.4 mg/kg every three weeks”

“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.”

“In a three-month repeat-dose toxicity study in monkeys, intravenous administration of DS-8201a decreased numbers of round spermatids in the testes at seminiferous tubule stages V to VI at doses ≥ 30 mg/kg (≥ 7 times the exposure at the human recommended dose of 5.4 mg/kg based on AUC).”

“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”

“The anti-tumor activity of DS-8201a was evaluated in several mouse models of breast cancer. In a mouse xenograft model of HER2-positive breast cancer, the activity of a single dose of 10 mg/kg DS-8201a or MAAL-9001 was evaluated 13 days after inoculation of KPL-4 cells to female CAnN.Cg-Foxn1nu/CrlCrlj nude mice”

“Results in patient-derived xenograft (PDX) models of breast cancer suggest that DS-8201a is effective even in T-DM1 refractory HER2-expressing breast cancer tumours due to the drug-linker system with a different mechanism of action. However, it is unexpected that DS-8201a has a clear, although not significant, lesser effect than MAAL-9002b which has a two times lower drug-to-antibody ratio (DAR) in the HER2-positive CTG-0708 model.”