How long were the pivotal tox studies for approved ADCs?

“The haematologic changes observed in the 26-week repeat-dose toxicity study were similar to those of the 11-week study.”

“With repeat-dose administration of brentuximab vedotin, unconjugated brentuximab, and MMAE in rats and monkeys the principal test article-related effects of brentuximab vedotin and MMAE in both species included changes in the bone marrow and lymphoid tissues;”

“The Applicant conducted repeat-dose toxicity studies of up to 6 months duration in rats and cynomolgus monkeys to investigate the chronic toxicity of inotuzumab ozogamicin;”

“In the 6-month cynomolgus monkey study, inotuzumab ozogamicin was administered IV at doses of 0.5, 1.5, or 5 μg/kg once weekly.”

“Therefore, long-term (e.g., 3- and 6-month) repeat-dose toxicology studies with ado-trastuzumab emtansine were conducted in monkeys.”

“The Applicant did a second multidose toxicology study in Cynomolgus monkeys (study 07-0653). The animals received doses of TDM1 of 0 1, 3, or 10 mg/kg once every three weeks for 8 doses.”

“Datopotamab deruxtecan was administered i.v. to cynomolgus monkeys at doses of 10, 30 or 80 mg/kg every three weeks on five occasions in a GLP-compliant 3-month toxicity study with a 2-month recovery period, no deaths or moribundity were noted up to 80 mg/kg.”

“Datopotamab deruxtecan was administered i.v. to cynomolgus monkeys at doses of 10, 30 or 80 mg/kg every three weeks on five occasions in a GLP-compliant 3-month toxicity study with a 2-month recovery period, no deaths or moribundity were noted up to 80 mg/kg.”

“Groups of monkeys received 0, 0.01, 0.03, 0.1 mg/kg intravenous doses once every 21 days for 13 weeks.”

“The toxicity of PVEK has been characterized in single- and repeat-dose studies (up to 13 weeks in duration).”

“The Applicant evaluated the safety of telisotuzumab vedotin in GLP-compliant 4- and 13-week studies in cynomolgus monkeys with the intended IV route of administration.”

“In the 13-week GLP-compliant repeat-dose toxicology study in monkeys (Report No. R&D/18/0622, Study No. 2100-287), telisotuzumab vedotin was intravenously administered at doses of 0.5, 1.5, and 3 mg/kg every 2 weeks for a total of seven doses, followed by an 8-week recovery period.”

“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.”

“No mortalities were reported in the 13-week study in rats administered enfortumab vedotin at doses up to 5 mg/kg once weekly (at 0.94-fold the exposure in human at the clinical recommended dose).”

“The Applicant conducted GLP intravenous repeat-dose (weekly) general toxicology studies in rats (4 and 13-week) with enfortumab vedotin, and the unconjugated antibody (AGS-22M6)”

“A GLP compliant repeat-dose toxicology study with tisotumab vedotin was conducted in monkeys (13-week), and the payload was assessed in rats (4-week) and monkeys (11-week) using the clinical intravenous route of administration.”

“In a 13-week GLP repeat-dose study with a 6-week recovery period tisotumab vedotin was administered i.v. at doses of 1, 3 or 5 mg/kg every three weeks on five occasions to cynomolgus monkeys.”

“In a 13-week toxicity study, monkeys were given sacituzumab govitecan at doses of 12.5, 25, and 50 mg/kg once weekly via a 1-hour infusion for 2 weeks of a 3-week cycle for 4 treatment cycles.”

“In a 13-week toxicity study, monkeys were given sacituzumab govitecan at doses of 12.5, 25, and 50 mg/kg once weekly via a 1-hour infusion for 2 weeks of a 3-week cycle for 4 treatment cycles.”

“The Applicant conducted GLP 4‐week and 13‐week repeat‐dose general toxicology studies in which cynomolgus monkeys were dosed with the ADC, followed by a 12‐week recovery period.”

“The Applicant conducted GLP 4‐week and 13‐week repeat‐dose general toxicology studies in which cynomolgus monkeys were dosed with the ADC, followed by a 12‐week recovery period.”

“A GLP-compliant general toxicity study in monkeys was also completed in which 12 doses of gemtuzumab ozogamicin were given once weekly by intravenous bolus injection to groups of 3 male and 3 female cynomolgus monkeys at doses of 0 (sterile water), 2.2, 6.6, or 11 mg/m2 /week.”

“Rats were administered 6 weekly doses at 0 (PBS control), 7.2 (hP67.6 antibody control), or CL 555,201 (GO) at doses of 0.6, 2.4, or 7.2 mg/m2 /week and observed for an additional 4 weeks.”

“A 10-week GLP compliant repeat-dose toxicity study with mirvetuximab soravtansine was conducted in cynomolgus monkey using the clinical IV route of administration”

“IMGN853 at doses of 0, 2, 4, and 8 mg/kg/dose was administered intravenously (slow push) to cynomolgus monkeys once every 3 weeks for up to 10 weeks (a total of 4 doses) with a 5- week recovery period (n=6/sex/group).”

“Cardiovascular, respiratory, and neurologic assessments were included in the 10-week repeat-dose toxicology study in cynomolgus monkeys, using polatuzumab vedotin or the surrogate ADC (10-0044).”

“In Cynomolgus monkeys, IV doses of 1, 3, and 5 mg/kg polatuzumab vedotin or 3 and 5 mg/kg of the surrogate ADC were administered Q3W for a total of 4 doses, followed by a 9-week recovery period.”