What safety margins were accepted for approved ADCs?

“When monkey AUC0-24 was compared to human AUCtau (area under the concentration vs. time curve over the dosing interval 21 days) exposure margin was 0.09; however, when monkey AUC0-∞ was used for comparison the exposure multiple was 0.57.”

“In a 10-week toxicity study in monkeys a mid-dose of 4 mg/kg/dose Q3W of MIRV was selected to characterize potential toxicity at an exposure metric which was predicted to be similar to that of the IV dose (6 mg/kg, AIBW) utilized for the registrational studies. This dose was considered as NOAEL.”

“The NOAEL for pulmonary, corneal, dermal, hepatic and lymphoid (thymic) toxicity was concluded to be 10 mg/kg corresponding to a margin of exposure of 0.25.”

“The NOAELs for pulmonary, corneal, dermal, hepatic, and lymphoid (thymic) toxicity was concluded to be 10 mg/kg.”

“The NOAEL was not identified for the effects on male reproductive organs, which were observed at approximately 0.3 times the human clinical exposure based on AUC (SmPC section 5.3).”

“Taken together, the primary inotuzumab ozogamicin target organs identified by the chronic toxicity studies were the liver, hematolymphopoietic tissues, and the male and female reproductive organs.”

“Administration of trastuzumab emtansine was well tolerated in rats and monkeys at doses up to 20 and 10 mg/kg, respectively, corresponding to 2040 µg DM1/m2 in both species, which is approximately equivalent to the clinical dose of trastuzumab emtansine in patients.”

“Based on overall tolerability and reversibility of findings, the Applicant considered 10 mg/kg of trastuzumab emtansine given as four injections to Cynomolgus monkeys every 3 weeks to be the highest non-severely toxic dose.”

“The applicant also provided exposure (Cmax and AUC) ratios between monkey and human at the highest non-severely toxic dose of 3 mg/kg, which was approximately 1.35- to 2.56-fold that in humans.”

“The NOAEL for males was <1 mg/kg. The applicant also provided exposure (Cmax and AUC) ratios between monkey and human at the highest non-severely toxic dose of 3 mg/kg, which was approximately 1.35- to 2.56-fold that in humans.”

“The serum exposure to SGN-35 in monkeys at the NOAEL was approximately 2 to 3 times that in humans.”

“At 3 mg/kg (HNSTD), a similar, but less severe cyclic decrease in neutrophil counts was observed, while at 1 mg/kg (NOAEL) no biologically relevant effects on neutrophil counts was observed.”

“The systematic exposure to AGS-22M6E in cynomolgus monkeys was ~3-fold the human systemic exposure at the recommended clinical dose. In rats, at the maximum tolerated dose (MTD), the systematic exposure was also ~2-fold the human systemic exposure at the recommended clinical dose.”

“In the 4-week monkey study (# 20005664), AGS-22M6E systemic exposure at 3 mg/kg (MTD/HNSTD) was 2450 µg.hr/mL (Day 1) and 903 µg.hr/mL (Day 22).”

“The dose of 0.3 mg/kg in animals results in an exposure (AUC) that is approximately 3 times the exposure at the maximum recommended human recommended dose [MRHD] of 0.15 mg/kg.”

“Also, adverse findings in male reproductive organs were present at 0.6 mg/kg only in the 4‐week study and at all doses (≥ 0.075 mg/kg) in the 13‐week study.”

“A comparison of the exposure in cynomolgus at the NOAEL/HNSTD (50 mg/kg) and in humans at the proposed clinical dose (10 mg/kg) was made. The exposure margin was 6.4x for total antibody, 4.6x for total SN-38 and 3.1x for free SN-38.”

“In the absence of a NOAEL, the HNSTD in this study was 60 mg/kg/dose.”

“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”

“Adverse toxicity was observed at all doses since even the lowest tested dose of 0.01 Ab mg/kg produced thymic atrophy in males.”

“Adverse toxicity was observed at all doses since even the lowest tested dose of 0.01 Ab mg/kg produced thymic atrophy in males.”

“Myelosuppression occurred at the middle and high doses, which correlated histologically with decreased bone marrow cellularity.”

“The NOAEL was defined at 2.4 mg/m2 /week based on target organ toxicity in the kidney, liver, and lympho-hematopoietic organs at ≥7.2 mg/m2 /week.”

“The main target organs are bone marrow, lymphoid organs, reproductive organs and liver with less severe effects on eye, skin and pancreas.”