Adcetris
brentuximab vedotin · CD30Monkey NOAEL serum exposure ~2 to 3x human exposure at the clinical dose
Elahere: what safety margin did regulators accept?
mirvetuximab soravtansine · FRα
Safety margin at NOAEL
Monkey NOAEL 4 mg/kg: AUC margin 0.09 (AUC0-24 vs AUCtau) to 0.57 (AUC0-∞)
“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.”
NOAEL / key findings
10-week monkey NOAEL 4 mg/kg q3w (Cmax margin ~1); single-dose HNSTD 10 mg/kg, NOAEL 3 mg/kg; cornea, skin, bone marrow
“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.”
Same question, other ADCs
Besponsa
inotuzumab ozogamicin · CD22No NOAEL for rat male reproductive effects, seen at ~0.3x human AUC
Datroway
datopotamab deruxtecan · Trop-2Monkey NOAEL 10 mg/kg (lung, cornea, skin, liver, thymus): margin of exposure 0.25 (below human exposure)
Decnupaz
pivekimab sunirine · CD123No NOAEL in 13-week monkey study: thymic atrophy at the lowest dose (0.01 mg/kg)
Enhertu
fam-trastuzumab deruxtecan · HER2Monkey 30 mg/kg (3-month study) ≥7x human AUC at 5.4 mg/kg
Kadcyla
ado-trastuzumab emtansine · HER2Monkey HNSTD 10 mg/kg (2040 µg DM1/m2) approximately equivalent to the clinical dose
Padcev
enfortumab vedotin · Nectin-4Monkey ~3-fold and rat (MTD) ~2-fold human systemic exposure at recommended dose
Tivdak
tisotumab vedotin · Tissue factorMonkey HNSTD 3 mg/kg ~1.35-2.56x human exposure (Cmax and AUC)
Trodelvy
sacituzumab govitecan · Trop-2Monkey NOAEL/HNSTD 50 mg/kg: 6.4x (total antibody), 4.6x (total SN-38), 3.1x (free SN-38) human exposure at 10 mg/kg
Zynlonta
loncastuximab tesirine · CD19Monkey 0.3 mg/kg ~3x human AUC at MRHD 0.15 mg/kg
Emrelis
telisotuzumab vedotin · c-MetNot stated in public reviews
Mylotarg
gemtuzumab ozogamicin · CD33Not stated in public reviews
Polivy
polatuzumab vedotin · CD79bNot stated in public reviews