Adcetris
brentuximab vedotin · CD30Monkey NOAEL serum exposure ~2 to 3x human exposure at the clinical dose
Besponsa: what safety margin did regulators accept?
inotuzumab ozogamicin · CD22
Safety margin at NOAEL
No NOAEL for rat male reproductive effects, seen at ~0.3x human AUC
“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).”
NOAEL / key findings
No NOAEL in rat or monkey chronic studies; liver (sinusoidal injury), hematolymphoid, reproductive organs; monkey glomerulonephritis death at 5 ug/kg
“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.”
Same question, other ADCs
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)
Elahere
mirvetuximab soravtansine · FRαMonkey NOAEL 4 mg/kg: AUC margin 0.09 (AUC0-24 vs AUCtau) to 0.57 (AUC0-∞)
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