Adcetris
brentuximab vedotin · CD30Exposure ratios derived from single-dose studies and a different dosing scheme rather than repeat-dose data matching the clinical regimen
Decnupaz: what flexibility did regulators accept, and why?
pivekimab sunirine · CD123
Flexibility accepted
SpeciesVerdict not stated
No pharmacologically relevant toxicology species: no CD123 cross-reactivity in mouse, rat or cynomolgus monkey; monkey studies assess off-target and payload toxicity only
“pivekimab sunirine does not cross-react with CD123 in standard animal species used for toxicology studies (mouse, rat, or cynomolgus monkey).”
DARTAccepted
No reproductive and developmental toxicity studies, including embryo-fetal development, for the ADC
Why: In accordance with ICH S9 and prior FDA feedback · Within the guideline
“No reproductive and developmental studies have been conducted with PVEK, in accordance with ICH S9 and FDA feedback (Reference ID: 4704103). The FDA's Assessment: The FDA concurs.”
Safety marginVerdict not stated
No NOAEL in the 13-week monkey study: thymic atrophy at the lowest dose tested
“Adverse toxicity was observed at all doses since even the lowest tested dose of 0.01 Ab mg/kg produced thymic atrophy in males.”
Same question, other ADCs
Besponsa
inotuzumab ozogamicin · CD22No pharmacologically relevant toxicology species: antibody does not bind rat or monkey CD22, so only target-independent payload toxicity assessed
Datroway
datopotamab deruxtecan · Trop-2No fertility, embryo-fetal or pre- and postnatal development studies; fertility assessed from repeat-dose studies
Elahere
mirvetuximab soravtansine · FRαNo reproductive or developmental toxicity studies at all, including embryo-fetal development
Emrelis
telisotuzumab vedotin · c-MetNo fertility, embryo-fetal or pre/postnatal development studies with the ADC; MMAE payload EFD data relied on
Enhertu
fam-trastuzumab deruxtecan · HER2No embryo-fetal development or other reproductive toxicity studies with the ADC
Kadcyla
ado-trastuzumab emtansine · HER2No embryo-fetal development studies with the ADC
Mylotarg
gemtuzumab ozogamicin · CD33No pharmacologically relevant species: antibody does not bind monkey CD33 or rat and monkey tissues; toxicity studies address off-target effects only
Padcev
enfortumab vedotin · Nectin-4Chronic (13-week) toxicity in rat only; monkey limited to 4 weeks
Polivy
polatuzumab vedotin · CD79bPolatuzumab does not bind monkey CD79b; target-mediated toxicity assessed with a surrogate ADC binding monkey CD79b
Tivdak
tisotumab vedotin · Tissue factorNo embryo-fetal development study with the ADC; rat EFD study of the MMAE payload (from brentuximab vedotin) relied on
Trodelvy
sacituzumab govitecan · Trop-2No embryo-fetal development or fertility studies; genotoxic SN-38 payload assumed teratogenic
Zynlonta
loncastuximab tesirine · CD19No pharmacologically relevant species; CD19-mediated toxicity could not be evaluated in any nonclinical species