Adcetris
brentuximab vedotin · CD30Exposure ratios derived from single-dose studies and a different dosing scheme rather than repeat-dose data matching the clinical regimen
Padcev: what flexibility did regulators accept, and why?
enfortumab vedotin · Nectin-4
Flexibility accepted
SpeciesAccepted
Chronic (13-week) toxicity in rat only; monkey limited to 4 weeks
Why: Comparable rat and monkey toxicity profiles; equivalent binding affinity to human Nectin-4 in both species · Within the guideline · Weight of evidence
“In general, similar toxicity profiles were observed across species and therefore only the rat was studied in the chronic (13-week) repeat dose toxicity study (please refer to ICH S6, S9, S9 Q&A).”
“As the toxicity profiles seem to be comparable between rat and cynomolgus, and considering that cross-reactivity in the rat and cynomolgus monkey have equivalent binding affinity to human Nectin-4, it is acceptable to conduct the chronic (13-week) repeat dose toxicity study only in the rat.”
DARTAccepted
No fertility/early embryonic or pre- and postnatal development studies; male fertility risk from repeat-dose testicular findings
Why: ICH S9: advanced cancer population · Within the guideline · Serious disease
“Dedicated fertility and early embryonic development studies were not conducted in accordance with ICH S9.”
“Fertility and early embryonic development studies were not conducted or needed to support marketing of PADCEV in patients with advanced cancer.”
DARTAcceptedBeyond the letter
ADC tested only in a preliminary rat EFD study; definitive EFD run with MMAE and another MMAE ADC (SGN-35)
Why: Embryo-fetal toxicity judged appropriately evaluated; findings reported in the SmPC · Class precedent
“Embryo-fetal development toxicity of SGN-35 and SGD-1010 was evaluated in a GLP-compliant repeat-dose IV embryo-fetal development study in pregnant rats.”
“The embryo-fetal toxicity was appropriately evaluated and the observed findings are correctly reported in the SmPC.”
OtherAccepted
No separate local tolerance studies
Why: ICH S6 · Within the guideline
“Separate studies evaluating local tolerance of enfortumab vedotin were not performed. In accordance with ICH S6, the omission of dedicated local tolerance studies is acceptable.”
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
Decnupaz
pivekimab sunirine · CD123No pharmacologically relevant toxicology species: no CD123 cross-reactivity in mouse, rat or cynomolgus monkey; monkey studies assess off-target and payload toxicity only
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
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