Adcetris
brentuximab vedotin · CD30Exposure ratios derived from single-dose studies and a different dosing scheme rather than repeat-dose data matching the clinical regimen
Mylotarg: what flexibility did regulators accept, and why?
gemtuzumab ozogamicin · CD33
Flexibility accepted
SpeciesVerdict not stated
No pharmacologically relevant species: antibody does not bind monkey CD33 or rat and monkey tissues; toxicity studies address off-target effects only
“hP67.6 bound strongly to human CD33-transfected CHO cells but did not bind to the monkey CD33-transfected CHO cells (study 084032).”
DARTAcceptedBeyond the letter
Embryo-fetal development studied in one species (rat) only
Why: Unequivocally positive pilot study results; leukemia indication · Weight of evidence · Serious disease
“Based on the unequivocally positive results obtained from a pilot study, the Agency previously agreed with the Applicant that one species would be sufficient to support an NDA application for CMA-676 in a leukemia indication.”
GLPVerdict not stated
Safety pharmacology studies not GLP compliant
“Safety pharmacology studies were not GLP compliant.”
Impurity or metaboliteVerdict not stated
In vivo metabolism not studied with gemtuzumab ozogamicin; inotuzumab ozogamicin data in rats used instead
Why: Inotuzumab ozogamicin shares the same linker-payload and IgG subclass · Class precedent
“In vivo metabolism of gemtuzumab ozogamicin was not evaluated in nonclinical species; however, in vivo metabolism was evaluated in rats after IV administration of [3H]inotuzumab ozogamicin, which shares the same linker-payload and mAb IgG subclass as gemtuzumab ozogamicin”
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
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