Adcetris
brentuximab vedotin · CD30Exposure ratios derived from single-dose studies and a different dosing scheme rather than repeat-dose data matching the clinical regimen
Trodelvy: what flexibility did regulators accept, and why?
sacituzumab govitecan · Trop-2
Flexibility accepted
DARTAccepted
No embryo-fetal development or fertility studies; genotoxic SN-38 payload assumed teratogenic
Why: SN-38 is genotoxic and targets rapidly dividing cells; advanced cancer indication · Within the guideline
“No embryo-fetal developmental toxicology studies were conducted or warranted to support this BLA submission, based on ICH S9.”
“The applicant did not conduct fertility studies with sacituzumab govitecan, and these studies are not warranted to support a marketing application in the proposed patient population, according to ICH S9.”
OtherAccepted
No general toxicity studies with the SN-38 payload alone; published irinotecan and SN-38 toxicity data relied on
Why: ICH S9 and published literature on irinotecan and SN-38 toxicity · Within the guideline · Class precedent
“General toxicity studies with the toxin moiety SN-38 were not conducted. This is acceptable, in line with ICH S9 and taking into account published literature on the toxicity of irinotecan and its active metabolite SN-38.”
Impurity or metaboliteAcceptedBeyond the letter
No nonclinical metabolism or excretion studies; literature on irinotecan metabolism in humans used instead
Why: Known human metabolism of irinotecan · Class precedent · Human data
“Studies on metabolism and excretion were not performed for sacituzumab govitecan. , instead the applicant refers to literature on the metabolism of irinotecan in humans which is accepted.”
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
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
Zynlonta
loncastuximab tesirine · CD19No pharmacologically relevant species; CD19-mediated toxicity could not be evaluated in any nonclinical species