Adcetris
brentuximab vedotin · CD30Exposure ratios derived from single-dose studies and a different dosing scheme rather than repeat-dose data matching the clinical regimen
Polivy: what flexibility did regulators accept, and why?
polatuzumab vedotin · CD79b
Flexibility accepted
SpeciesVerdict not stated
Polatuzumab does not bind monkey CD79b; target-mediated toxicity assessed with a surrogate ADC binding monkey CD79b
Why: Three amino-acid difference in the CD79b epitope between humans and cynomolgus monkeys · No relevant species
“Peptide sequence alignment of CD79b between humans and cynomolgus monkeys showed a variation in three amino acids in the N-terminal epitope region. Therefore, a surrogate ADC (DCDS5017A) that binds specifically to cynomolgus monkey CD79b was generated for testing target-mediated effects.”
DARTVerdict not stated
No embryo-fetal study with the ADC; embryo-fetal toxicity assessed with the MMAE payload in rats
“Dedicated embryo-fetal developmental toxicity studies were not conducted with polatuzumab vedotin. However, MMAE (SGD-1010) was evaluated in rats in a GLP embryo-fetal developmental and TK study (Study 8204397) to determine maternal and embryo-fetal toxicity and teratogenic potential.”
DARTAccepted
No fertility study with the ADC or MMAE; male fertility risk inferred from repeat-dose rat studies
Why: Not needed for the proposed indication; repeat-dose rat studies indicate potential male fertility impairment · Within the guideline · Weight of evidence
“A designated fertility study was not conducted with polatuzumab vedotin or MMAE and is not needed for the proposed indication. However, results of repeat-dose toxicity studies in rats indicate the potential for polatuzumab vedotin to impair fertility 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
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
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