Adcetris
brentuximab vedotin · CD30Exposure ratios derived from single-dose studies and a different dosing scheme rather than repeat-dose data matching the clinical regimen
Kadcyla: what flexibility did regulators accept, and why?
ado-trastuzumab emtansine · HER2
Flexibility accepted
DARTAccepted
No embryo-fetal development studies with the ADC
Why: DM1 is genotoxic; consistent with ICH S9 for the indicated patient population · Within the guideline · Pharmacology or kinetics
“In addition, DM1 was demonstrated to be genotoxic. Based on these findings and consistent with ICH S9, embryo-fetal developmental toxicity studies were not required for the indicated patient population.”
DARTVerdict not stated
No dedicated fertility studies; fertility risk inferred from general toxicity studies
Why: General toxicity studies indicate adverse effects on fertility can be expected · Weight of evidence
“Dedicated fertility studies have not been conducted with trastuzumab emtansine. However, based on results from general animal toxicity studies, adverse effects on fertility can be expected (see SmPC section 5.3).”
Safety marginVerdict not stated
Highest well-tolerated doses in rats and monkeys approximately equivalent to the clinical dose (no margin)
“Administration of trastuzumab emtansine was well tolerated in rats and monkeys at doses up to 20 and 10 mg/kg, respectively, corresponding to 2040 µg DM1/m2 in both species, which is approximately equivalent to the clinical dose of trastuzumab emtansine in patients.”
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
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