Adcetris
brentuximab vedotin · CD30Exposure ratios derived from single-dose studies and a different dosing scheme rather than repeat-dose data matching the clinical regimen
Elahere: what flexibility did regulators accept, and why?
mirvetuximab soravtansine · FRα
Flexibility accepted
DARTAccepted
No reproductive or developmental toxicity studies at all, including embryo-fetal development
Why: Cytotoxic payload targets rapidly dividing cells; maytansinoid class has described developmental toxicity · Within the guideline · Class precedent · Pharmacology or kinetics
“The absence of any reproductive or developmental studies was justified by referring to ICH S9.”
“The payload of MIRV, DM4 (and the active metabolite S-methyl DM4), is cytotoxic, targets rapidly dividing cells and belongs to a class of compounds (maytansinoid) for which developmental toxicity/teratogenicity has been described in the literature (Sieber 1978; Issell 1978).”
Safety marginVerdict not stated
No exposure margin at the monkey NOAEL: AUC multiple 0.09 (AUC0-24 vs AUCtau) to 0.57 (AUC0-∞)
“When monkey AUC0-24 was compared to human AUCtau (area under the concentration vs. time curve over the dosing interval 21 days) exposure margin was 0.09; however, when monkey AUC0-∞ was used for comparison the exposure multiple was 0.57.”
Impurity or metaboliteAcceptedBeyond the letter
Maytansinoid impurities qualified with single-dose mouse studies only
Why: Patients are dosed once every 3 weeks · Pharmacology or kinetics
“The impurities were dosed only once in mouse qualification studies; however this can be accepted since posology in patients is once every 3 weeks (21-day cycle).”
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
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
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