Besponsa
inotuzumab ozogamicin · CD22No pharmacologically relevant toxicology species: antibody does not bind rat or monkey CD22, so only target-independent payload toxicity assessed
Adcetris: what flexibility did regulators accept, and why?
brentuximab vedotin · CD30
Flexibility accepted
Safety marginAcceptedBeyond the letter
Exposure ratios derived from single-dose studies and a different dosing scheme rather than repeat-dose data matching the clinical regimen
Why: Similar single- and multiple-dose kinetics and the life-threatening indication · Pharmacology or kinetics · Serious disease
“Basis for calculation of exposure ratios were non-clinical studies with a different dosing scheme than the clinical one (for Cmax data from rat study) or single dose studies instead of repeat-dose studies (for AUC data from rat and monkey studies).”
“In light of the similarity of single and multiple dose kinetics and the life-threatening indication, calculation of exposure ratios can, however be accepted.”
Safety marginCriticised but acceptedBeyond the letter
Patient MMAE plasma levels about two orders of magnitude above those in monkeys; animal hepatotoxicity data do not cover human exposure
Why: Hepatobiliary enzyme elevations were reversible and easily monitored in patients · Human data
“However, it should be considered that MMAE plasma levels in patients are two orders of magnitude higher than those observed in monkeys. Therefore, hepatotoxicity might still be of concern.”
“Yet, the hepatobiliary enzyme elevations were reversible and can be easily monitored in patients.”
OtherAcceptedBeyond the letter
No studies of interaction with Fc-gamma receptors submitted
Why: Brentuximab vedotin lacks immunological effector functions · Pharmacology or kinetics
“No studies addressing the potential interaction of brentuximab vedotin with FC-gamma receptors were submitted. However, this is acceptable given the lack of immunological effector functions induced by brentuximab vedotin.”
OtherVerdict not stated
No dedicated local tolerance studies; injection sites examined within repeat-dose studies in rats and monkeys
Why: No injection-site effects in rat and monkey repeat-dose studies
“Dedicated studies evaluating local tolerance of brentuximab vedotin were not submitted. Microscopic examination of the injections sites as part of the repeat-dose toxicology studies in both rats and monkeys identified no test article-related effects at the injection sites.”
Same question, other ADCs
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
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