Adcetris
brentuximab vedotin · CD30Exposure ratios derived from single-dose studies and a different dosing scheme rather than repeat-dose data matching the clinical regimen
Zynlonta: what flexibility did regulators accept, and why?
loncastuximab tesirine · CD19
Flexibility accepted
SpeciesAcceptedBeyond the letter
No pharmacologically relevant species; CD19-mediated toxicity could not be evaluated in any nonclinical species
Why: Considerable nonclinical and clinical safety data exist for CD19- and CD20-specific B-cell-depleting agents · No relevant species · Class precedent · Human data
“Importantly, on‐target (ie, CD19‐mediated) toxicity cannot be evaluated in this or any other nonclinical species; however, a considerable body of data on the nonclinical and clinical safety of CD19‐ and CD20‐specific B‐cell‐depleting agents exists.”
“FDA generally concurs with the Applicant’s assessment.”
DARTVerdict not stated
No reproductive and developmental toxicity studies
Why: Genotoxic cytotoxic drug expected to be embryo-fetal toxic and teratogenic · Pharmacology or kinetics
“Reproductive and developmental toxicology studies were not conducted since cytotoxic (i.e. genotoxic) drugs that affect actively dividing cells, such as loncastuximab tesirine, are expected to be embryo/feto toxic and teratogenic.”
GLPCriticised but acceptedBeyond the letter
GLP deviation in a monkey study: formulation analyses out of range with an unvalidated analytical method
Why: Dose-related toxicities indicate correct dosing · Weight of evidence
“Study No. 8374716: Some of the analysed concentrations for formulations were out of range (below LOD), therefore not valid and the analytical method used for those analysis was not validated. The applicant was requested to justify why those deviations to GLP do not jeopardise the validity of the study.”
“Dose-related effects such as skin effects, nephropathy and testicular changes were observed in toxicology studies. These results indicate the correct dosage.”
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
Trodelvy
sacituzumab govitecan · Trop-2No embryo-fetal development or fertility studies; genotoxic SN-38 payload assumed teratogenic