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Precedia/Antibody-drug conjugates/Besponsa/Flexibility

Besponsa: what flexibility did regulators accept, and why?

inotuzumab ozogamicin · CD22
Check my plan vs. these
Flexibility accepted
SpeciesVerdict not stated
No pharmacologically relevant toxicology species: antibody does not bind rat or monkey CD22, so only target-independent payload toxicity assessed
“The lack of G544 cross-species reactivity indicates the utility of the nonclinical toxicology studies will be limited to the assessment of target-independent toxicities associated with conjugated and unconjugated calicheamicin.”
✓ VerifiedFDA multi-discipline review, p. 36Source ↗
Safety marginVerdict not stated
No NOAEL for male reproductive organ toxicity in rats; effects at approximately 0.3 times human clinical AUC
“The NOAEL was not identified for the effects on male reproductive organs, which were observed at approximately 0.3 times the human clinical exposure based on AUC (SmPC section 5.3).”
✓ VerifiedEMA assessment report, p. 42Source ↗

Same question, other ADCs

Adcetris

brentuximab vedotin · CD30
Exposure ratios derived from single-dose studies and a different dosing scheme rather than repeat-dose data matching the clinical regimen

Datroway

datopotamab deruxtecan · Trop-2
No fertility, embryo-fetal or pre- and postnatal development studies; fertility assessed from repeat-dose studies

Decnupaz

pivekimab sunirine · CD123
No 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 · FRα
No reproductive or developmental toxicity studies at all, including embryo-fetal development

Emrelis

telisotuzumab vedotin · c-Met
No fertility, embryo-fetal or pre/postnatal development studies with the ADC; MMAE payload EFD data relied on

Enhertu

fam-trastuzumab deruxtecan · HER2
No embryo-fetal development or other reproductive toxicity studies with the ADC

Kadcyla

ado-trastuzumab emtansine · HER2
No embryo-fetal development studies with the ADC

Mylotarg

gemtuzumab ozogamicin · CD33
No 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-4
Chronic (13-week) toxicity in rat only; monkey limited to 4 weeks

Polivy

polatuzumab vedotin · CD79b
Polatuzumab does not bind monkey CD79b; target-mediated toxicity assessed with a surrogate ADC binding monkey CD79b

Tivdak

tisotumab vedotin · Tissue factor
No embryo-fetal development study with the ADC; rat EFD study of the MMAE payload (from brentuximab vedotin) relied on

Trodelvy

sacituzumab govitecan · Trop-2
No embryo-fetal development or fertility studies; genotoxic SN-38 payload assumed teratogenic

Zynlonta

loncastuximab tesirine · CD19
No pharmacologically relevant species; CD19-mediated toxicity could not be evaluated in any nonclinical species

Summary across all 14 ADCs →