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Precedia/Antibody-drug conjugates/Enhertu/Flexibility

Enhertu: what flexibility did regulators accept, and why?

fam-trastuzumab deruxtecan · HER2
Check my plan vs. these
Flexibility accepted
DARTAccepted
No embryo-fetal development or other reproductive toxicity studies with the ADC
Why: ICH S9; genotoxic payload targeting dividing cells; HER2-directed antibody use in pregnancy caused oligohydramnios · Within the guideline · Class precedent · Human data
“As recommended by ICH S9 guidance, embryo-fetal toxicity studies were not conducted based on the justification that these studies are not warranted to support the proposed indication because MAAA-1181a is genotoxic and targets rapidly dividing cells, and the use of a HER2 directed antibody during pregnancy resulted in cases of oligohydramnios.”
✓ VerifiedFDA multi-discipline review, p. 43Source ↗
Safety marginAccepted with a conditionBeyond the letter
Clinical deruxtecan (payload) plasma exposures exceed animal exposures at the NOAEL
Why: Observed animal toxicities treated as potential safety concerns and addressed in the risk management plan
“Considering that toxicity is likely related to continuous exposure to deruxtecan after treatment with trastuzumab deruxtecan, and clinical deruxtecan plasma exposures exceed plasma exposures in animals at the NOAEL, the observed toxicities in cynomolgus monkeys are potential safety concerns (see also Clinical Safety section).”
✓ VerifiedEMA assessment report, p. 58Source ↗
“Intestinal, lymphatic/haematopoietic, pulmonary, skin, renal and testicular toxicity have been addressed in the RMP.”
✓ VerifiedEMA assessment report, p. 58Source ↗

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

Besponsa

inotuzumab ozogamicin · CD22
No pharmacologically relevant toxicology species: antibody does not bind rat or monkey CD22, so only target-independent payload toxicity assessed

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

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 →