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Precedia/Antibody-drug conjugates/Emrelis/Flexibility

Emrelis: what flexibility did regulators accept, and why?

telisotuzumab vedotin · c-Met
Check my plan vs. these
Flexibility accepted
DARTAccepted
No fertility, embryo-fetal or pre/postnatal development studies with the ADC; MMAE payload EFD data relied on
Why: MMAE is genotoxic and affects actively dividing cells; advanced cancer indication per ICH S9 · Within the guideline · Pharmacology or kinetics · Serious disease
“The Applicant did not conduct reproductive or embryofetal development (EFD) toxicology studies with telisotuzumab vedotin as MMAE is genotoxic and affects rapidly dividing cells and the intended indication is for the treatment of patients with advanced cancer, in accordance with the ICH S9 guidance.”
✓ VerifiedFDA multi-discipline review, p. 35Source ↗
“The FDA's Assessment: Reproductive toxicology studies with telisotuzumab vedotin are not warranted to support this application because MMAE is genotoxic and affects actively dividing cells.”
✓ VerifiedFDA multi-discipline review, p. 52Source ↗

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

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 →