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Precedia/Antibody-drug conjugates/Blenrep/Flexibility

Blenrep: what flexibility did regulators accept, and why?

belantamab mafodotin · BCMA
Check my plan vs. these
Flexibility accepted
DARTAccepted
No fertility, embryo-fetal or pre/postnatal development studies
Why: Cytotoxic (genotoxic) ADC targeting rapidly dividing cells expected to be embryo/fetotoxic and teratogenic; consistent with ICH S9 · Within the guideline · Pharmacology or kinetics
“Reproductive and developmental studies were not conducted since cytotoxic (i.e. genotoxic) drugs such as belantamab mafodotin which target rapidly dividing cells, are expected to be embryo/feto toxic and teratogenic. This position is consistent with the ICH S9 guidance.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 31Source ↗
“FDA concurs that belantamab mafodotin is anticipated to be embryo/feto toxic and teratogenic based on the mechanism of action belantamab mafodotin, which targets rapidly dividing cells, and the fact that the payload (MMAF) conjugated to belantamab mafodotin is aneugenic.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 67Source ↗
GenotoxicityCriticised but acceptedBeyond the letter
No definitive genotoxicity studies with the ADC; only a non-GLP in vitro micronucleus screen plus payload battery
Why: Expected genotoxic by mechanism; FDA judged the conducted studies sufficient for labeling given the drug class and indication · Class precedent · Pharmacology or kinetics
“Definitive genetic toxicology studies with belantamab mafodotin have not been conducted as it would be expected to be genotoxic based on its mechanism of action. Belantamab mafodotin was genotoxic in an in vitro micronucleus screening assay in human lymphocytes.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 65Source ↗
“FDA disagrees with the Applicant's statement that the genetic toxicology studies are not applicable, but agrees with the Applicant that the data indicate that MMAF is genotoxic based on an aneugenic mechanism and that the genetic toxicology studies conducted, given the class of drug and the proposed indication, are sufficient to communicate a genotoxic risk in the product labeling.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 65Source ↗
Safety marginVerdict not stated
No exposure margin: monkey mid-dose ADC AUC approximately equal to human exposure at 2.5 mg/kg
“Although ADA formation was evident in monkey studies, the exposures were generally maintained at low and mid-dose animals and were approximately at the same level in mid-dose animals as the recommended human dose of 2.5 mg/kg, based on ADC area under concentration curve (AUC).”
✓ VerifiedEMA assessment report (EPAR EMEA/H/C/004935/0000, 23 July 2020), p. 44Source ↗

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Flexibility for Blenrep, each with the regulator's own words, the page and a link. Ready to paste into a briefing document or send to your team.

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

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 15 ADCs →