Adcetris
brentuximab vedotin · CD30Conducted on MMAE: Ames and mouse lymphoma negative; rat micronucleus positive (aneugenic)
Emrelis: genotox, carcinogenicity and repro: done or skipped?
telisotuzumab vedotin · c-Met
Genotoxicity
Not conducted with ADC; MMAE aneugenic (positive rat micronucleus), Ames and mouse lymphoma negative
“Genetic toxicology studies were not conducted with telisotuzumab vedotin but were conducted with the MMAE payload.”
Carcinogenicity
Not conducted (not warranted for advanced cancer)
“FDA agrees that carcinogenicity studies are not warranted to support this application.”
Instead of carcinogenicity
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Instead of genotoxicity
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
DRG histopathology
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Reproductive & developmental
Not conducted with ADC (ICH S9); MMAE rat EFD teratogenic; ovary/uterus and testis findings in repeat-dose
“Reproductive toxicology studies with telisotuzumab vedotin are not warranted to support this application because MMAE is genotoxic and affects actively dividing cells.”
Safety pharmacology
Incorporated into GLP monkey repeat-dose studies (ECG, clinical signs); MMAE hERG IC50 >100 µM
“Stand-alone safety pharmacology studies were not conducted with telisotuzumab vedotin.”
Genotox: Ames
MMAE payload: negative in Ames assay
“MMAE was not mutagenic in the bacterial reverse mutation (Ames) assay or the L5178Y TK +/- mouse lymphoma forward mutation assay.”
Genotox: in vitro mammalian
MMAE payload: negative in L5178Y TK+/- mouse lymphoma forward mutation assay
“MMAE was not mutagenic in the bacterial reverse mutation (Ames) assay or the L5178Y TK +/- mouse lymphoma forward mutation assay.”
Genotox: in vivo
MMAE payload: positive in rat bone marrow micronucleus (aneugenic)
“MMAE was positive for genotoxicity in the in vivo rat bone marrow micronucleus study through an aneugenic mechanism.”
Carcinogenicity model
Not conducted (ADC or MMAE)
“Carcinogenicity studies in animals have not been performed with telisotuzumab vedotin-tllv or the small molecule MMAE.”
Carcinogenicity timing
Not required: FDA agreed carcinogenicity studies not warranted
“FDA agrees that carcinogenicity studies are not warranted to support this application.”
hERG / QT
MMAE: <50% hERG inhibition up to 100 µM; no QT prolongation in monkey repeat-dose study
“The MMAE payload exhibited limited (<50%) inhibition of human ether-a-go-go (hERG) channel currents up to 100 µM. Additionally, in vivo assessments in the repeat-dose toxicology study in monkeys with telisotuzumab vedotin did not show QT prolongation or any other cardiac electrophysiologic effect.”
Same question, other ADCs
Besponsa
inotuzumab ozogamicin · CD22Conducted: calicheamicin positive in Ames and in vitro micronucleus; ADC clastogenic in mouse micronucleus
Datroway
datopotamab deruxtecan · Trop-2Not conducted with ADC; DXd Ames negative, clastogenic in vitro chromosome aberration and in vivo rat micronucleus
Decnupaz
pivekimab sunirine · CD123Not conducted with ADC (ICH S9); FGN849 positive in Ames TA102, in vitro and in vivo micronucleus
Elahere
mirvetuximab soravtansine · FRαNot conducted with ADC; DM4 and S-methyl-DM4 Ames negative, rat bone marrow micronucleus positive
Enhertu
fam-trastuzumab deruxtecan · HER2Not conducted with ADC; DXd clastogenic (rat micronucleus, CHL chromosome aberration), Ames negative
Kadcyla
ado-trastuzumab emtansine · HER2Conducted on DM1: Ames negative; rat micronucleus positive (aneugenic/clastogenic); monkey micronucleus inconclusive
Mylotarg
gemtuzumab ozogamicin · CD33Conducted: ADC clastogenic in mouse micronucleus; free calicheamicin DMH mutagenic and clastogenic in vitro
Padcev
enfortumab vedotin · Nectin-4Not conducted with ADC; MMAE Ames and mouse lymphoma negative, rat micronucleus positive (aneugenic)
Polivy
polatuzumab vedotin · CD79bNot conducted with ADC; MMAE Ames and mouse lymphoma negative, rat micronucleus positive (aneugenic)
Tivdak
tisotumab vedotin · Tissue factorNot conducted with ADC; MMAE: Ames and mouse lymphoma negative, rat micronucleus positive (aneugenic)
Trodelvy
sacituzumab govitecan · Trop-2Not conducted with ADC; SN-38 Ames negative, in vitro micronucleus positive (clastogenic)
Zynlonta
loncastuximab tesirine · CD19Not conducted with ADC; SG3199 clastogenic in vitro (micronucleus, chromosome aberration); Ames not assessable (cytotoxicity)