Which nonclinical studies did approved ADCs skip?

“MMAE was genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism.”

“Carcinogenicity studies with brentuximab vedotin or the small molecule (MMAE) have not been conducted.”

“In rats, brentuximab vedotin was clearly embryo-foetal toxic, causing loss of almost all embryos at 3 mg/kg and above.”

“Inotuzumab ozogamicin was clastogenic in mice at doses ≥28 µg/kg (approximately 1.1 mg/m2 of the ADC), consistent with the known DNA-reactive activity of the calicheamicin payload.”

“No carcinogenicity studies were conducted or required to support a marketing application for the current indication.”

“Embryo-fetal development studies were conducted in rabbits and rats.”

“In genetic toxicology studies, deruxtecan was not mutagenic in an Ames assay but demonstrated clastogenic potential in an in vitro Chinese hamster lung chromosome aberration assay and an in vivo rat bone marrow micronucleus assay.”

“Carcinogenicity studies are not warranted to support the current application.”

“The Applicant did not conduct fertility or embryo-fetal development toxicology studies with datopotamab deruxtecan as DXd is genotoxic and affects actively dividing cells, and therefore, these studies are not warranted to support the proposed indication.”

“In accordance with ICH S9, genotoxicity studies have not been conducted with PVEK.”

“In accordance with ICH S9, carcinogenicity studies have not been conducted with PVEK.”

“No reproductive and developmental studies have been conducted with PVEK, in accordance with ICH S9 and FDA feedback (Reference ID: 4704103).”

“DM4 and S-methyl-DM4 were negative in the vitro bacterial reverse mutation assay but positive in the in vivo rat bone marrow micronucleus assay.”

“Carcinogenicity studies were not needed to support the advanced cancer indication, consistent with ICH S9 guidance.”

“No reproductive or developmental animal toxicity studies were conducted with mirvetuximab soravtansine.”

“Genetic toxicology studies were not conducted with telisotuzumab vedotin but were conducted with the MMAE payload.”

“FDA agrees that carcinogenicity studies are not warranted to support this application.”

“Reproductive toxicology studies with telisotuzumab vedotin are not warranted to support this application because MMAE is genotoxic and affects actively dividing cells.”

“MAAA-1181a was clastogenic in both an in vivo rat bone marrow micronucleus assay and an in vitro Chinese hamster lung chromosome aberration assay but was not mutagenic in an in vitro bacterial reverse mutation assay.”

“Carcinogenicity studies are not warranted to support the licensing application of fam-trastuzumab deruxtecan-nxki for the proposed indication.”

“The Applicant did not conduct any reproductive toxicology studies with DS-8201a.”

“DM1 was positive in an in vivo rat bone marrow micronucleus assay at exposures similar to the mean maximum concentrations of DM1 in patients in clinical trials, which is consistent with its mechanism of action.”

“8 Carcinogenicity Not required and not submitted.”

“Based on these findings and consistent with ICH S9, embryo-fetal developmental toxicity studies were not required for the indicated patient population.”

“Gemtuzumab ozogamicin was found to be clastogenic. This is consistent with the known induction of DNA breaks by calicheamicin and other enediyne antitumour antibiotics.”

“No carcinogenicity studies have been conducted with gemtuzumab ozogamicin (see discussion on non-clinical aspects).”

“Based on the unequivocally positive results obtained from a pilot study, the Agency previously agreed with the Applicant that one species would be sufficient to support an NDA application for CMA-676 in a leukemia indication.”

“Using the standard core battery of genetic toxicology studies recommended in the ICH S2 guidance, MMAE was reported to be genotoxic in the in vivo rat bone marrow micronucleus assay through an aneugenic mechanism.”

“Carcinogenicity studies were not conducted or needed to support marketing of PADCEV in patients with advanced cancer.”

“Fertility and early embryonic development studies were not conducted or needed to support marketing of PADCEV in patients with advanced cancer.”

“MMAE was genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism.”

“Carcinogenicity studies in animals have not been performed with polatuzumab vedotin or MMAE and are not warranted for the proposed indication.”

“A designated fertility study was not conducted with polatuzumab vedotin or MMAE and is not needed for the proposed indication.”

“Genetic toxicology studies were not conducted with tisotumab vedotin; rather, the applicant submitted studies that evaluated the payload.”

“Carcinogenicity studies were not conducted with tisotumab vedotin in accordance with ICH S9 guidance.”

“MMAE was teratogenic and embryo lethal when administered to pregnant rats via two intravenous doses of 0.2 mg/kg during the period of organogenesis on gestational days 6 and 13.”

“SN-38 was negative for mutagenicity in a bacterial reverse mutation (Ames) test but was clastogenic in the in vitro mammalian cell micronucleus test.”

“No carcinogenicity studies were conducted or warranted to support this NDA, as the proposed indication was for advanced cancer.”

“No embryo-fetal developmental toxicology studies were conducted or warranted to support this BLA submission, based on ICH S9.”

“No genotoxicity studies were conducted with ADCT-402. SG3199 was genotoxic in GLP in vitro studies (in vitro micronucleus assay and the chromosome aberration assay in human lymphocytes from whole blood).”

“In accordance with ICH S9, ICH S6(R1) and ICH S1A (Guideline on the Need for Carcinogenicity Studies of Pharmaceuticals) no carcinogenicity studies were conducted or are planned with ADCT-402 or SG3199”

“Reproductive and developmental toxicology studies were not conducted since cytotoxic (i.e. genotoxic) drugs that affect actively dividing cells, such as loncastuximab tesirine, are expected to be embryo/feto toxic and teratogenic.”