Trodelvy
sacituzumab govitecan
Species
MonkeyMouse
Longest study
13 wk
Genotox
Partial / alternative Partial / alternative
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only (mouse for target-independent toxicity only)
“Cynomolgus monkeys were identified as the only relevant toxicity species due to cross-reactivity of the target, Trop-2 with the hRS7antibody, the binding moiety of sacituzumab govitecan.”
Why that species
hRS7 binds human and monkey Trop-2 comparably; no binding to mouse or rat Trop-2 despite ~80% homology
“Despite approx. 80% sequence homology at the protein level between human and rodent Trop-2, hRS7 did not bind to mouse and rat Trop-2.”
Surrogate molecule
No surrogate; clinical ADC tested in monkey; no separate SN-38 general tox (irinotecan literature)
“General toxicity studies with the toxin moiety SN-38 were not conducted. This is acceptable, in line with ICH S9 and taking into account published literature on the toxicity of irinotecan and its active metabolite SN-38.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“In a 13-week toxicity study, monkeys were given sacituzumab govitecan at doses of 12.5, 25, and 50 mg/kg once weekly via a 1-hour infusion for 2 weeks of a 3-week cycle for 4 treatment cycles.”
Pivotal GLP studies
GLP monkey 2-dose acute study (60, 120 mg/kg) and 13-week monkey study (days 1, 8 q21d x4 cycles, 6-week recovery), IV
“In a 13-week toxicity study, monkeys were given sacituzumab govitecan at doses of 12.5, 25, and 50 mg/kg once weekly via a 1-hour infusion for 2 weeks of a 3-week cycle for 4 treatment cycles.”
Route in tox
IV (1-hour infusion, clinical route); IP in non-GLP mouse studies
“Dose and frequency of dosing: 0, 60, & 120 mg/kg; 2 doses three days apart (days 1 and 4) Route of administration: IV (1-hr)”
Skipped studiesopen answer page →
Genotoxicity
Not conducted with ADC; SN-38 Ames negative, in vitro micronucleus positive (clastogenic)
“SN-38 was negative for mutagenicity in a bacterial reverse mutation (Ames) test but was clastogenic in the in vitro mammalian cell micronucleus test.”
Carcinogenicity
Not conducted (advanced cancer, ICH S9)
“No carcinogenicity studies were conducted or warranted to support this NDA, as the proposed indication was for advanced cancer.”
Reproductive & developmental
Not conducted (ICH S9); SN-38 genotoxic so embryo-fetal toxicity expected; female repro organ findings in monkey
“No embryo-fetal developmental toxicology studies were conducted or warranted to support this BLA submission, based on ICH S9.”
Safety pharmacology
Incorporated into repeat-dose monkey studies; no CNS, CV or respiratory findings; no hERG
“Safety pharmacology endpoints were assessed in the repeat-dose toxicity studies in monkeys. There were no sacituzumab govitecan-related findings on the central nervous, cardiovascular, or respiratory systems.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
Acute study HNSTD 60 mg/kg (no NOAEL); 13-week NOAEL/HNSTD 50 mg/kg; bone marrow, lymphoid, GI, liver, skin, female reproductive organs
“In the absence of a NOAEL, the HNSTD in this study was 60 mg/kg/dose.”
Risksopen answer page →
Immune & cytokine safety
ADA in all monkeys at all doses in 13-week study, reducing low-dose exposure; reduced thymic/lymphoid cellularity
“Anti-drug antibodies were detected in all animals at all doses tested in the chronic toxicity study.”
Biodistribution & persistence
Mouse xenograft: radiolabeled ADC to tumour plus liver, spleen, kidney, lung; SN-38 released in serum (t1/2 ~1-2 days); free SN-38 ~2.3% of total
“In addition to tumour, both hRS7 and sacituzumab govitecan distributed to normal tissues, primarily to liver, spleen, kidney and lungs among the normal tissues analysed.”
Modality-specific risk
SN-38 payload myelosuppression and GI toxicity (UGT1A1-dependent), Trop-2-dependent skin toxicity; hydrolysable linker releases payload
“Findings in the gastrointestinal tract and reductions in white blood cells are known toxicities of irinotecan-derived SN-38. Findings in skin may represent Trop-2-dependent toxicity.”