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.”
Species: general tox
Cynomolgus monkey (repeat-dose); mouse (acute, target-independent)
“The toxicity of sacituzumab govitecan was assessed in mice (acute toxicity) and in cynomolgus monkeys (long-term toxicity).”
Species: DART
Not conducted (not warranted per ICH S9)
“No embryo-fetal developmental toxicology studies were conducted or warranted to support this BLA submission, based on ICH S9.”
Species: carcinogenicity
Not conducted (advanced cancer indication)
“No carcinogenicity studies were conducted or warranted to support this NDA, as the proposed indication was for advanced cancer.”
Surrogate used in
No surrogate used; clinical ADC in monkey (target-dependent) and mouse (target-independent)
“In mice, sacituzumab govitecan does not recognise the target antigen Trop-2, thus these studies provide information on target-independent toxicity. Target-dependent toxicity was assessed in cynomolgus monkeys.”
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.”
Genotox: Ames
SN-38: negative in Ames assay
“SN-38 was negative for mutagenicity in a bacterial reverse mutation (Ames) test but was clastogenic in the in vitro mammalian cell micronucleus test.”
Genotox: in vitro mammalian
SN-38: positive (clastogenic) in in vitro mammalian cell micronucleus test
“SN-38 was negative for mutagenicity in a bacterial reverse mutation (Ames) test but was clastogenic in the in vitro mammalian cell micronucleus test.”
Genotox: in vivo
Not conducted (SN-38 genotoxicity assessed in vitro only)
“Genotoxic potential of SN-38 was assessed in vitro.”
Carcinogenicity model
Not conducted (advanced cancer indication)
“No carcinogenicity studies were conducted or warranted to support this NDA, as the proposed indication was for advanced cancer.”
Carcinogenicity timing
Not required for advanced cancer (ICH S9)
“No assessment of carcinogenicity has been conducted in accordance with ICH S9 according to which carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer.”
hERG / QT
No CNS, cardiovascular (incl. QT/QTc) or respiratory effects in monkeys up to 120 mg/kg
“there were no apparent adverse effects on the CNS, the cardiovascular system including assessment of QT or corrected QT (QTc) interval or respiratory function following intravenous dosing of sacituzumab govitecan in cynomolgus monkeys at doses up to 120 mg/kg.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Trodelvy don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for ADCs
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
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 (EMA assessment report, p. 30)
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.”
Anti-drug antibodies: animals
ADA in all treated monkey groups; reduced exposure mainly in the low-dose group
“ADA were detected in all sacituzumab govitecan treated groups and appeared to affect primarily the exposure in the low dose group, as exposures to total Ab, total SN-38 and free SN-38 were lower on after last dose compared to the first dose.”
Anti-drug antibodies: patients
1.2% (13/1058) treatment-emergent ADA (single agent); 77% of ADA-positive neutralizing
“Among patients who received TRODELVY as a single agent over a median 5-month treatment period across 5 clinical studies, 1.2% (13/1058) of patients developed treatment-emergent ADA to sacituzumab govitecan and 77% (10/13) of ADA-positive patients developed neutralizing antibodies against sacituzumab govitecan.”
Label warnings
Boxed warning: Neutropenia and diarrhea
- Neutropenia
- Diarrhea
- Hypersensitivity and Infusion-Related Reactions
- Nausea and Vomiting
- Increased Risk of Adverse Reactions in Patients with Reduced UGT1A1 Activity
- Embryo-Fetal Toxicity
CytopeniasGastrointestinalHypersensitivity & infusion reactionsEmbryo-fetal toxicity
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
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.
Repeat-dose tox before first-in-human
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.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Trodelvy don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for ADCs
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
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 (EMA assessment report, p. 30)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week cynomolgus monkey, IV once weekly for 2 weeks of each 3-week cycle, 4 cycles; recovery phase included
“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.”
DART package
Species: DART
Not conducted (not warranted per ICH S9)
“No embryo-fetal developmental toxicology studies were conducted or warranted to support this BLA submission, based on ICH S9.”
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.”
PPND / ePPND: when
No reproductive and developmental toxicity studies conducted or required (genotoxic SN-38 payload)
“There were no reproductive and developmental toxicology studies conducted with sacituzumab govitecan or required to support this BLA. Sacituzumab govitecan contains a genotoxic component, SN-38, and is toxic to rapidly dividing cells.”
Carcinogenicity
Species: carcinogenicity
Not conducted (advanced cancer indication)
“No carcinogenicity studies were conducted or warranted to support this NDA, as the proposed indication was for advanced cancer.”
Carcinogenicity model
Not conducted (advanced cancer indication)
“No carcinogenicity studies were conducted or warranted to support this NDA, as the proposed indication was for advanced cancer.”
Carcinogenicity timing
Not required for advanced cancer (ICH S9)
“No assessment of carcinogenicity has been conducted in accordance with ICH S9 according to which carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL/HNSTD 50 mg/kg: 6.4x (total antibody), 4.6x (total SN-38), 3.1x (free SN-38) human exposure at 10 mg/kg
“A comparison of the exposure in cynomolgus at the NOAEL/HNSTD (50 mg/kg) and in humans at the proposed clinical dose (10 mg/kg) was made. The exposure margin was 6.4x for total antibody, 4.6x for total SN-38 and 3.1x for free SN-38.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse xenografts bearing human Trop-2-expressing tumours
“Primary pharmacology was tested in murine xenograft models bearing human Trop-2 expressing tumors.”
Why that model
hRS7 does not bind 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.”
Reviewer's view of the efficacy data
EMA: adequate pharmacodynamic data; ADC inhibits Trop-2-positive tumour growth in vitro and in mouse xenografts
“The applicant has presented adequate non-clinical data which characterise the pharmacodynamic properties of sacituzumab govitecan. These data were presented in research study reports and in form of publications from the group in scientific journals. The ADC inhibits growth of Trop-2-positive tumour cells, including TNBC cells, in vitro as well as in xenograft transplant models in mice.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted
No embryo-fetal development or fertility studies; genotoxic SN-38 payload assumed teratogenic
Why: SN-38 is genotoxic and targets rapidly dividing cells; advanced cancer indication · Within the guideline
“No embryo-fetal developmental toxicology studies were conducted or warranted to support this BLA submission, based on ICH S9.”
“The applicant did not conduct fertility studies with sacituzumab govitecan, and these studies are not warranted to support a marketing application in the proposed patient population, according to ICH S9.”
OtherAccepted
No general toxicity studies with the SN-38 payload alone; published irinotecan and SN-38 toxicity data relied on
Why: ICH S9 and published literature on irinotecan and SN-38 toxicity · Within the guideline · Class precedent
“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.”
Impurity or metaboliteAcceptedBeyond the letter
No nonclinical metabolism or excretion studies; literature on irinotecan metabolism in humans used instead
Why: Known human metabolism of irinotecan · Class precedent · Human data
“Studies on metabolism and excretion were not performed for sacituzumab govitecan. , instead the applicant refers to literature on the metabolism of irinotecan in humans which is accepted.”
Similar precedents
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