Padcev
enfortumab vedotin
Species
MonkeyRat
Longest study
13 wk
Genotox
Partial / alternative Partial / alternative
Carcinogenicity
Not conducted Not conducted
Repro
Partial / alternative Partial / alternative
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“Binding affinity of enfortumab vedotin to Nectin-4 was similar between humans, cynomolgus monkeys, and rats, but enfortumab vedotin bound to murine Nectin-4 at 10-fold lower affinity, thus supporting the use of the rat and monkey in the nonclinical toxicology studies.”
Why that species
Nectin-4 homology >99% monkey, ~94% rat; similar binding affinity in human, monkey and rat (mouse 10-fold lower)
“Orthologs of Nectin-4 share >99%, ~94%, and ~92% homology to the human protein in cynomolgus monkeys, rats, and mice, respectively.”
Surrogate molecule
No surrogate; early hybridoma-derived ADC (AGS-22M6E) bridged to clinical material in monkey
“Enfortumab vedotin and AGS-22M6E comparability was confirmed in a subsequent bridging toxicology study in monkeys (20021751), and comparable PK, immunogenicity, and toxicity profiles were observed.”
Species: general tox
Rat (4- and 13-week) and cynomolgus monkey (4-week), weekly IV
“The Applicant conducted GLP intravenous repeat-dose (weekly) general toxicology studies in rats (4 and 13-week) with enfortumab vedotin, and the unconjugated antibody (AGS-22M6); and in monkeys (4-week) with enfortumab vedotin”
Species: DART
Rat only (pilot embryo-fetal study with the ADC; complete litter loss at 5 mg/kg)
“In a rat pilot embryo-fetal development study, administration of enfortumab vedotin-ejfv on gestation day 6 and 13 during the period of organogenesis resulted in a complete litter loss in all pregnant rats at the maternally toxic dose of 5 mg/kg”
Species: carcinogenicity
Not conducted
“Carcinogenicity studies with enfortumab vedotin-ejfv or the small molecule cytotoxic agent (MMAE) have not been conducted.”
Surrogate used in
No surrogate used; rat and monkey Nectin-4 bind the clinical ADC with similar affinity
“Binding affinity of enfortumab vedotin to Nectin-4 was similar between humans, cynomolgus monkeys, and rats, but enfortumab vedotin bound to murine Nectin-4 at 10-fold lower affinity, thus supporting the use of the rat and monkey in the nonclinical toxicology studies.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“No mortalities were reported in the 13-week study in rats administered enfortumab vedotin at doses up to 5 mg/kg once weekly (at 0.94-fold the exposure in human at the clinical recommended dose).”
Pivotal GLP studies
Weekly IV GLP: rat 4- and 13-week; monkey 4-week (ADC, naked Ab, MMAE); monkey bridging; rat 4-week testicular study
“The Applicant conducted GLP intravenous repeat-dose (weekly) general toxicology studies in rats (4 and 13-week) with enfortumab vedotin, and the unconjugated antibody (AGS-22M6)”
Route in tox
IV (weekly)
“The Applicant conducted GLP intravenous repeat-dose (weekly) general toxicology studies in rats (4 and 13-week) with enfortumab vedotin, and the unconjugated antibody (AGS-22M6)”
Skipped studiesopen answer page →
Genotoxicity
Not conducted with ADC; MMAE Ames and mouse lymphoma negative, rat micronucleus positive (aneugenic)
“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
Not conducted (ICH S9, advanced cancer)
“Carcinogenicity studies were not conducted or needed to support marketing of PADCEV in patients with advanced cancer.”
Reproductive & developmental
No fertility or PPND studies (ICH S9); preliminary rat EFD with ADC and MMAE EFD: embryolethal, teratogenic
“Fertility and early embryonic development studies were not conducted or needed to support marketing of PADCEV in patients with advanced cancer.”
Safety pharmacology
Incorporated into repeat-dose tox studies; MMAE hERG negative; no CV, respiratory or CNS effects
“No effect was reported on ECG, heart rate, blood pressure, respiratory or CNS endpoints.”
Genotox: Ames
MMAE payload: negative in Ames test
“MMAE was not mutagenic in the bacterial reverse mutation assay (Ames test) or the L5178Y mouse lymphoma forward mutation assay.”
Genotox: in vitro mammalian
MMAE payload: negative in L5178Y mouse lymphoma forward mutation assay
“MMAE was not mutagenic in the bacterial reverse mutation assay (Ames test) or the L5178Y mouse lymphoma forward mutation assay.”
Genotox: in vivo
MMAE payload: positive in rat bone marrow micronucleus (aneugenic)
“MMAE was genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism.”
Carcinogenicity model
Not conducted (ADC or MMAE); ICH S9, metastatic UC
“In accordance with International Council for Harmonisation (ICH) S9, carcinogenicity studies were not conducted for enfortumab vedotin as it is intended for treatment of metastatic UC.”
Carcinogenicity timing
Not required for advanced cancer; none conducted
“Carcinogenicity studies were not conducted or needed to support marketing of PADCEV in patients with advanced cancer.”
hERG / QT
MMAE: <50% hERG inhibition at >19,000-fold clinical Cmax; no significant inhibition at 10 µM
“MMAE, at concentrations greater than 19,000-fold higher than the clinically observed Cmax had limited (less than 50%) inhibition of potassium conductance via hERG channels, and at 10 µmol/L there was no significant inhibition of hERG channel activity.”
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 Padcev 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: Monkey HNSTD/MTD 3 mg/kg, rat MTD 5 mg/kg; skin, injection site, bone marrow, liver, eye, male reproductive organs (FDA multi-discipline review, p. 56)
NOAEL / key findings
Monkey HNSTD/MTD 3 mg/kg, rat MTD 5 mg/kg; skin, injection site, bone marrow, liver, eye, male reproductive organs
“In the 4-week monkey study (# 20005664), AGS-22M6E systemic exposure at 3 mg/kg (MTD/HNSTD) was 2450 µg.hr/mL (Day 1) and 903 µg.hr/mL (Day 22).”
Risksopen answer page →
Immune & cytokine safety
ADA in rats and monkeys reduced exposure on repeat dosing; no ADCC/CDC, ADCP activity in vitro
“Decreases in systemic exposure levels were reported in rats and monkeys following repeat dosing (Day 85 or 22, respectively), due to the presence of anti-drug antibodies (ADAs).”
Biodistribution & persistence
Rat [3H]MMAE QWBA: wide distribution, bile/bladder highest; prolonged uveal retention (melanin binding); fecal excretion
“Elimination of radioactivity from most tissues was observed at 96 hours post dose, except for the eye uveal tract (t½ = 672 hours post dose), indicating that [ 3H]MMAE likely bound melanin.”
Modality-specific risk
On-target skin and eye toxicity (Nectin-4 expression) plus MMAE myelosuppression, liver, neuropathy, hyperglycemia
“The eye and skin were identified in tissue cross reactivity studies in human and/or monkey (skin) as Nectin-4 expressing tissues, as such they were considered target-mediated toxicities.”
Anti-drug antibodies: animals
ADA in rats and monkeys decreased exposure on repeat dosing (Day 85 rat, Day 22 monkey)
“Decreases in systemic exposure levels were reported in rats and monkeys following repeat dosing (Day 85 or 22, respectively), due to the presence of anti-drug antibodies (ADAs).”
Anti-drug antibodies: patients
3.7% (25/684) single agent; 1.3% and 7% with pembrolizumab; effect unknown
“Anti‑enfortumab vedotin-ejfv antibodies developed in: • 3.7% (25/684) of patients who received PADCEV as a single agent. • 1.3% (2/156) of patients who received PADCEV in combination with intravenous pembrolizumab for the treatment of MIBC. • 7% (34/485) of patients”
Label warnings
Boxed warning: Serious skin reactions
- Skin Reactions
- Hyperglycemia
- Pneumonitis/Interstitial Lung Disease (ILD)
- Peripheral Neuropathy
- Ocular Disorders
- Infusion Site Extravasation
- Embryo-Fetal Toxicity
Skin reactionsMetabolic & endocrineImmune-mediated reactionsPulmonary toxicityNeurotoxicityOcular toxicityHypersensitivity & 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 Padcev 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: Monkey HNSTD/MTD 3 mg/kg, rat MTD 5 mg/kg; skin, injection site, bone marrow, liver, eye, male reproductive organs (FDA multi-discipline review, p. 56)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week GLP rat IV study (once weekly); no recovery phase
“Methods: In this study, rats were intravenously administered enfortumab vedotin (0.5, 2, or 5 mg/kg) once weekly for 13 weeks. Recovery was not evaluated.”
Pivotal GLP studies
Weekly IV GLP: rat 4- and 13-week; monkey 4-week (ADC, naked Ab, MMAE); monkey bridging; rat 4-week testicular study
“The Applicant conducted GLP intravenous repeat-dose (weekly) general toxicology studies in rats (4 and 13-week) with enfortumab vedotin, and the unconjugated antibody (AGS-22M6)”
DART package
Species: DART
Rat only (pilot embryo-fetal study with the ADC; complete litter loss at 5 mg/kg)
“In a rat pilot embryo-fetal development study, administration of enfortumab vedotin-ejfv on gestation day 6 and 13 during the period of organogenesis resulted in a complete litter loss in all pregnant rats at the maternally toxic dose of 5 mg/kg”
Reproductive & developmental
No fertility or PPND studies (ICH S9); preliminary rat EFD with ADC and MMAE EFD: embryolethal, teratogenic
“Fertility and early embryonic development studies were not conducted or needed to support marketing of PADCEV in patients with advanced cancer.”
PPND / ePPND: when
PPND not conducted: late stage and advanced cancer indication
“Since enfortumab vedotin is intended for the treatment of patients with late stage and advanced cancer, studies of fertility and early embryonic development and pre- and postnatal toxicity were not conducted.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Carcinogenicity studies with enfortumab vedotin-ejfv or the small molecule cytotoxic agent (MMAE) have not been conducted.”
Carcinogenicity model
Not conducted (ADC or MMAE); ICH S9, metastatic UC
“In accordance with International Council for Harmonisation (ICH) S9, carcinogenicity studies were not conducted for enfortumab vedotin as it is intended for treatment of metastatic UC.”
Carcinogenicity timing
Not required for advanced cancer; none conducted
“Carcinogenicity studies were not conducted or needed to support marketing of PADCEV in patients with advanced cancer.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey ~3-fold and rat (MTD) ~2-fold human systemic exposure at recommended dose
“The systematic exposure to AGS-22M6E in cynomolgus monkeys was ~3-fold the human systemic exposure at the recommended clinical dose. In rats, at the maximum tolerated dose (MTD), the systematic exposure was also ~2-fold the human systemic exposure at the recommended clinical dose.”
NOAEL / key findings
Monkey HNSTD/MTD 3 mg/kg, rat MTD 5 mg/kg; skin, injection site, bone marrow, liver, eye, male reproductive organs
“In the 4-week monkey study (# 20005664), AGS-22M6E systemic exposure at 3 mg/kg (MTD/HNSTD) was 2450 µg.hr/mL (Day 1) and 903 µg.hr/mL (Day 22).”
Efficacy evidenceopen answer page →
Efficacy evidence
Nectin-4-expressing patient-derived bladder cancer xenografts (AG-B1, AG-B8) in mice: >75% tumor growth inhibition
“In vivo, enfortumab vedotin administration to AG-B1 and AG-B8 (cells expressing human Nectin-4) patient-derived human bladder cancer xenograft mouse models resulted in >75% tumor growth inhibition relative to the unconjugated antibody and the control (5% dextrose).”
Why that model
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.
Reviewer's view of the efficacy data
EMA: adequate in vitro and in vivo pharmacology in disease models, supporting clinical use
“An adequate program of in vitro and in vivo pharmacology was conducted in disease models for enfortumab vedotin, supporting the intended clinical use.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAccepted
Chronic (13-week) toxicity in rat only; monkey limited to 4 weeks
Why: Comparable rat and monkey toxicity profiles; equivalent binding affinity to human Nectin-4 in both species · Within the guideline · Weight of evidence
“In general, similar toxicity profiles were observed across species and therefore only the rat was studied in the chronic (13-week) repeat dose toxicity study (please refer to ICH S6, S9, S9 Q&A).”
“As the toxicity profiles seem to be comparable between rat and cynomolgus, and considering that cross-reactivity in the rat and cynomolgus monkey have equivalent binding affinity to human Nectin-4, it is acceptable to conduct the chronic (13-week) repeat dose toxicity study only in the rat.”
DARTAccepted
No fertility/early embryonic or pre- and postnatal development studies; male fertility risk from repeat-dose testicular findings
Why: ICH S9: advanced cancer population · Within the guideline · Serious disease
“Dedicated fertility and early embryonic development studies were not conducted in accordance with ICH S9.”
“Fertility and early embryonic development studies were not conducted or needed to support marketing of PADCEV in patients with advanced cancer.”
DARTAcceptedBeyond the letter
ADC tested only in a preliminary rat EFD study; definitive EFD run with MMAE and another MMAE ADC (SGN-35)
Why: Embryo-fetal toxicity judged appropriately evaluated; findings reported in the SmPC · Class precedent
“Embryo-fetal development toxicity of SGN-35 and SGD-1010 was evaluated in a GLP-compliant repeat-dose IV embryo-fetal development study in pregnant rats.”
“The embryo-fetal toxicity was appropriately evaluated and the observed findings are correctly reported in the SmPC.”
OtherAccepted
No separate local tolerance studies
Why: ICH S6 · Within the guideline
“Separate studies evaluating local tolerance of enfortumab vedotin were not performed. In accordance with ICH S6, the omission of dedicated local tolerance studies is acceptable.”
Similar precedents
AdcetrisADCs · brentuximab vedotin · CD30Monkey + rodent · 26 wkBesponsaADCs · inotuzumab ozogamicin · CD22Monkey + rodent · 26 wkDatrowayADCs · datopotamab deruxtecan · Trop-2Monkey + rodent · 13 wkDecnupazADCs · pivekimab sunirine · CD123Monkey + rodent · 13 wkElahereADCs · mirvetuximab soravtansine · FRαMonkey + rodent · 10 wkEmrelisADCs · telisotuzumab vedotin · c-MetMonkey + rodent · 13 wk