Padcev
enfortumab vedotin
Sources:FDA multi-discipline review ↗
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.”
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.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
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.”