Enhertu
fam-trastuzumab deruxtecan · HER2Japan and US: multicenter first-in-human study (Study DS8201-A-J101)
Padcev: what was done before first-in-human, and what came after?
enfortumab vedotin · Nectin-4
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.”
Same question, other ADCs
Adcetris
brentuximab vedotin · CD30Not stated in public reviews
Besponsa
inotuzumab ozogamicin · CD22Not stated in public reviews
Datroway
datopotamab deruxtecan · Trop-2Not stated in public reviews
Decnupaz
pivekimab sunirine · CD123Not stated in public reviews
Elahere
mirvetuximab soravtansine · FRαNot stated in public reviews
Emrelis
telisotuzumab vedotin · c-MetNot stated in public reviews
Kadcyla
ado-trastuzumab emtansine · HER2Not stated in public reviews
Mylotarg
gemtuzumab ozogamicin · CD33Not stated in public reviews
Polivy
polatuzumab vedotin · CD79bNot stated in public reviews
Tivdak
tisotumab vedotin · Tissue factorNot stated in public reviews
Trodelvy
sacituzumab govitecan · Trop-2Not stated in public reviews
Zynlonta
loncastuximab tesirine · CD19Not stated in public reviews