Enhertu
fam-trastuzumab deruxtecan · HER2Japan and US: multicenter first-in-human study (Study DS8201-A-J101)
Datroway: what was done before first-in-human, and what came after?
datopotamab deruxtecan · Trop-2
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 Datroway 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 NOAEL 10 mg/kg for lung, cornea, skin, liver, thymus (intestinal toxicity at ≥10); rat NOAEL 20-60 mg/kg; ADA limits margins (FDA multi-discipline review, p. 66)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
3-month rat and cynomolgus monkey IV studies (every 3 weeks, five doses) with 2-month recovery
“To assess the general toxicity profile, 3-month intermittent intravenous dose toxicity studies (every 3 weeks (Q3W), five times in total) in rats and monkeys were conducted. The reversibility of toxic changes was also evaluated following a 2-month recovery period in the intermittent dose toxicity studies.”
Pivotal GLP studies
GLP 3-month q3w IV: rat (20, 60, 200 mg/kg) and monkey (10, 30, 80 mg/kg), 2-month recovery; DXd 1-month rat and monkey
“Datopotamab deruxtecan was administered i.v. to cynomolgus monkeys at doses of 10, 30 or 80 mg/kg every three weeks on five occasions in a GLP-compliant 3-month toxicity study with a 2-month recovery period, no deaths or moribundity were noted up to 80 mg/kg.”
DART package
Species: DART
Not conducted (DXd is genotoxic and affects dividing cells)
“The Applicant did not conduct fertility or embryo-fetal development toxicology studies with datopotamab deruxtecan as DXd is genotoxic and affects actively dividing cells, and therefore, these studies are not warranted to support the proposed indication.”
Reproductive & developmental
Not conducted (genotoxic payload); testis/ovary findings in rat; embryo-fetal toxicity warning
“The Applicant did not conduct fertility or embryo-fetal development toxicology studies with datopotamab deruxtecan as DXd is genotoxic and affects actively dividing cells, and therefore, these studies are not warranted to support the proposed indication.”
PPND / ePPND: when
PPND not conducted (ICH S9)
“In accordance with ICH guideline S9 no prenatal and postnatal development, including maternal function studies were conducted.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Carcinogenicity studies are not warranted to support the current application.”
Carcinogenicity model
Not conducted (not warranted for advanced cancer application)
“Carcinogenicity studies are not warranted to support the current application.”
Carcinogenicity timing
Not required: carcinogenicity studies not warranted for this application
“Carcinogenicity studies are not warranted to support the current application.”
Same question, other ADCs
Adcetris
brentuximab vedotin · CD30Not stated in public reviews
Besponsa
inotuzumab ozogamicin · CD22Not 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
Padcev
enfortumab vedotin · Nectin-4Not 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