Datroway
datopotamab deruxtecan
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 (non-binding) and cynomolgus monkey (relevant); DXd payload in rat and monkey
“Though datopotamab deruxtecan did not bind rat Trop2 in an in vitro assay, the monkey is a pharmacologically relevant species considering datopotamab deruxtecan demonstrated similar binding to human and monkey Trop2.”
Why that species
Similar binding to human and monkey Trop2; weak to no binding to mouse and rat Trop2
“Datopotamab deruxtecan bound to human and monkey Trop2 similarly in an ELISA-based assay but demonstrated weak to no binding to mouse and rat Trop2.”
Surrogate molecule
No surrogate; clinical ADC in rat and monkey; DXd payload in GLP 1-month rat and monkey studies
“The toxicity of DXd was also evaluated in GLP-compliant 1-month repeat-dose toxicology studies in rats and monkeys.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“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.”
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.”
Route in tox
IV (clinical route)
“In 3-month repeat-dose toxicology studies evaluating the safety of datopotamab deruxtecan administered intravenously, the intended route of administration, there were no mortalities at doses up to 200 mg/kg in rats or doses up to 80 mg/kg in monkeys.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted with ADC; DXd Ames negative, clastogenic in vitro chromosome aberration and in vivo rat micronucleus
“In genetic toxicology studies, deruxtecan was not mutagenic in an Ames assay but demonstrated clastogenic potential in an in vitro Chinese hamster lung chromosome aberration assay and an in vivo rat bone marrow micronucleus assay.”
Carcinogenicity
Not conducted (not warranted, advanced cancer)
“Carcinogenicity studies are not warranted to support the current application.”
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.”
Safety pharmacology
Stand-alone monkey CV/respiratory/neuro study plus repeat-dose endpoints; DXd hERG negative up to 10 µM
“Datopotamab deruxtecan did not have significant effects on cardiovascular, respiratory, or neurobehavior in safety pharmacology studies in monkeys.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
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
“The NOAELs for pulmonary, corneal, dermal, hepatic, and lymphoid (thymic) toxicity was concluded to be 10 mg/kg.”
Risksopen answer page →
Immune & cytokine safety
ADA in 5/6 monkeys at 10 mg/kg reducing exposure; minimal in vitro cytokine release; transient CRP increases
“Five of 6 monkeys given 10 mg/kg showed ADA positive responses after the 3-month dosing period, and there was a reduction in Dato-DXd exposure after the 4th dose compared to the 1st dose.”
Biodistribution & persistence
14C-DXd rapid wide distribution without retention (highest intestine, bladder, kidney); low DXd release in plasma (≤6.5%); biliary/fecal excretion
“Tissues with the highest concentrations of radioactivity included the small and large intestines, urinary bladder, and kidney.”
Modality-specific risk
Interstitial lung disease (Trop2 in alveolar epithelium), ocular surface/corneal toxicity, GI and hematologic DXd payload toxicity
“Lung toxicity noted in monkeys is consistent with expression of Trop2 in the lung, and Trop2 staining was noted on the plasma membrane of the alveolar epithelium in humans and monkeys with similar frequency and intensity in a tissue-cross reactivity study.”