Adcetris
brentuximab vedotin
Species
MonkeyRat
Longest study
26 wk
Genotox
Partial / alternative Partial / alternative
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey (monkey the antigen-binding species)
“Single- and repeat-dose toxicology studies were conducted in rats and monkeys. The pivotal repeat-dose toxicity studies were GLP compliant.”
Why that species
Binds human and cynomolgus CD30 with equal affinity (Kd 0.2 nM), not rat or mouse; rat used for target-independent payload toxicity
“Both brentuximab vedotin and unconjugated brentuximab bound with a Kd of 0.2 nM to human and cynomolgus CD30-positive primary lymphocytes, but not to rat or mouse CD30-positive cells or cells not expressing CD30.”
Surrogate molecule
No surrogate; clinical ADC tested in rat and monkey, with free MMAE and unconjugated cAC10 comparator arms
“The administration of unconjugated brentuximab at all doses was well tolerated, with no apparent target organ toxicity or clinically significant adverse effects.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“The haematologic changes observed in the 26-week repeat-dose toxicity study were similar to those of the 11-week study.”
Pivotal GLP studies
Rat 4-week IV (weekly x4) with recovery; cynomolgus 9-week (q3w x4) and 24/26-week (q3w x9) IV infusion studies
“With repeat-dose administration of brentuximab vedotin, unconjugated brentuximab, and MMAE in rats and monkeys the principal test article-related effects of brentuximab vedotin and MMAE in both species included changes in the bone marrow and lymphoid tissues;”
Route in tox
IV (bolus in rat, 30-60 min infusion in monkey)
“Since SGN-35 has been developed for intravenous (IV) administration all non-clinical studies were conducted using the IV route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Conducted on MMAE: Ames and mouse lymphoma negative; rat micronucleus positive (aneugenic)
“MMAE was genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism.”
Carcinogenicity
Not conducted (relapsed/refractory HL and sALCL indication)
“Carcinogenicity studies with brentuximab vedotin or the small molecule (MMAE) have not been conducted.”
Reproductive & developmental
Rat EFD: embryo-fetal lethality at >=3 mg/kg, placental transfer; no fertility studies; testicular toxicity in rat repeat-dose
“In rats, brentuximab vedotin was clearly embryo-foetal toxic, causing loss of almost all embryos at 3 mg/kg and above.”
Safety pharmacology
Dedicated GLP telemetry study in cynomolgus (CV, respiratory, CNS) plus in vitro hERG with MMAE
“In a dedicated safety pharmacology study in cynomolgus monkeys a single IV infusion of brentuximab vedotin up to 3 mg/kg had no effect on the cardiovascular, respiratory or central nervous systems.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
Monkey NOAEL 1 mg/kg, HNSTD 3 mg/kg, 6 mg/kg lethal; rat HNSTD 5 mg/kg; bone marrow/neutropenia, lymphoid, rat liver and testis
“At 3 mg/kg (HNSTD), a similar, but less severe cyclic decrease in neutrophil counts was observed, while at 1 mg/kg (NOAEL) no biologically relevant effects on neutrophil counts was observed.”
Risksopen answer page →
Immune & cytokine safety
Anti-drug antibodies (PAHA) in monkeys reduced ADC exposure but increased MMAE exposure without added toxicity
“The positive immunogenic responses in monkeys appeared to reduce the concentrations of brentuximab vedotin and TAb after multiple doses, and conversely increased the concentrations of MMAE after multiple doses in of the animals with high anti-brentuximab antibody (PAHA) levels.”
Biodistribution & persistence
Low Vss for ADC; free MMAE widely distributed (pituitary, adrenal, thyroid, lung, kidney, liver), biliary/fecal excretion; placental transfer
“MMAE was mainly distributed to pituitary gland, adrenal gland, thyroid, lung, kidney, liver and subsequently bile and intestine.”
Modality-specific risk
MMAE payload toxicity: myelotoxicity/neutropenia, testicular toxicity; peripheral neuropathy not reproduced in animals
“Neutropenia and associated mortality was the clinically most significant toxicity observed in non-clinical studies in monkeys.”