Tivdak
tisotumab vedotin
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
Cynomolgus monkey only for ADC; rat and monkey for MMAE payload
“The data suggests that the cynomolgus monkey was the only relevant toxicological species.”
Why that species
Tisotumab binds human and cynomolgus TF similarly; no binding to mouse, rat, rabbit, pig or dog TF
“Tisotumab did not bind to mouse, rat, rabbit, pig, or dog TF.”
Surrogate molecule
No surrogate; clinical ADC tested in monkey, payload (MMAE) separately in rat and monkey
“A GLP compliant repeat-dose toxicology study with tisotumab vedotin was conducted in monkeys (13-week), and the payload was assessed in rats (4-week) and monkeys (11-week) using the clinical intravenous route of administration.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“A GLP compliant repeat-dose toxicology study with tisotumab vedotin was conducted in monkeys (13-week), and the payload was assessed in rats (4-week) and monkeys (11-week) using the clinical intravenous route of administration.”
Pivotal GLP studies
13-week GLP monkey ADC (q3w IV, 6-week recovery); MMAE 4-week rat, 11-week monkey; 13-week monkey naked antibody
“In a 13-week GLP repeat-dose study with a 6-week recovery period tisotumab vedotin was administered i.v. at doses of 1, 3 or 5 mg/kg every three weeks on five occasions to cynomolgus monkeys.”
Route in tox
IV (clinical route)
“A GLP compliant repeat-dose toxicology study with tisotumab vedotin was conducted in monkeys (13-week), and the payload was assessed in rats (4-week) and monkeys (11-week) using the clinical intravenous route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted with ADC; MMAE: Ames and mouse lymphoma negative, rat micronucleus positive (aneugenic)
“Genetic toxicology studies were not conducted with tisotumab vedotin; rather, the applicant submitted studies that evaluated the payload.”
Carcinogenicity
Not conducted (ICH S9)
“Carcinogenicity studies were not conducted with tisotumab vedotin in accordance with ICH S9 guidance.”
Reproductive & developmental
Not conducted with ADC (ICH S9); MMAE rat EFD teratogenic/embryolethal; male repro toxicity in monkey
“MMAE was teratogenic and embryo lethal when administered to pregnant rats via two intravenous doses of 0.2 mg/kg during the period of organogenesis on gestational days 6 and 13.”
Safety pharmacology
Incorporated into repeat-dose monkey studies (ICH S9); MMAE hERG in vitro
“Additionally, safety pharmacology endpoints for tisotumab vedotin representative of the cardiovascular (ECG and heart rate), central nervous (cageside observations) and respiratory systems (breaths per minute) were assessed as part of the repeat-dose toxicity studies as outlined in ICH S9 guideline.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
Monkey NOAEL 1 mg/kg (females; <1 mg/kg males), HNSTD 3 mg/kg; skin, bone marrow, eye, testes; skin deaths at 5 mg/kg
“The NOAEL for males was <1 mg/kg. The applicant also provided exposure (Cmax and AUC) ratios between monkey and human at the highest non-severely toxic dose of 3 mg/kg, which was approximately 1.35- to 2.56-fold that in humans.”
Risksopen answer page →
Immune & cytokine safety
ADA in most monkeys after repeat dosing, reduced exposure in some; immunotoxic potential minimal
“Most monkeys developed ADAs following repeated doses of tisotumab vedotin.”
Biodistribution & persistence
Monkey 89Zr-PET: highest uptake liver and bone marrow (~20% each); MMAE fecal elimination
“In cynomolgus monkeys, liver and bone marrow received the highest percent (approx. 20% each) of the injected dose of 89Zr-tisotumab and long persistence were noted.”
Modality-specific risk
Target-mediated skin and ocular toxicity plus MMAE myelosuppression, testicular toxicity; bleeding (TF/coagulation)
“Skin and ocular toxicities could be expected from the TF-directed antibody portion of tisotumab vedotin as tisotumab was shown to positively stain skin epithelial cells (squamous epidermis, hair follicle), and corneal and conjunctiva epithelial cells, in both human and monkey in a tissue cross reactivity study.”