Entyvio
vedolizumab
Species
MonkeyRabbit
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rabbit and cynomolgus monkey
“Toxicology studies were conducted with MLN0002 in two species (rabbit and Cynomolgus monkeys) by intravenous (IV) route to support the chronic use of MLN0002.”
Why that species
Similar binding affinity to rabbit, monkey and human leukocytes; no binding to mouse, rat or guinea pig leukocytes
“MLN0002 bound with similar affinity to leukocytes from rabbits, monkeys, and humans, but not from mice, rats, or guinea pigs.”
Surrogate molecule
No surrogate; the clinical antibody was tested in rabbits and cynomolgus monkeys
“Toxicology studies were conducted with MLN0002 in two species (rabbit and Cynomolgus monkeys) by intravenous (IV) route to support the chronic use of MLN0002.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“repeated dose IV toxicology (14-day, 13-week, 26-week) in Cynomolgus monkeys and rabbits (3-month)”
Pivotal GLP studies
3- and 6-month IV monkey studies (10, 30, 100 mg/kg every two weeks); 3-month IV rabbit study (30, 100 mg/kg)
“A 3-month IV toxicology study was conducted with MLN0002 in New Zealand white rabbits at 30 and 100 mg/kg and 3- and 6-month IV toxicology studies were conducted with MLN0002 in Cynomolgus monkeys at 10, 30 and 100 mg/kg administered once every two weeks.”
Route in tox
Intravenous
“Toxicology studies were conducted with MLN0002 in two species (rabbit and Cynomolgus monkeys) by intravenous (IV) route to support the chronic use of MLN0002.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“Genotoxicity studies were not conducted as vedolizumab is a humanized monoclonal antibody and so are not required in-line with ICH Guideline S6(R1).”
Carcinogenicity
Not conducted (ICH S6(R1)); no pharmacological activity in mice and rats
“In accordance with ICH Guideline S6(R1), conventional carcinogenicity studies (i.e., rodent bioassays) have not been conducted with MLN0002 to assess its carcinogenic potential as it lacks pharmacological activity in mice and rats.”
Reproductive & developmental
Rabbit embryo-fetal and monkey pre-/postnatal development studies: no adverse effects
“MLN0002 did not cause any adverse effect on embryofetal development in rabbits or on pre- and postnatal development in monkeys.”
Safety pharmacology
Telemetered cynomolgus monkey cardiovascular study: no effect on ECG, arterial blood pressure or heart rate
“In a cardiovascular safety pharmacology study in telemetered Cynomolgus monkeys, MLN0002 did not show any effect on ECG parameters, arterial blood pressure or heart rate.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Entyvio 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 monoclonal antibodies outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: NOAEL 100 mg/kg in monkeys, about 18 times the human AUC at 300 mg (FDA pharmacology/toxicology review, p. 158)
NOAEL / key findings
NOAEL 100 mg/kg in monkeys, about 18 times the human AUC at 300 mg
“The exposure (AUC) at the NOAEL dose of 100 mg/kg in monkeys is approximately 18 times higher than the mean AUC at the recommended human dose of 300 mg.”
Risksopen answer page →
Immune & cytokine safety
No T-lymphocyte activation or cytokine release in human whole blood in vitro
“MLN0002 did not induce T lymphocyte activation or cytokine release in whole human blood.”
Biodistribution & persistence
Tissue cross-reactivity: monkey staining similar to human, consistent with α4β7 expression; no off-target staining
“Vedolizumab staining pattern observed in Cynomolgus monkey tissues appeared to be similar to that observed in the human tissues and results were stated to be consistent with the pattern of expression of α4β7 integrin. No unanticipated tissue cross-reactivity or off-target staining was observed in TCR studies.”
Modality-specific risk
Loss of CNS immune surveillance (natalizumab-like): not seen in a rhesus monkey EAE model, whereas natalizumab blocked it
“MLN0002 did not appear to inhibit immune surveillance of the CNS as assessed in this model of EAE in Rhesus monkeys. In contrast, natalizumab blocked immune surveillance of the CNS in this model.”