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.”
Species: general tox
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.”
Species: DART
Rabbit (embryo-fetal) and cynomolgus monkey (pre- and postnatal development)
“MLN0002 did not cause any adverse effect on embryofetal development in rabbits or on pre- and postnatal development in monkeys.”
Species: carcinogenicity
Not conducted (no pharmacological activity in mice and rats; ICH S6(R1))
“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.”
Surrogate used in
Yes: murine homologue Act-1 used for in vitro carcinogenic-potential assessment in human tumor cells
“However, carcinogenic potential of Act-1 (murine homologue of MLN0002) was assessed in an in vitro study using human tumor cells that expressed”
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.”
Genotox: Ames
Not conducted (humanized monoclonal antibody, 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).”
Genotox: in vitro mammalian
Not conducted (humanized monoclonal antibody, 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).”
Genotox: in vivo
Not conducted (humanized monoclonal antibody, 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 model
Not conducted (no rodent pharmacological activity); in vitro Act-1 tumor-cell growth study instead
“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. However, carcinogenic potential of Act-1 (murine homologue of MLN0002) was assessed in an in vitro study using human tumor cells that expressed”
Carcinogenicity timing
Not required (rodents not pharmacologically responsive; ICH S6(R1))
“Conventional carcinogenicity risk assessment studies (ie, rodent bioassays) have not been conducted with vedolizumab as rodents are not pharmacologically responsive to this mAb. This is consistent with ICH Guideline S6(R1).”
hERG / QT
No effect on ECG, arterial blood pressure or heart rate in telemetered cynomolgus monkeys
“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
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
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.”
Anti-drug antibodies: animals
Variable RAHA/PAHA in rabbits and monkeys; neutralizing effect on PK and PD in some animals at 10 and 30 mg/kg
“In some animals, RAHA/PAHA had a neutralizing effect on the PK and PD of MLN0002 at the low and mid doses (10 and 30 mg/kg); however, saturation of receptors was achieved in animals that did not develop a neutralizing RAHA/PAHA effect.”
Anti-drug antibodies: patients
6% (86/1,427) over 52 weeks of IV treatment in UC and CD trials
“The incidence of anti-drug antibodies to intravenous ENTYVIO using a drug-tolerant electrochemiluminescence (ECL) method for patients in UC Trials I and II and CD Trials I and III who had continuous ENTYVIO treatment administered as an intravenous infusion for 52 weeks was 6% (86 out of 1,427 total ENTYVIO-treated patients).”
Label warnings
- Infusion-Related Reactions and Hypersensitivity Reactions
- Infections
- Progressive Multifocal Leukoencephalopathy
- Liver Injury
- Immunizations
Hypersensitivity & infusion reactionsInfectionsNeurotoxicityHepatotoxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
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 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
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week cynomolgus monkey (IV) study with 12-week recovery
“26-Week Toxicology Study of MLN0002 Administered by Intravenous Infusion to Cynomolgus Monkeys, with a 12-Week Recovery Period (KLA00290)”
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.”
DART package
Species: DART
Rabbit (embryo-fetal) and cynomolgus monkey (pre- and postnatal development)
“MLN0002 did not cause any adverse effect on embryofetal development in rabbits or on pre- and postnatal development in monkeys.”
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.”
PPND / ePPND: when
PPND in cynomolgus monkey completed before the marketing application
“A pre and postnatal development study in monkeys showed no evidence of any adverse effect on pre and postnatal development at IV doses up to 100 mg/kg (about 6.5 times the recommended human dose based on the body surface area).”
Carcinogenicity
Species: carcinogenicity
Not conducted (no pharmacological activity in mice and rats; ICH S6(R1))
“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.”
Carcinogenicity model
Not conducted (no rodent pharmacological activity); in vitro Act-1 tumor-cell growth study instead
“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. However, carcinogenic potential of Act-1 (murine homologue of MLN0002) was assessed in an in vitro study using human tumor cells that expressed”
Carcinogenicity timing
Not required (rodents not pharmacologically responsive; ICH S6(R1))
“Conventional carcinogenicity risk assessment studies (ie, rodent bioassays) have not been conducted with vedolizumab as rodents are not pharmacologically responsive to this mAb. This is consistent with ICH Guideline S6(R1).”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL 100 mg/kg ~18x 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.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Spontaneous-colitis cotton-top tamarins treated with Act-1, the murine vedolizumab precursor (2.0 mg/kg for 8 days)
“In vivo, colitic cotton-top tamarins (these develop a type of colitis spontaneously) were used to determine the functional relevance of α4β7 in the pathogenesis of chronic inflammatory disease. Animals were given 2.0 mg/kg Act-1, the murine vedolizumab precursor, for 8 days.”
Why that model
Cotton-top tamarins develop colitis spontaneously, allowing in vivo test of α4β7 in chronic intestinal inflammation
“In vivo, colitic cotton-top tamarins (these develop a type of colitis spontaneously) were used to determine the functional relevance of α4β7 in the pathogenesis of chronic inflammatory disease.”
Reviewer's view of the efficacy data
FDA: pharmacology results support the mechanism of action and proposed indication
“Overall, the results of pharmacology studies appear to support the mechanism of action and the proposed indication of MLN0002.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted
No rodent carcinogenicity bioassay for a chronic IBD therapy; in vitro tumour-cell study with murine homologue Act-1 instead
Why: No pharmacological activity in mice and rats (ICH S6(R1)); weight of evidence indicates no significant carcinogenic potential · Within the guideline · No relevant species · Weight of evidence
“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.”
“Overall, MLN0002 does not appear to have significant carcinogenic potential.”
DARTAccepted with a conditionBeyond the letter
No fertility studies; 26-week monkey study insufficient to exclude effects on male reproductive organs
Why: Effect on male fertility unlikely; uncertainty stated in the SmPC
“Concerning fertility, the 26 week general toxicity study in monkeys given vedolizumab is judged insufficient to conclude an absence of an effect, although an effect on male fertility is unlikely.”
“However as no definitive conclusion can be drawn on the male reproductive organs in the cynomolgus monkey repeat dose general toxicity study the following wording has been included in the SmPC:”
Juvenile toxVerdict not stated
No juvenile animal toxicity studies; β7 integrin knockout mouse data used instead
Why: α4β7 integrin plays no role in growth and development; β7 knockout mice suffice to study developmental effects · Pharmacology or kinetics
“Toxicology studies in juvenile animals have not been conducted. The Applicant argued that α4β7 integrin does not play a role in mammalian growth and development (literature references have been provided) and that the developmental effects of inhibiting the α4β7 integrin can be studied sufficiently in mice with genetic ablation of the β7 integrin gene (Itgb7)”
OtherAccepted with a conditionBeyond the letter
No animal model of PML; CNS immune surveillance tested in a rhesus EAE model instead
Why: PML handled as a potential risk in the RMP with postmarketing monitoring
“However, since EAE is not an animal model of PML; the results of this study do not directly demonstrate that MLN0002 has no potential to cause PML.”
“The PML risk is considered a potential risk as described in the RMP and will be monitored in the post marketing setting.”
Safety pharmacologyAcceptedBeyond the letter
No stand-alone gastrointestinal, urinary, pulmonary or CNS safety pharmacology; endpoints in repeat-dose toxicology studies
“The effects of vedolizumab on the gastrointestinal, urinary, pulmonary and central nervous systems were evaluated for functional and structural changes in GLP-compliant repeat-dose toxicology studies of up to 26 weeks in pharmacologically responsive species. This is acceptable to the CHMP.”
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