Remicade
infliximab
Species
MonkeyMouse
Longest study
26 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Chimpanzee (limited studies) and mouse (surrogate anti-mouse TNF-α antibody)
“A small number of chimpanzees, the only relevant species identified for safety testing, were given single or up to 5 once daily repeated doses of infliximab.”
Why that species
Infliximab neutralizes only human and chimpanzee TNF-α; no activity on macaque, other primate, pig, rabbit, rat or mouse TNF-α
“infliximab could neutralise human and chimpanzee TNFα with similar potency, while TNFα from a number of other species (rhesus cynomolgous, pigtail macaque, cotton-top tamarin, baboon, marmoset, pig, rabbit, rat and mouse) was not affected by infliximab.”
Surrogate molecule
Yes: anti-mouse TNF-α antibody cV1q, used for mouse reproductive and developmental studies
“In an attempt to mimic the clinical situation of TNFα inhibition, studies were conducted in mice using a monoclonal antibody against mouse TNFα (cV1q).”
Species: general tox
Chimpanzee only (small number; single or up to 5 daily doses); rat studies not relevant
“Although single and repeated dose toxicity studies were performed in rats, these studies are not considered to have any relevance for the human safety assessment. A small number of chimpanzees, the only relevant species identified for safety testing, were given single or up to 5 once daily repeated doses of infliximab.”
Species: DART
Mouse only, using surrogate anti-mouse TNFα antibody cV1q
“In an attempt to mimic the clinical situation of TNFα inhibition, studies were conducted in mice using a monoclonal antibody against mouse TNFα (cV1q).”
Species: carcinogenicity
CD-1 mouse, 6-month tumorigenicity study with surrogate cV1q
“A 6-month study in CD-1 mice was conducted to assess the tumorigenic potential of cV1q anti-mouse TNFα, an analogous antibody.”
Surrogate used in
Yes: anti-mouse TNFα antibody plus transgenic/knockout mice for carcinogenicity and reproductive toxicity
“Data from genetically modified animals (i.e. transgenic and knock-out models) and from studies of a monoclonal antibody against mouse TNFα have provided some reassurance regarding carcinogenic potential and reproductive toxicity, although some effects on fertility were observed in mice.”
Study lengthopen answer page →
Longest pivotal study
26 (mouse surrogate antibody)
“A 6 months toxicity study with an anti-mouse TNFα monoclonal antibody (chimeric V1q muG2a, which has functional characteristics similar to infliximab) was submitted in year 2001.”
Pivotal GLP studies
CD-1 mouse study with surrogate cV1q, 25 weekly IV doses of 10 or 40 mg/kg; short chimpanzee studies
“In this study, CD-1 mice were given 25 weekly i.v. doses of 10 or 40 mg/kg cV1q. No cV1q treatment-related mortality or clinical signs of toxicity were observed.”
Route in tox
IV
“In this study, CD-1 mice were given 25 weekly i.v. doses of 10 or 40 mg/kg cV1q.”
Skipped studiesopen answer page →
Genotoxicity
Complete battery performed despite limited value; no genotoxic activity
“Genotoxicity tests are considered to be of limited value for this type of product. Still, a complete test battery has been performed. Infliximab did not show any genotoxic activity in these studies.”
Carcinogenicity
No standard studies; TNF-α knockout mice and anti-murine TNF-α antibody data gave no support for increased tumour risk
“These data gave no support for the hypothesis that inhibition of TNFα is associated with an enhanced risk for tumour development.”
Reproductive & developmental
Mouse surrogate (cV1q) studies: crossed placenta; no impairment of reproductive function, embryotoxicity or teratogenicity
“In these experiments, it was demonstrated that cV1q crossed the placenta but there was no indication of impairment of reproductive function, embryotoxicity or teratogenicity.”
Safety pharmacology
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.
Genotox: Ames
Negative (complete standard battery)
“Genotoxicity tests are considered to be of limited value for this type of product. Still, a complete test battery has been performed. Infliximab did not show any genotoxic activity in these studies.”
Genotox: in vitro mammalian
Negative (complete standard battery)
“Genotoxicity tests are considered to be of limited value for this type of product. Still, a complete test battery has been performed. Infliximab did not show any genotoxic activity in these studies.”
Genotox: in vivo
Negative (complete standard battery)
“Genotoxicity tests are considered to be of limited value for this type of product. Still, a complete test battery has been performed. Infliximab did not show any genotoxic activity in these studies.”
Carcinogenicity model
No standard studies; 6-month CD-1 mouse study with surrogate cV1q (10 or 40 mg/kg weekly): no tumorigenicity
“A 6-month study in CD-1 mice was conducted to assess the tumorigenic potential of cV1q anti-mouse TNFα, an analogous antibody. No evidence of tumorigenicity was observed in mice that received intravenous doses of 10 mg/kg or 40 mg/kg cV1q given weekly.”
Carcinogenicity timing
No standard studies; 6-month surrogate cV1q mouse study submitted in 2001, after initial EU authorisation
“A 6 months toxicity study with an anti-mouse TNFα monoclonal antibody (chimeric V1q muG2a, which has functional characteristics similar to infliximab) was submitted in year 2001.”
hERG / QT
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 doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Remicade 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: No toxicity in mouse surrogate study except dose-related bilateral lens capsule crystalline deposits in males (EMA assessment report, p. 8)
NOAEL / key findings
No toxicity in mouse surrogate study except dose-related bilateral lens capsule crystalline deposits in males
“However, ophthalmic examinations revealed a dose-related increase of bilateral crystalline deposits in the lens capsule of treated male mice. The relevance of this finding for humans is not known.”
Risksopen answer page →
Immune & cytokine safety
Anti-TNF-α antibodies reduce host defence in intracellular infection models, increasing infection-induced mortality
“Data from the literature have shown that anti-TNFα monoclonal antibodies reduce host defence in various clinically relevant intracellular infection models”
Biodistribution & persistence
Human TCR: staining of mononuclear and stromal cells and vascular smooth muscle, consistent with TNF-α distribution
“Consistent with the known distribution of TNFα, reactivity was observed with mononuclear and stromal cells in most tissues as well as in smooth musculature associated with vascular walls or selected muscle bundles in a number of tissues.”
Modality-specific risk
Increased susceptibility to infections from long-term TNF-α inhibition
“Since TNFα plays an important role in the defence against various infections, long-term inhibition of TNFα may be associated with an increased susceptibility for infectious disease.”
Anti-drug antibodies: animals
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.
Anti-drug antibodies: patients
Approximately 10% in RA and CD through 1 to 2 years of treatment
“The incidence of antibodies to infliximab in patients with RA and CD given a 3-dose induction regimen followed by maintenance dosing was approximately 10% as assessed through 1 to 2 years of REMICADE treatment.”
Label warnings
Boxed warning: SERIOUS INFECTIONS and MALIGNANCY
- Serious Infections
- Malignancies
- Hepatitis B Virus Reactivation
- Hepatotoxicity
- Heart Failure
- Hematologic Reactions
- Hypersensitivity
- Cardiovascular and Cerebrovascular Reactions During and After Infusion
- Neurologic Reactions
- Concurrent Administration with Other Biological Products
- Switching Between Biological Disease-Modifying Antirheumatic Drugs (DMARDs)
- Autoimmunity
- Vaccinations and Use of Live Vaccines/Therapeutic Infectious Agents
InfectionsSecondary malignancyHepatotoxicityCardiovascularCytopeniasHypersensitivity & infusion reactionsNeurotoxicityImmune-mediated reactions
US prescribing information, Boxed Warning and 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 Remicade 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: No toxicity in mouse surrogate study except dose-related bilateral lens capsule crystalline deposits in males (EMA assessment report, p. 8)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Surrogate antibody cV1q in CD-1 mice, 25 weekly IV doses; recovery not stated
“In this study, CD-1 mice were given 25 weekly i.v. doses of 10 or 40 mg/kg cV1q.”
Pivotal GLP studies
CD-1 mouse study with surrogate cV1q, 25 weekly IV doses of 10 or 40 mg/kg; short chimpanzee studies
“In this study, CD-1 mice were given 25 weekly i.v. doses of 10 or 40 mg/kg cV1q. No cV1q treatment-related mortality or clinical signs of toxicity were observed.”
DART package
Species: DART
Mouse only, using surrogate anti-mouse TNFα antibody cV1q
“In an attempt to mimic the clinical situation of TNFα inhibition, studies were conducted in mice using a monoclonal antibody against mouse TNFα (cV1q).”
Reproductive & developmental
Mouse surrogate (cV1q) studies: crossed placenta; no impairment of reproductive function, embryotoxicity or teratogenicity
“In these experiments, it was demonstrated that cV1q crossed the placenta but there was no indication of impairment of reproductive function, embryotoxicity or teratogenicity.”
PPND / ePPND: when
Not conducted: no standard reproductive studies with infliximab (no relevant species); surrogate cV1q mouse studies instead
“Standard reproductive/developmental toxicity studies have not been performed with infliximab due to lack of relevant animal models. In an attempt to mimic the clinical situation of TNFα inhibition, studies were conducted in mice using a monoclonal antibody against mouse TNFα (cV1q).”
Carcinogenicity
Species: carcinogenicity
CD-1 mouse, 6-month tumorigenicity study with surrogate cV1q
“A 6-month study in CD-1 mice was conducted to assess the tumorigenic potential of cV1q anti-mouse TNFα, an analogous antibody.”
Carcinogenicity model
No standard studies; 6-month CD-1 mouse study with surrogate cV1q (10 or 40 mg/kg weekly): no tumorigenicity
“A 6-month study in CD-1 mice was conducted to assess the tumorigenic potential of cV1q anti-mouse TNFα, an analogous antibody. No evidence of tumorigenicity was observed in mice that received intravenous doses of 10 mg/kg or 40 mg/kg cV1q given weekly.”
Carcinogenicity timing
No standard studies; 6-month surrogate cV1q mouse study submitted in 2001, after initial EU authorisation
“A 6 months toxicity study with an anti-mouse TNFα monoclonal antibody (chimeric V1q muG2a, which has functional characteristics similar to infliximab) was submitted in year 2001.”
Safety marginopen answer page →
Safety margin at NOAEL
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.
NOAEL / key findings
No toxicity in mouse surrogate study except dose-related bilateral lens capsule crystalline deposits in males
“However, ophthalmic examinations revealed a dose-related increase of bilateral crystalline deposits in the lens capsule of treated male mice. The relevance of this finding for humans is not known.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human TNFα transgenic mouse models and rhTNFα-challenged normal mice
“Studies in normal mice given rhTNFα and different transgenic mice models that expressed recombinant forms of soluble or transmembrane human TNFα showed that infliximab inhibited the pathological effects mediated by human TNFα.”
Why that model
Infliximab neutralises only human and chimpanzee TNFα, not TNFα of macaques, other primates, pig, rabbit, rat or mouse
“It was also shown that infliximab could neutralise human and chimpanzee TNFα with similar potency, while TNFα from a number of other species (rhesus cynomolgous, pigtail macaque, cotton-top tamarin, baboon, marmoset, pig, rabbit, rat and mouse) was not affected by infliximab.”
Reviewer's view of the efficacy data
EMA: transgenic arthritis-model data (murine anti-human TNFα mA2, joint healing) support use in RA
“These data indicated that the murine anti-human TNFα monoclonal antibody (mA2) inhibited effects mediated by human TNFα, which also resulted in joint healing. Thus, these preclinical data would support the use of infliximab in RA.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAccepted
Chimpanzee the only relevant species; only a small, limited single/short repeat-dose chimpanzee study, rat studies not relevant
Why: Lack of relevant animal models · No relevant species · Within the guideline
“A small number of chimpanzees, the only relevant species identified for safety testing, were given single or up to 5 once daily repeated doses of infliximab.”
“Due to the lack of relevant animal models, the absence of more detailed toxicity data with infliximab was considered acceptable.”
DARTAcceptedBeyond the letter
No standard reproductive toxicity studies with infliximab; mouse studies with surrogate anti-mouse TNFα antibody cV1q instead
Why: No relevant animal models; surrogate and genetically modified animal data gave some reassurance · No relevant species · Weight of evidence
“Standard reproductive/developmental toxicity studies have not been performed with infliximab due to lack of relevant animal models. In an attempt to mimic the clinical situation of TNFα inhibition, studies were conducted in mice using a monoclonal antibody against mouse TNFα (cV1q).”
“Data from genetically modified animals (i.e. transgenic and knock-out models) and from studies of a monoclonal antibody against mouse TNFα have provided some reassurance regarding carcinogenic potential and reproductive toxicity, although some effects on fertility were observed in mice.”
CarcinogenicityAcceptedBeyond the letter
No standard carcinogenicity studies; TNFα knockout mice and anti-murine TNFα antibody data used to address tumour risk
Why: TNFα knockout and anti-murine TNFα antibody data gave no support for enhanced tumour risk · Weight of evidence
“Standard carcinogenicity studies have not been performed with infliximab. A concern was expressed regarding the consequences of long-term inhibition of TNFα in relation to proliferative changes and a potential risk of tumour development.”
“These data gave no support for the hypothesis that inhibition of TNFα is associated with an enhanced risk for tumour development.”
OtherAcceptedBeyond the letter
Limited preclinical pharmacokinetic documentation
Why: Animal pharmacokinetic data of marginal relevance for safety assessment · No relevant species
“The preclinical pharmacokinetic documentation is limited. Since the relevance of animal pharmacokinetic data on infliximab is marginal for the safety assessment, this was considered acceptable.”
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