Remicade
infliximab
Sources:EMA assessment report ↗
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).”
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.
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 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: 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.”