Cimzia
certolizumab pegol
Species
Monkey
Longest study
52 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey (main species)
“Based on the species specificity of target binding, the cynomolgus monkey has been selected as the main species for toxicity testing.”
Why that species
No binding to rodent, rabbit, guinea pig or dog TNFα; inhibits non-human primate TNFα, though with at least 1000-fold lower activity
“Certolizumab pegol did not bind TNFα from rodents, rabbit, guinea pigs and dog, but it inhibited TNFα from non-human primates, with at least a 1000-fold lower activity than against hTNFα.”
Surrogate molecule
Yes: cTN3 PF, a chimeric PEGylated anti-rat TNFα Fab' fragment, used for rat fertility, embryo-fetal and pre/postnatal studies
“Instead, the homologous agent cTN3 PF, which is a chimeric Fab' fragment conjugated to 40 kDa PEG, was tested in the reproductive and developmental toxicity studies.”
Study lengthopen answer page →
Longest pivotal study
52 weeks
“The pivotal repeat dose toxicity studies consisted of a 26-week repeat-dose toxicity study and a 52-week immunotoxicity study, both performed in cynomolgus monkeys.”
Pivotal GLP studies
Cynomolgus monkey 26-week SC (10, 100 mg/kg/week) and 52-week SC immunotoxicity study (50, 100 mg/kg/week)
“The animals were administered 10 and 100 mg/kg/week s.c. certolizumab pegol and 50 and 100 mg/kg/week s.c. in the 26- and 52- week study, respectively.”
Route in tox
Subcutaneous (weekly); intravenous in 4-week monkey and rat studies
“The animals were administered 10 and 100 mg/kg/week s.c. certolizumab pegol and 50 and 100 mg/kg/week s.c. in the 26- and 52- week study, respectively.”
Skipped studiesopen answer page →
Genotoxicity
Conducted: negative in Ames, human lymphocyte chromosomal aberration and mouse micronucleus assays
“Certolizumab pegol was not genotoxic in the Ames test, the human peripheral blood lymphocytes chromosomal aberration assay, or the mouse bone marrow micronucleus assay.”
Carcinogenicity
Not conducted; acceptable given nature of compound and lack of pharmacological activity in species normally used
“No conventional carcinogenicity testing was performed with certolizumab pegol, which was acceptable considering the nature of the compound and the lack of pharmacological activity and immunogenicity of certolizumab pegol in species normally used for such testing.”
Reproductive & developmental
Rat surrogate studies over the full reproductive cycle: no effects on female fertility, reproductive function or offspring development; reduced sperm motility in males
“In female rat studies covering dosing throughout the complete reproductive cycle, there were no effects on fertility, reproductive function or developmental effects on offspring.”
Safety pharmacology
No in vivo safety pharmacology studies; monitoring incorporated into repeat-dose monkey studies with no effects
“No in vivo safety pharmacology studies have been conducted with certolizumab pegol, however monitoring of potential undesirable pharmacological activity was incorporated in both the repeat dose toxicity studies and single dose Phase 1 clinical studies.”
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 Cimzia 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: Cellular vacuolation, mainly in macrophages, in multiple organs including choroid plexus of the brain (EMA assessment report, p. 14)
NOAEL / key findings
Cellular vacuolation, mainly in macrophages, in multiple organs including choroid plexus of the brain
“In rats and monkeys histopathology revealed cellular vacuolation, present mainly in macrophages, in a number of organs (lymph nodes; injection sites, spleen; adrenal; uterine, cervix; choroid plexus of the brain, and in the epithelial cells of the choroid plexus).”
Risksopen answer page →
Immune & cytokine safety
Anti-drug antibody incidence 10-20% in main monkey toxicity studies
“The antibody incidence in the main monkey toxicity studies were 10-20%.”
Biodistribution & persistence
Rat study: highest PEG level in liver (7% of dose); no TNF-associated tissue uptake of PEG
“The highest level of PEG was detected in the liver (7% of the dose administered). There was no indication of tissue uptake of PEG, associated with binding to membrane bound TNF alpha.”
Modality-specific risk
Lymphoma/malignancy risk from long-term TNF-α inhibition
“the possible risk for the development of lymphomas or other malignancies in patients treated with TNF antagonists is reflected in the SPC and PL, and warrants post marketing surveillance.”