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.”
Species: general tox
Cynomolgus monkey (pivotal 26-week and 52-week studies)
“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.”
Species: DART
Rat, using rodent surrogate cTN3 PF (no cross-reactivity with rodent TNFα)
“Since certolizumab pegol does not cross-react with mouse or rat TNFα, reproduction studies were performed in rats using a rodent anti-murine TNFα pegylated Fab fragment (cTN3 PF), similar to certolizumab pegol.”
Species: carcinogenicity
Not conducted
“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.”
Surrogate used in
Yes: homologous PEGylated Fab' cTN3 PF for reproductive and developmental toxicity
“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.”
Genotox: Ames
Negative
“Certolizumab pegol was not genotoxic in the Ames test, the human peripheral blood lymphocytes chromosomal aberration assay, or the mouse bone marrow micronucleus assay.”
Genotox: in vitro mammalian
Human peripheral blood lymphocyte chromosomal aberration assay: negative
“Certolizumab pegol was not genotoxic in the Ames test, the human peripheral blood lymphocytes chromosomal aberration assay, or the mouse bone marrow micronucleus assay.”
Genotox: in vivo
Mouse bone marrow micronucleus assay: negative
“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 model
Not conducted: no pharmacological activity and immunogenicity in standard carcinogenicity species
“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.”
Carcinogenicity timing
Not required (accepted by CHMP)
“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.”
hERG / QT
No dedicated safety pharmacology studies; monitoring incorporated into repeat-dose toxicity studies
“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
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: 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.”
Anti-drug antibodies: animals
10-20% ADA incidence in main monkey studies (assay interference); shortened half-life, no toxicological consequences
“The antibody incidence in the main monkey toxicity studies were 10-20%. It should be noted that the presence of CDP870 in the plasma sample interferes with the antibody analyses, and thus data are uncertain. Presence of antibodies resulted in shortened t1/2. There were no apparent toxicological consequences of antibody formation.”
Anti-drug antibodies: patients
7% (105/1,509) in RA placebo-controlled trials; 3% (39/1,509) neutralizing
“The overall percentage of patients with antibodies to certolizumab pegol detectable on at least one occasion was 7% (105 of 1,509) in the rheumatoid arthritis placebo-controlled trials. Approximately one third (3%, 39 of 1,509) of these patients had antibodies with neutralizing activity in vitro.”
Label warnings
Boxed warning: SERIOUS INFECTIONS and MALIGNANCY
- Risk of Serious Infections
- Malignancies
- Heart Failure
- Hypersensitivity Reactions
- Hepatitis B Virus Reactivation
- Neurologic Reactions
- Hematological Reactions
- Use with Biological Disease-Modifying Antirheumatic Drugs (Biological DMARDs)
- Autoimmunity
- Immunizations
- Immunosuppression
InfectionsSecondary malignancyCardiovascularHypersensitivity & infusion reactionsHepatotoxicityNeurotoxicityCytopeniasImmune-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 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
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: Cellular vacuolation, mainly in macrophages, in multiple organs including choroid plexus of the brain (EMA assessment report, p. 14)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
52-week cynomolgus monkey (SC) immunotoxicity study with treatment-free period to Week 78
“Other toxicity Once weekly sc dosing for 52 weeks Cynomolgus monkey 0, 50 and 100 (Immunotoxicity) during Week 52 or 78)”
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.”
DART package
Species: DART
Rat, using rodent surrogate cTN3 PF (no cross-reactivity with rodent TNFα)
“Since certolizumab pegol does not cross-react with mouse or rat TNFα, reproduction studies were performed in rats using a rodent anti-murine TNFα pegylated Fab fragment (cTN3 PF), similar to certolizumab pegol.”
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.”
PPND / ePPND: when
Rat studies (rodent surrogate) covering the full reproductive cycle incl. pre/postnatal development: completed before the marketing application
“In female rat studies covering dosing throughout the complete reproductive cycle, there were no effects on fertility, reproductive function or developmental effects on offspring.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“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.”
Carcinogenicity model
Not conducted: no pharmacological activity and immunogenicity in standard carcinogenicity species
“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.”
Carcinogenicity timing
Not required (accepted by CHMP)
“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.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey single-dose IV NOAEL 400 mg/kg: maximal exposure ~200-fold the plasma level at the maximal recommended human dose (~50 µg/ml)
“The no observed adverse effect level (NOAEL) was 400 mg/kg.. The maximal exposure attained was approximately 200-fold higher than that observed at the maximal recommended human dose (approximately 50 µg/ml)”
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).”
Efficacy evidenceopen answer page →
Efficacy evidence
Human TNFα challenge in normal mice and rabbits; transgenic mouse polyarthritis model (protection at 10 and 30 mg/kg)
“Certolizumab pegol was studied in two in vivo models where normal mice or rabbits were challenged with hTNFα. In these models, certolizumab pegol inhibited hTNFα induced effects. Effective doses ranged from 3-3000 µg/kg. certolizumab pegol also protected against development of arthritis in one transgenic mouse, serving as a disease model for polyarthritis, at 10 and 30 mg/kg”
Why that model
Poor cross-reactivity with rodent and rabbit TNF, so in vivo models used human TNFα as the active molecule
“Certolizumab pegol cross-reacts poorly with TNF from rodents and rabbits, therefore in vivo efficacy was evaluated using animal models in which human TNFα was the physiologically active molecule.”
Reviewer's view of the efficacy data
EMA: low potency on monkey TNFα questions model relevance, but monkey exposures exceeded IC90 and saturated TNFα binding
“These facts may question the relevance of this model to fully identify effects related to inhibition of TNFα. Nevertheless, it is acknowledged that plasma levels in monkeys were above the IC90 for monkey TNFα and the plasma concentrations obtained resulted in saturation of membrane TNFα binding as well as binding of soluble TNFα.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesCriticised but acceptedBeyond the letter
Toxicology in cynomolgus monkey, a species in which certolizumab pegol is far less potent against TNFα than in human
Why: Clinical safety profile adequately established from experience with other anti-TNFα agents · Class precedent · Human data
“Thus, certolizumab pegol was considerably less potent in binding monkey TNFα than human, and the excess of the plasma levels above IC90 for TNFα is 10,000-fold higher in patients than in the monkey studies.”
“Furthermore, the clinical safety profile is considered adequately well established from experience with other anti-TNFα agents, and therefore these limitations are accepted.”
DARTVerdict not stated
Reproductive toxicity tested in rats with the homologous rodent surrogate cTN3 PF instead of certolizumab pegol
Why: Certolizumab pegol does not recognise rodent TNF and is immunogenic in rats · No relevant species
“Reproductive studies with certolizumab pegol have not been undertaken due to the lack of recognition of rodent TNF and immunogenicity in rats. 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.”
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies for a chronic inflammatory indication
Why: Nature of the compound; no pharmacological activity and immunogenicity in species normally used · No relevant species · Low-risk modality
“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.”
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