Cosentyx
secukinumab
Species
Monkey
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
Cynomolgus monkey only
“Secukinumab crossreacts with cynomolgus, rhesus and marmoset monkey IL-17A, but not with rodent IL-17A, making the cynomolgus monkey the most appropriate nonclinical species.”
Why that species
Cross-reacts with cynomolgus, rhesus and marmoset IL-17A but not rodent IL-17A
“Secukinumab crossreacts with cynomolgus, rhesus and marmoset monkey IL-17A, but not with rodent IL-17A, making the cynomolgus monkey the most appropriate nonclinical species.”
Surrogate molecule
Yes: murine anti-mouse IL-17A antibody BZN035, used for mouse fertility/early embryonic and peri-/postnatal development studies
“A murine surrogate antibody against mouse IL-17A (BZN035) was developed and used for fertility and early embryonic development and peri- and postnatal development studies in mice.”
Species: general tox
Cynomolgus monkey only
“Secukinumab crossreacts with cynomolgus, rhesus and marmoset monkey IL-17A, but not with rodent IL-17A, making the cynomolgus monkey the most appropriate nonclinical species.”
Species: DART
Cynomolgus monkey (EFD, secukinumab); mouse (fertility/early embryonic and pre/postnatal, surrogate BZN035)
“Single-dose and repeat-dose toxicity and embryofetal development studies have been conducted with the cynomolgus monkey. A murine surrogate antibody against mouse IL-17A (BZN035) was developed and used for fertility and early embryonic development and peri- and postnatal development studies in mice.”
Species: carcinogenicity
Not conducted
“No genetic toxicity or carcinogenicity studies have been conducted with secukinumab.”
Surrogate used in
Yes: mouse surrogate anti-mouse IL-17A antibody (BZN035) for fertility/early embryonic and pre/postnatal development studies
“A murine surrogate antibody against mouse IL-17A (BZN035) was developed and used for fertility and early embryonic development and peri- and postnatal development studies in mice.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“In the pivotal cynomolgus monkey study, AIN457 derived from CHO cells was administered intravenously (15, 50, 150 mg/kg/week; 4/sex/group) for 26 weeks followed by a 13-week recovery period”
Pivotal GLP studies
Cynomolgus 26-week IV study (15, 50, 150 mg/kg/week) followed by 13-week recovery
“In the pivotal cynomolgus monkey study, AIN457 derived from CHO cells was administered intravenously (15, 50, 150 mg/kg/week; 4/sex/group) for 26 weeks followed by a 13-week recovery period”
Route in tox
Intravenous and subcutaneous
“In a 13-week toxicology study (study # 0770712-01), AIN457 derived from CHO cells was administered by the subcutaneous route to cynomolgus monkeys at 15, 50, and 150 mg/kg/week”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“Based on the ICH Guideline for the Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (ICH S6(R1) 2011), genotoxicity studies have not been conducted for secukinumab which is acceptable to CHMP.”
Carcinogenicity
Not conducted (species-specific binding precludes rodent study); malignancy monitored clinically via risk management plan
“Since secukinumab cannot be tested in a traditional 2-year rodent study to evaluate carcinogenic potential due to its species specific binding, the sponsor will monitor malignancy in psoriasis patients administered secukinumab as a part of a comprehensive Risk Management Plan.”
Reproductive & developmental
Monkey EFD: maternal NOAEL 150 mg/kg/week; fetal NOAEL 50 mg/kg/week (dose-related tail vertebra misalignment)
“Therefore, the NOAEL for maternal toxicity was determined to be 150 mg/kg/week but for fetal toxicity the NOAEL was 50 mg/kg/week.”
Safety pharmacology
Stand-alone monkey safety pharmacology study: no significant CNS, respiratory or cardiovascular effects up to 100 mg/kg IV (NOAEL)
“A safety Pharmacology study conducted in cynomolgus monkeys revealed no significant adverse treatment related effects on CNS, respiratory and cardiovascular functions after i.v. administration of secukinumab up to 100 mg/kg dose (NOAEL = 100 mg/kg).”
Genotox: Ames
Not conducted (ICH S6)
“Based on the ICH Guideline for the Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (ICH S6(R1) 2011), genotoxicity studies have not been conducted for secukinumab which is acceptable to CHMP.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Based on the ICH Guideline for the Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (ICH S6(R1) 2011), genotoxicity studies have not been conducted for secukinumab which is acceptable to CHMP.”
Genotox: in vivo
Not conducted (ICH S6)
“Based on the ICH Guideline for the Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (ICH S6(R1) 2011), genotoxicity studies have not been conducted for secukinumab which is acceptable to CHMP.”
Carcinogenicity model
Not conducted: species-specific binding precludes a 2-year rodent study; malignancy monitored clinically under the Risk Management Plan
“Since secukinumab cannot be tested in a traditional 2-year rodent study to evaluate carcinogenic potential due to its species specific binding, the sponsor will monitor malignancy in psoriasis patients administered secukinumab as a part of a comprehensive Risk Management Plan.”
Carcinogenicity timing
Not required; no nonclinical carcinogenicity studies recommended
“No nonclinical studies to address the carcinogenic potential of secukinumab are recommended.”
hERG / QT
No hERG assay; monkey safety pharmacology showed no relevant ECG or QTc effects
“There were no biologically relevant secukinumab related effects noted on heart’s electrical cycle; activation of the right and left ventricles and heart rate corrected QT (QTc) intervals on the electrocardiograms.”
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 Cosentyx 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 50 mg/kg/week in monkey repeat-dose studies, based on clinical chemistry effects and immunotoxicity (lymphocyte, B- and T-cell decreases) at high dose (FDA pharmacology/toxicology review, p. 7)
NOAEL / key findings
NOAEL 50 mg/kg/week in monkey repeat-dose studies, based on clinical chemistry effects and immunotoxicity (lymphocyte, B- and T-cell decreases) at high dose
“Due to clinical chemistry effects and immunotoxicity (decreases in total lymphocytes, B cells and T cells) observed at the high dose, the NOAEL appears to be 50 mg/kg/week.”
Risksopen answer page →
Immune & cytokine safety
Immunotoxicity in one high-dose female: skin lesions, splenic lymphocytic atrophy, decreased NK cell activity and TDAR
“Immunotoxicity was observed in one high-dose female (#451) that developed skin lesions (treated with antibiotics), splenic lymphocytic atrophy, decreased NK cell activity, and decreased T-cell dependent antigen response (TDAR; see below).”
Biodistribution & persistence
Placental transfer in cynomolgus and marmoset monkeys; fetal exposure about 2% of maternal serum concentration
“Serum analysis revealed that that secukinumab is transferred across the placenta during the pregnancy in cynomolgus monkeys and in marmosets, and that the fetuses are exposed to secukinumab at the level corresponding approximately 2% of the mean maternal serum concentration.”
Modality-specific risk
Increased infection susceptibility from neutralizing IL-17A, a mediator of innate and adaptive immunity
“Secukinumab therapy is designed to neutralize critical mediators of innate and adaptive immunity. Thus it may carry the risk of an increased susceptibility to infection.”
Anti-drug antibodies: animals
ADA in one monkey in the 13-week study; assay interference from high drug levels means ADA cannot be excluded
“Immunogenicity was observed in one animal in the 13 week repeat dose toxicity study. However, due to assay interference caused by high serum concentrations of secukinumab, occurrence of anti-secukinumab antibodies cannot be excluded.”
Anti-drug antibodies: patients
Less than 1% (25 of 6268) developed ADA; about 8% of those were neutralizing
“anti-secukinumab antibodies (referred as ADA) formation was less than 1% (25 of 6268 total of subjects treated with COSENTYX). Of the subjects treated with COSENTYX who developed ADA, approximately 8% developed neutralizing antibodies.”
Label warnings
- Infections
- Hypersensitivity Reactions
- Pre-Treatment Evaluation for Tuberculosis
- Inflammatory Bowel Disease
- Eczematous Eruptions
- Risk of Hypersensitivity in Latex-Sensitive Individuals
- Immunizations
InfectionsHypersensitivity & infusion reactionsGastrointestinalSkin reactions
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 Cosentyx 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 50 mg/kg/week in monkey repeat-dose studies, based on clinical chemistry effects and immunotoxicity (lymphocyte, B- and T-cell decreases) at high dose (FDA pharmacology/toxicology review, p. 7)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week IV cynomolgus monkey study with 13-week recovery
“AIN457 derived from CHO cells was administered intravenously (15, 50, 150 mg/kg/week; 4/sex/group) for 26 weeks followed by a 13-week recovery period (2/sex for control and high dose group only; study # 502618; IND 100418, entered in DARRTS 2-4-2010).”
Pivotal GLP studies
Cynomolgus 26-week IV study (15, 50, 150 mg/kg/week) followed by 13-week recovery
“In the pivotal cynomolgus monkey study, AIN457 derived from CHO cells was administered intravenously (15, 50, 150 mg/kg/week; 4/sex/group) for 26 weeks followed by a 13-week recovery period”
DART package
Species: DART
Cynomolgus monkey (EFD, secukinumab); mouse (fertility/early embryonic and pre/postnatal, surrogate BZN035)
“Single-dose and repeat-dose toxicity and embryofetal development studies have been conducted with the cynomolgus monkey. A murine surrogate antibody against mouse IL-17A (BZN035) was developed and used for fertility and early embryonic development and peri- and postnatal development studies in mice.”
Reproductive & developmental
Monkey EFD: maternal NOAEL 150 mg/kg/week; fetal NOAEL 50 mg/kg/week (dose-related tail vertebra misalignment)
“Therefore, the NOAEL for maternal toxicity was determined to be 150 mg/kg/week but for fetal toxicity the NOAEL was 50 mg/kg/week.”
PPND / ePPND: when
PPND in mouse with surrogate anti-IL-17A antibody BZN035, completed before the marketing application
“The sponsor has generated a mouse IgG1/k monoclonal antibody (BZN035) with appropriate neutralizing activity and specificity for mouse IL-17A for use as a murine surrogate for AIN457. It has been tested in the fertility and early embryonic development (Section 9.1) and prenatal and postnatal development (Section 9.3) studies summarized below.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No genetic toxicity or carcinogenicity studies have been conducted with secukinumab.”
Carcinogenicity model
Not conducted: species-specific binding precludes a 2-year rodent study; malignancy monitored clinically under the Risk Management Plan
“Since secukinumab cannot be tested in a traditional 2-year rodent study to evaluate carcinogenic potential due to its species specific binding, the sponsor will monitor malignancy in psoriasis patients administered secukinumab as a part of a comprehensive Risk Management Plan.”
Carcinogenicity timing
Not required; no nonclinical carcinogenicity studies recommended
“No nonclinical studies to address the carcinogenic potential of secukinumab are recommended.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey exposure 48-108-fold human AUC (53-100-fold Cmax) at doses giving maximal IL-17A neutralization
“Exposure multiples for safety in humans at dose levels that produce maximal neutralising effect of IL-17A were significant; for the AUC 48-108 fold and for the Cmax 53-100 fold.”
NOAEL / key findings
NOAEL 50 mg/kg/week in monkey repeat-dose studies, based on clinical chemistry effects and immunotoxicity (lymphocyte, B- and T-cell decreases) at high dose
“Due to clinical chemistry effects and immunotoxicity (decreases in total lymphocytes, B cells and T cells) observed at the high dose, the NOAEL appears to be 50 mg/kg/week.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse knee-joint inflammation and air pouch models driven by locally produced human IL-17A; no psoriasis-like disease model
“Functionally in vivo, secukinumab inhibited IL-17A induced inflammatory reactions in two mouse models, the knee joint inflammatory model and the air pouch model where human IL-17A was produced locally.”
Why that model
Secukinumab does not recognize mouse or rat IL-17A, so a mouse surrogate antibody (BZN035) was developed
“Secukinumab does not recognize mouse and rat IL-17A, and therefore mouse surrogate antibody BZN035 was developed.”
Reviewer's view of the efficacy data
EMA: package adequately shows target specificity and mode of action (neutralizing IL-17A-related cellular events)
“A comprehensive non-clinical data package was submitted which adequately provides evidence on target specificity and mode of action i.e. neutralising the IL-17A related cellular events.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity study for chronic psoriasis use; literature-based weight-of-evidence assessment plus clinical malignancy monitoring
Why: Species-specific binding precludes a rodent study; literature indicates no increased carcinogenic potential from IL-17A inhibition · No relevant species · Weight of evidence
“Since secukinumab cannot be tested in a traditional 2-year rodent study to evaluate carcinogenic potential due to its species specific binding, the sponsor will monitor malignancy in psoriasis patients administered secukinumab as a part of a comprehensive Risk Management Plan.”
“The literature results were not definitive but the majority of the literature references indicate no increased carcinogenic potential after inhibition of IL-17A. In addition, no preneoplastic lesions were noted during the 26-week repeat-dose toxicity study in monkeys.”
DARTVerdict not stated
Fertility and pre-/postnatal development studies in mice used a murine surrogate anti-IL-17A antibody (BZN035)
Why: Surrogate has appropriate neutralizing activity and specificity for mouse IL-17A
“The sponsor has generated a mouse IgG1/k monoclonal antibody (BZN035) with appropriate neutralizing activity and specificity for mouse IL-17A for use as a murine surrogate for AIN457.”
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