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.”
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).”
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 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: 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.”