Ilaris
canakinumab
Species
MonkeyMouse
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
Marmoset monkey only (plus mouse with surrogate antibody)
“Toxicity of canakinumab was analysed in marmoset monkeys. Additional toxicity studies were conducted with the murine surrogate mAb 01BSUR in mice.”
Why that species
No binding to mouse, rat, rabbit or cynomolgus IL-1β; marmoset is the only cross-reactive non-human species
“Canakinumab does not bind to IL-1β from mouse, rat, rabbit, or cynomolgus monkey. The only nonhuman species specifically recognized by canakinumab is the marmoset monkey.”
Surrogate molecule
Yes: mouse surrogate antibody 01BSUR, used for mouse fertility, embryo-fetal and pre/postnatal reproductive toxicity studies
“In addition a full panel of reproductive toxicity studies was performed with the surrogate mAb 01BSUR in mice.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“In the second study 26 weeks of treatment were followed by 6 weeks of recovery.”
Pivotal GLP studies
Marmoset IV twice-weekly studies at 0, 10, 30, 100 mg/kg: 4-week and 26-week
“In two IV repeat-dose studies canakinumab was given twice a week at doses of 0, 10, 30 and 100 mg/kg. In the first study, a 4-week treatment period was followed by 8 weeks of recovery.”
Route in tox
Intravenous and subcutaneous
“The local tolerance to canakinumab at the SC and IV injection sites were assessed in the course of the repeat-dose toxicity studies in marmoset.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (protein; ICH S6)
“No genotoxicity studies were performed with canakinumab, as it is a protein. This is acceptable according to guideline ICH S6.”
Carcinogenicity
Not conducted (ICH S6); generally not required for monoclonal antibodies
“No carcinogenicity studies were performed with canakinumab. According to guideline ICH S6 carcinogenicity studies are generally not required for monoclonal antibodies.”
Reproductive & developmental
Marmoset and mouse surrogate reproductive toxicity studies identified no signal for reproductive toxicity from IL-1β neutralization
“Taken together the reproductive toxicity studies in marmosets and in mice did not identify a signal for reproductive toxicity by neutralization of IL-1b.”
Safety pharmacology
No stand-alone studies; cardiovascular system assessed within toxicology studies
“Stand-alone safety pharmacology studies were not conducted with canakinumab. However, the cardiovascular system was analyzed as part of the toxicology 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 Ilaris 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: NOEL/NOAEL at highest dose (100 mg/kg IV or 150 mg/kg SC); no general or reproductive toxicity signals (EMA assessment report, p. 15)
NOAEL / key findings
NOEL/NOAEL at highest dose (100 mg/kg IV or 150 mg/kg SC); no general or reproductive toxicity signals
“In all the studies, NOEL or NOAEL was the highest dose administered (100 mg/kg/dose IV or 150 mg/kg/dose SC). No signals were identified for general toxicity and for reproductive toxicity.”
Risksopen answer page →
Immune & cytokine safety
No anti-drug antibodies detected in marmoset or mouse surrogate toxicity studies
“Regarding toxicokinetics, exposure to canakinumab or 01BSUR was demonstrated in each study. With the analysis method used, no anti-drug antibodies were detected.”
Biodistribution & persistence
Small volume of distribution, low clearance; half-life 4-7 days in marmosets vs 17.4 days rhesus, 14.5 days mice
“Of note, with 4-7 days the elimination half-life of canakinumab in marmosets was shorter than in rhesus monkeys (17.4 days), mice (14.5 days) and humans (26 days).”
Modality-specific risk
Immunosuppression/infection risk from IL-1 blockade, including in utero exposed infants
“Because IL-1 blockade may interfere with immune response to infections, risks and benefits should be considered prior to administering live vaccines to infants who were exposed to ILARIS in utero”