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.”
Species: general tox
Marmoset monkey (canakinumab); mouse with surrogate mAb 01BSUR
“Toxicity of canakinumab was analysed in marmoset monkeys. Additional toxicity studies were conducted with the murine surrogate mAb 01BSUR in mice.”
Species: DART
Marmoset (male fertility, EFD) and mouse with surrogate mAb (fertility, EFD, pre/postnatal)
“Reproductive toxicity studies in marmosets were limited to evaluation of male fertility (part of the 26 weeks repeat-dose toxicity study) and an embryo-fetal development study.”
Species: carcinogenicity
Not conducted (ICH S6; 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.”
Surrogate used in
Yes: murine surrogate mAb 01BSUR for full reproductive toxicity panel and juvenile study in mice
“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.”
Genotox: Ames
Not conducted (ICH S6)
“No genotoxicity studies were performed with canakinumab, as it is a protein. This is acceptable according to guideline ICH S6.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“No genotoxicity studies were performed with canakinumab, as it is a protein. This is acceptable according to guideline ICH S6.”
Genotox: in vivo
Not conducted (ICH S6)
“No genotoxicity studies were performed with canakinumab, as it is a protein. This is acceptable according to guideline ICH S6.”
Carcinogenicity model
Not conducted; IL-1 neutralization not expected to promote tumour development
“Since pro-inflammatory cytokines such as IL-1 are implicated in tumor development, neutralization of IL-1 is not expected to promote tumour development.”
Carcinogenicity timing
Not required (ICH S6; pharmacodynamics does not warrant studies)
“Also, the pharmacodynamics of canakinumab does not warrant carcinogenicity studies.”
hERG / QT
No stand-alone safety pharmacology; no ECG effects in marmoset toxicology studies
“Stand-alone safety pharmacology studies were not conducted with canakinumab. However, the cardiovascular system was analyzed as part of the toxicology studies. No treatment-related effects on electrocardiography data were observed throughout treatment and recovery periods.”
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
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: 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”
Anti-drug antibodies: animals
No anti-drug antibodies detected in marmoset or mouse surrogate studies; exposure demonstrated in each study
“Regarding toxicokinetics, exposure to canakinumab or 01BSUR was demonstrated in each study. With the analysis method used, no anti-drug antibodies were detected.”
Anti-drug antibodies: patients
ADA in about 1.4% (CAPS), 1.2% (SJIA) and 3.5% (gout flares); neutralizing <1% in gout flares
“Following treatment with ILARIS, antibodies against ILARIS were observed in approximately 1.4%, 1.2%, and 3.5% of the patients with CAPS, SJIA, and gout flares, respectively. Neutralizing antibodies were detected in < 1% of patients with gout flares.”
Label warnings
- Serious Infections
- Immunosuppression
- Hypersensitivity Reactions
- Immunizations
- Macrophage Activation Syndrome
InfectionsHypersensitivity & infusion 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 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
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: 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week IV study (twice weekly) with 6-week recovery
“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. 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.”
DART package
Species: DART
Marmoset (male fertility, EFD) and mouse with surrogate mAb (fertility, EFD, pre/postnatal)
“Reproductive toxicity studies in marmosets were limited to evaluation of male fertility (part of the 26 weeks repeat-dose toxicity study) and an embryo-fetal development study.”
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.”
PPND / ePPND: when
PPND in mouse with surrogate antibody 01BSUR (gestation and lactation): completed before the marketing application; no maternal toxicity
“In the pre-/post-natal development study, mice were exposed to 01BSUR throughout gestation and lactation. Such treatment resulted in no evidence of maternal toxicity.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S6; 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.”
Carcinogenicity model
Not conducted; IL-1 neutralization not expected to promote tumour development
“Since pro-inflammatory cytokines such as IL-1 are implicated in tumor development, neutralization of IL-1 is not expected to promote tumour development.”
Carcinogenicity timing
Not required (ICH S6; pharmacodynamics does not warrant studies)
“Also, the pharmacodynamics of canakinumab does not warrant carcinogenicity studies.”
Safety marginopen answer page →
Safety margin at NOAEL
Marmoset EFD doses ~11x human AUC at MRHD and greater; no embryotoxicity or malformations
“In an embryo-fetal development study, pregnant marmoset monkeys received canakinumab from gestation days 25 to 109 at doses that produced exposures approximately 11 times that achieved with MRHD and greater (on a plasma area under the curve [AUC] basis with maternal subcutaneous doses of 15, 50, or 150 mg/kg twice weekly).”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Canakinumab inhibited human IL-1β-induced mouse joint inflammation, rat fever and mouse air-pouch neutrophil infiltration
“Since canakinumab does not react with rodent IL-1β, the in vivo activity of canakinumab was demonstrated in models of inflammation induced by human IL-1β in rodents (i.e. mouse joint inflammation, rat fever, neutrophil infiltration into mouse air pouch).”
Why that model
No cross-reactivity with rodent IL-1β, so classical animal disease models not possible
“Due to the lack of crossreactivity to IL-1β from rodent species, the in vivo activity of Canakinumab could not be demonstrated in classical animal disease models.”
Reviewer's view of the efficacy data
EMA: pharmacology adequately characterized; inhibition of IL-1 effects in vitro and in vivo supports CAPS development
“Overall, the pharmacological studies have adequately characterized the profile of the product.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesVerdict not stated
Marmoset is the only cross-reactive species (no binding to mouse, rat, rabbit or cynomolgus IL-1β), so canakinumab toxicology was run in marmoset
Why: Marmoset is the only nonhuman species recognized by canakinumab · No relevant 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.”
DARTVerdict not stated
Marmoset reproductive testing limited to male fertility and EFD; full reproductive panel run with the mouse surrogate antibody
Why: Late placental IgG transfer meant little fetal exposure during organogenesis in marmoset, so surrogate studies were added · Pharmacology or kinetics
“However, given that transfer of IgG across the placenta starts late during gestation, it is unlikely that the fetus was exposed to canakinumab during the period of organogenesis. In addition a full panel of reproductive toxicity studies was performed with the surrogate mAb 01BSUR in mice.”
Juvenile toxAccepted with a conditionBeyond the letter
Juvenile surrogate study lacked immune function testing; juvenile immunotoxicity study committed
Why: To exclude effects of IL-1β neutralization on the developing immune system
“To exclude possible effects of neutralization of IL-1β on the developing immune system, the applicant committed to perform a juvenile immunotoxicity study, assessing the effect of the canakinumab surrogate on immune function in juvenile animals.”
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