Skyrizi
risankizumab
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
“The cynomolgus monkey was the only relevant species due to insufficient cross-reactivity of risankizumab to IL-23 from rodents.”
Why that species
High affinity for cynomolgus IL-23 (Kd below 1 pM); weak mouse IL-23 binding (Kd 15 nM)
“Binding of risankizumab to Cynomolgus monkey IL-23 was also high, with a dissociation constant (Kd) of less than 1 pM. Risankizumab bound to mouse IL-23 with a Kd of 15 nM.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys
“The Cynomologus monkey was identified as the pharmacologically relevant species and used in toxicology studies.”
Species: general tox
Cynomolgus monkey only
“The cynomolgus monkey was the only relevant species due to insufficient cross-reactivity of risankizumab to IL-23 from rodents.”
Species: DART
Cynomolgus monkey (ePPND; male fertility in 26-week sexually mature male study)
“The effects of risankizumab on embryo-foetal as well as on pre- and postnatal development were evaluated in an enhanced pre- and postnatal development (ePPND) toxicity study in cynomolgus monkeys.”
Species: carcinogenicity
Not conducted; rodents not pharmacologically relevant (weight-of-evidence assessment)
“Conventional rodent carcinogenicity studies were not conducted for the evaluation of the carcinogenic potential of risankizumab, as rodents are not a pharmacologically relevant species.”
Surrogate used in
No surrogate used; clinical antibody tested in cynomolgus monkeys
“The Cynomologus monkey was identified as the pharmacologically relevant species and used in toxicology studies.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“BI 655066: A 26-Week subcutaneous toxicity and toxicokinetics study in Cynomolgus monkeys with an 8-week recovery period”
Pivotal GLP studies
Cynomolgus monkey: 4-week IV (up to 50 mg/kg/week) or SC (20 mg/kg/week); 26-week SC up to 50 mg/kg/week
“Repeat dose toxicity of risankizumab was evaluated in a four-week study after IV administration of up to 50 mg/kg/week and at 20 mg/kg/week after SC administration, and in a 26 week chronic study with subcutaneous doses of up to 50 mg/kg/week.”
Route in tox
SC and IV
“Repeat dose toxicity of risankizumab was evaluated in a four-week study after IV administration of up to 50 mg/kg/week and at 20 mg/kg/week after SC administration”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“Genetic toxicology studies were not needed to support the development and approval of risankizumab, per the ICH S6(R1) guidance.”
Carcinogenicity
Not conducted; malignancy risk from long-term IL-23 inhibition considered low
“Overall the risk for malignancy associated with long-term inhibition of IL-23 following administration of risankizumab to humans is considered to be low.”
Reproductive & developmental
Monkey ePPND: dose-dependent fetal/infant loss (19%, 32%, 43% in control, 5 and 50 mg/kg groups)
“However, as compared to the control group, a dose-dependent increase in fetal/infant loss was noted in the risankizumab-treated groups. The percent fetal/infant loss was 19%, 32%, and 43% in the vehicle control, 5 mg/kg, and 50 mg/kg groups, respectively.”
Safety pharmacology
Assessed in 4-week IV monkey study; no neurological or cardiovascular effects up to 50 mg/kg/week
“Intravenous treatment with doses up to 50 mg/kg/week risankizumab for 4 weeks did not cause treatment-related effects on neurological or cardiovascular functions in Cynomolgus monkeys.”
Genotox: Ames
Not conducted (ICH S6)
“Therefore, genotoxicity testing was not carried out in line with ICH S6(R1) and this is acceptable.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Therefore, genotoxicity testing was not carried out in line with ICH S6(R1) and this is acceptable.”
Genotox: in vivo
Not conducted (ICH S6)
“Therefore, genotoxicity testing was not carried out in line with ICH S6(R1) and this is acceptable.”
Carcinogenicity model
Not conducted; weight-of-evidence assessment because rodents are not pharmacologically relevant
“Conventional rodent carcinogenicity studies were not conducted for the evaluation of the carcinogenic potential of risankizumab, as rodents are not a pharmacologically relevant species.”
Carcinogenicity timing
Not required; CDER ECAC concurred a 2-year rodent study is not needed
“Concurrence has been received from the Executive Carcinogenicity Assessment Committee of CDER that a 2-year rodent carcinogenicity study is not needed.”
hERG / QT
No hERG assay; no neurological or cardiovascular effects in 4-week IV monkey study up to 50 mg/kg/week
“Intravenous treatment with doses up to 50 mg/kg/week risankizumab for 4 weeks did not cause treatment-related effects on neurological or cardiovascular functions in Cynomolgus monkeys.”
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 Skyrizi 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 (highest dose), about 70-fold exposure margin; no toxicologically significant findings (EMA assessment report, p. 24)
NOAEL / key findings
NOAEL 50 mg/kg/week (highest dose), about 70-fold exposure margin; no toxicologically significant findings
“The NOAEL was 50 mg/kg/week, the highest dose tested, with exposure levels that were significantly above the recommended clinical dose in psoriasis patients (150 mg SC on Weeks 0 and 4, then every 12 weeks), providing a margin of exposure of approximately 70.”
Risksopen answer page →
Immune & cytokine safety
No immunosuppression (TDAR) or T-cell depletion in monkey toxicity studies
“The immune function tests in the monkey toxicity studies showed that risankizumab did not cause immunosuppression [(as assessed by T-dependent antibody response (TDAR)] or deplete T-cells.”
Biodistribution & persistence
Crosses placenta: infant serum exposure 25% and 17% of maternal on birth day 14 (5 and 50 mg/kg/week)
“The mean infant serum exposures were 25% and 17% of the mean maternal serum exposures on Birth Day (BD) 14 in the 5 and 50 mg/kg/week treatment groups, identifying the ability of risankizumab to cross the placenta.”
Modality-specific risk
Embryo-fetal risk: treatment-related fetal/infant loss at 50 mg/kg/week in monkey ePPND
“Therefore, the increased fetal/infant loss in the 50 mg/kg/week group was considered to be related to risankizumab treatment.”
Anti-drug antibodies: animals
26-week study: ADA in one of eight (5 mg/kg/week) and six of twelve (50 mg/kg/week) monkeys; exposure unaffected, no ADA-related safety events
“ADA positive results were observed in one of eight and six of twelve animals in the 5 and 50 mg/kg/week groups, respectively. Serum risankizumab concentrations were unaffected by ADAs and no ADA-dependent safety events were observed.”
Anti-drug antibodies: patients
Psoriasis: ~24% ADA by Week 52; ~57% of these neutralizing (14% of all subjects)
“By Week 52, approximately 24% (263/1079) of adults treated with SKYRIZI at the recommended dosage developed antibodies to risankizumab-rzaa. Of the subjects who developed antibodies to risankizumab-rzaa, approximately 57% (14% of all subjects treated with SKYRIZI) had antibodies that were classified as neutralizing.”
Label warnings
- Hypersensitivity Reactions
- 2 Infections
- 3 Tuberculosis
- 4 Hepatotoxicity
- Immunizations
Hypersensitivity & infusion reactionsInfectionsHepatotoxicity
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 Skyrizi 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 (highest dose), about 70-fold exposure margin; no toxicologically significant findings (EMA assessment report, p. 24)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week SC cynomolgus monkey study with 8-week recovery
“Repeat dose toxicity of risankizumab was evaluated in a four-week study after IV administration of up to 50 mg/kg/week and at 20 mg/kg/week after SC administration, and in a 26 week chronic study with subcutaneous doses of up to 50 mg/kg/week. Reversibility of effects after an 8-week recovery period was tested in both studies in the control and high-dose groups.”
Pivotal GLP studies
Cynomolgus monkey: 4-week IV (up to 50 mg/kg/week) or SC (20 mg/kg/week); 26-week SC up to 50 mg/kg/week
“Repeat dose toxicity of risankizumab was evaluated in a four-week study after IV administration of up to 50 mg/kg/week and at 20 mg/kg/week after SC administration, and in a 26 week chronic study with subcutaneous doses of up to 50 mg/kg/week.”
DART package
Species: DART
Cynomolgus monkey (ePPND; male fertility in 26-week sexually mature male study)
“The effects of risankizumab on embryo-foetal as well as on pre- and postnatal development were evaluated in an enhanced pre- and postnatal development (ePPND) toxicity study in cynomolgus monkeys.”
Reproductive & developmental
Monkey ePPND: dose-dependent fetal/infant loss (19%, 32%, 43% in control, 5 and 50 mg/kg groups)
“However, as compared to the control group, a dose-dependent increase in fetal/infant loss was noted in the risankizumab-treated groups. The percent fetal/infant loss was 19%, 32%, and 43% in the vehicle control, 5 mg/kg, and 50 mg/kg groups, respectively.”
PPND / ePPND: when
ePPND in cynomolgus monkey: completed before the marketing application
“The effects of risankizumab on embryo-foetal as well as on pre- and postnatal development were evaluated in an enhanced pre- and postnatal development (ePPND) toxicity study in cynomolgus monkeys.”
Carcinogenicity
Species: carcinogenicity
Not conducted; rodents not pharmacologically relevant (weight-of-evidence assessment)
“Conventional rodent carcinogenicity studies were not conducted for the evaluation of the carcinogenic potential of risankizumab, as rodents are not a pharmacologically relevant species.”
Carcinogenicity model
Not conducted; weight-of-evidence assessment because rodents are not pharmacologically relevant
“Conventional rodent carcinogenicity studies were not conducted for the evaluation of the carcinogenic potential of risankizumab, as rodents are not a pharmacologically relevant species.”
Carcinogenicity timing
Not required; CDER ECAC concurred a 2-year rodent study is not needed
“Concurrence has been received from the Executive Carcinogenicity Assessment Committee of CDER that a 2-year rodent carcinogenicity study is not needed.”
Safety marginopen answer page →
Safety margin at NOAEL
26-week monkey NOAEL 50 mg/kg/week: exposure 69-fold highest human exposure (AUC0-168hr)
“The NOAEL in this study was the highest dose tested (50 mg/kg/week) with an exposure level at Week 26 being 69-fold greater than the highest exposure in human subjects (a mean corresponding AUC0–168hr of 86 mg•hr/mL)”
NOAEL / key findings
NOAEL 50 mg/kg/week (highest dose), about 70-fold exposure margin; no toxicologically significant findings
“The NOAEL was 50 mg/kg/week, the highest dose tested, with exposure levels that were significantly above the recommended clinical dose in psoriasis patients (150 mg SC on Weeks 0 and 4, then every 12 weeks), providing a margin of exposure of approximately 70.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human IL-23-induced mouse ear thickening (skin inflammation) model; in vitro IL-23 signalling and IL-17 inhibition
“In an in vivo mouse ear thickening model, risankizumab inhibits human IL-23-induced ear thickening as well as the induction of tissue IL-17 and IL-22.”
Why that model
Inhibits human and monkey IL-23 but not mouse or rat IL-23
“Risankizumab inhibits cynomolgus monkey and human IL-23 functions, but not mouse or rat.”
Reviewer's view of the efficacy data
CHMP: nonclinical pharmacology adequately characterised
“The non-clinical pharmacological properties of risankizumab have been adequately characterised.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity study for chronic inflammatory indications; weight-of-evidence assessment with ECAC concurrence
Why: Rodents not pharmacologically relevant; low malignancy risk by weight of evidence; labeling and postmarketing malignancy monitoring · No relevant species · Weight of evidence
“A carcinogenicity study with long-term antagonism of IL23p19 in rodents will not be informative because rodents are not a pharmacologically relevant species. Concurrence has been received from the Executive Carcinogenicity Assessment Committee of CDER that a 2-year rodent carcinogenicity study is not needed.”
“Therefore, no additional nonclinical studies are recommended to evaluate the carcinogenic potential of risankizumab. Adequate labeling based on animal data from the sponsor and from literature as well as post-marketing patient monitoring of malignancy will be sufficient at this time.”
Juvenile toxAcceptedBeyond the letter
No dedicated juvenile toxicity study; infants in the monkey ePPND study followed for six months instead
Why: No risankizumab-related effects in infant monkeys up to six months of age in the ePPND study · Weight of evidence
“In the ePPND study infants were observed for six months post-partum, no dedicated juvenile toxicology studies were carried out and this is acceptable.”
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