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.”
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.”
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 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 (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.”