Risankizumab is a humanised immunoglobulin G1 (IgG1) monoclonal antibody that selectively binds with high affinity to the p19 subunit of human interleukin 23 (IL-23) cytokine without binding to IL-12 and inhibits its interaction with the IL-23 receptor complex. IL-23 is a cytokine that is involved in inflammatory and immune responses. By blocking IL-23 from binding to its receptor, risankizumab inhibits IL-23-dependent cell signalling and release of proinflammatory cytokines.
In a study of subjects with psoriasis, expression of genes associated with the IL-23/IL-17 axis was decreased in the skin after single doses of risankizumab. Reductions in epidermal thickness, infiltration of inflammatory cells, and expression of psoriatic disease markers were also observed in psoriatic lesions.
In a study of subjects with psoriatic arthritis, statistically significant and clinically meaningful reduction from baseline was observed at week 24 in IL-23 and IL-17-associated biomarkers, including serum IL-17A, IL-17F, and IL-22 following treatment with risankizumab 150 mg subcutaneously at week 0, week 4, and every 12 weeks thereafter.
In a Phase 2 study of subjects with Crohn’s disease, expression of genes associated with the IL-23/Th17 axis were decreased in gut tissue after multiple doses of risankizumab. Reductions in faecal calprotectin (FCP), serum C reactive protein (CRP) and IL-22 were also observed after multiple doses in Phase 3 induction studies in Crohn’s patients. Decreases in FCP, CRP and serum IL-22 were maintained out to week 52 of the maintenance study.
In a Phase 2b/3 study of subjects with ulcerative colitis, statistically significant and clinically meaningful reduction from baseline was observed in the inflammatory biomarkers, FCP and CRP, and in the IL-23 pathway-associated biomarker, serum IL-22, at week 12 of the induction study. Decreases in FCP, CRP and serum IL-22 were maintained out to week 52 of the maintenance study.
The pharmacokinetics of risankizumab was similar between plaque psoriasis and psoriatic arthritis, and between Crohn’s disease and ulcerative colitis.
Risankizumab exhibited linear pharmacokinetics with dose-proportional increase in exposure across dose ranges of 18 to 360 mg and 0.25 to 1 mg/kg administered subcutaneously, and 200 to 1 800 mg and 0.01 to 5 mg/kg administered intravenously.
Following subcutaneous dosing of risankizumab, peak plasma concentrations were achieved between 3-14 days after dosing with an estimated absolute bioavailability of 74-89%. With dosing of 150 mg at week 0, week 4 and every 12 weeks thereafter, estimated steady-state peak and trough plasma concentrations are 12 and 2 μg/mL, respectively.
Bioequivalence was demonstrated between a single risankizumab 150 mg injection and two risankizumab 75 mg injections in pre-filled syringe. Bioequivalence was also demonstrated between risankizumab 150 mg pre-filled syringe and pre-filled pen.
In subjects with Crohn’s disease treated with 600 mg intravenous induction dose at weeks 0, 4, and 8 followed by 360 mg subcutaneous maintenance dose at week 12 and every 8 weeks thereafter, maximum median peak and trough concentrations are estimated to be 156 and 38.8 μg/mL respectively during the induction period (weeks 8-12) and steady-state median peak and trough concentrations are estimated to be 28.0 and 8.13 μg/mL respectively during the maintenance period (weeks 40-48).
In subjects with ulcerative colitis treated with 1 200 mg intravenous induction dose at weeks 0, 4, and 8 followed by 180 mg or 360 mg subcutaneous maintenance dose at week 12 and every 8 week thereafter, maximum median peak and trough concentrations are estimated to be 350 and 87.7 μg/mL respectively during the induction period (weeks 8-12) and steady-state median peak and trough concentrations are estimated to be 19.6 and 4.64 μg/mL for the 180 mg subcutaneous dose and 39.2 and 9.29 μg/mL for the 360 mg subcutaneous dose, respectively, during the maintenance period (weeks 40-48).
The mean (±standard deviation) steady-state volume of distribution (Vss) of risankizumab was 11.4 (±2.7) L in Phase 3 studies in subjects with psoriasis, indicating that the distribution of risankizumab is primarily confined to the vascular and interstitial spaces. In a typical 70 kg subject with Crohn’s disease, Vss was 7.68 L.
Therapeutic IgG monoclonal antibodies are typically degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgGs. Risankizumab is not expected to be metabolised by cytochrome P450 enzymes.
The mean (±standard deviation) systemic clearance (CL) of risankizumab was 0.3 (±0.1) L/day in Phase 3 studies in subjects with psoriasis. The mean terminal elimination half-life of risankizumab ranged from 28 to 29 days in Phase 3 studies in subjects with psoriasis. For a typical 70 kg subject with Crohn’s disease, CL was 0.30 L/day and terminal elimination half-life was 21 days.
As an IgG1 monoclonal antibody, risankizumab is not expected to be filtered by glomerular filtration in the kidneys or to be excreted as an intact molecule in the urine.
Risankizumab exhibited linear pharmacokinetics with approximately dose-proportional increases in systemic exposure (Cmax and AUC) in the evaluated dose ranges of 18 to 360 mg or 0.25 to 1 mg/kg subcutaneous administration and 200 to 1 800 mg and 0.01 to 5 mg/kg administered intravenously in healthy subjects or subjects with psoriasis, Crohn’s disease or ulcerative colitis.
An interaction study was conducted in subjects with plaque psoriasis to assess the effect of repeated administration of risankizumab on the pharmacokinetics of cytochrome P450 (CYP) sensitive probe substrates. The exposure of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), metoprolol (CYP2D6 substrate) and midazolam (CYP3A substrate) following risankizumab treatment were comparable to their exposures prior to risankizumab treatment, indicating no clinically meaningful interactions through these enzymes.
Population pharmacokinetic analyses indicated that risankizumab exposure was not impacted by concomitant medicinal products used by some subjects with plaque psoriasis during the clinical studies. Similar lack of impact by concomitant medicinal products was observed based on population pharmacokinetic analyses in Crohn’s disease or ulcerative colitis.
The pharmacokinetics of risankizumab in paediatric subjects under 16 years of age has not been established. Of the 1 574 subjects with Crohn’s disease exposed to risankizumab, 12 were 16 to 17 years old. Risankizumab exposures in 16 to 17 year-old subjects with Crohn’s disease were similar to those in adults. Age was not found to have any significant impact on risankizumab exposures based on the population pharmacokinetic analyses.
Of the 2 234 subjects with plaque psoriasis exposed to risankizumab, 243 were 65 years or older and 24 subjects were 75 years or older. Of the 1 542 subjects with psoriatic arthritis exposed to risankizumab, 246 were 65 years or older and 34 subjects were 75 years or older. Of the 1 574 subjects with Crohn’s disease exposed to risankizumab, 72 were 65 years or older and 5 subjects were 75 years or older. Of the 1 512 subjects with ulcerative colitis exposed to risankizumab, 103 were 65 years or older and 8 subjects were 75 years or older. No overall differences in risankizumab exposure were observed between older and younger subjects who received risankizumab.
No specific studies have been conducted to determine the effect of renal or hepatic impairment on the pharmacokinetics of risankizumab. Based on population pharmacokinetic analyses, serum creatinine levels, creatinine clearance, or hepatic function markers (ALT/AST/bilirubin) did not have a meaningful impact on risankizumab clearance in subjects with plaque psoriasis, psoriatic arthritis, Crohn’s disease, or ulcerative colitis.
As an IgG1 monoclonal antibody, risankizumab is mainly eliminated via intracellular catabolism and is not expected to undergo metabolism via hepatic cytochrome P450 enzymes or renal elimination.
Risankizumab clearance and volume of distribution increase as body weight increases which may result in reduced efficacy in subjects with high body weight (>130 kg). However, this observation is based on a limited number of subjects with plaque psoriasis. Body weight had no clinically meaningful impact on risankizumab exposure or efficacy in psoriatic arthritis, Crohn’s disease, or ulcerative colitis. No dose adjustment based on body weight is currently recommended.
The clearance of risankizumab was not significantly influenced by gender or race in adult subjects with plaque psoriasis or psoriatic arthritis. No clinically meaningful differences in risankizumab exposure were observed in Chinese or Japanese subjects compared to Caucasian subjects in a clinical pharmacokinetic study in healthy volunteers.
Nonclinical data revealed no special hazard for humans based on repeat-dose toxicity studies including safety pharmacology evaluations, and an enhanced pre- and post-natal developmental toxicity study in cynomolgus monkeys at doses of up to 50 mg/kg/week (producing exposures of about 70 times the clinical exposure at maximum recommended human dose [MRHD]).
Mutagenicity and carcinogenicity studies have not been conducted with risankizumab. In a 26-week chronic toxicology study in cynomolgus monkeys at doses of up to 50 mg/kg/week (about 70 times the clinical exposure at the MRHD), there were no pre-neoplastic or neoplastic lesions observed and no adverse immunotoxicity or cardiovascular effects were noted.
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