Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties
Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC18
Mechanism of action
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.
Pharmacodynamic effects


SKY 360-600 API FEB24_CL                                                        Page 6 of 16 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 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.
Clinical efficacy
Skyrizi has been shown to improve signs and symptoms and health related quality of life, as well as decrease mucosal inflammation as measured by endoscopy.
The efficacy and safety of risankizumab were assessed in 1 419 subjects with moderately to severely active Crohn’s disease in three multicentre, randomised, double-blind, placebo-controlled clinical studies. Enrolled subjects were 16 years of age or older with a Crohn’s Disease Activity Index (CDAI) of 220 to 450, an average daily stool frequency (SF) ≥4 and/or average daily abdominal pain score (APS) ≥2, and a Simple Endoscopic Score for CD (SES-CD) of ≥6, or ≥4 for isolated ileal disease, excluding the narrowing component and confirmed by a central reviewer.
There were two 12-week intravenous induction studies (ADVANCE and
MOTIVATE), which included a 12-week extension period for subjects who did not achieve SF/APS clinical response at Week 12 (≥ 30% decrease in SF and/or ≥ 30% decrease in APS and both not worse than baseline) at Week 12. ADVANCE and MOTIVATE were followed by a 52-week randomized withdrawal study of subcutaneous maintenance treatment (FORTIFY) that enrolled subjects with SF/APS clinical response to IV induction treatment, representing at least 64 weeks of therapy.
ADVANCE and MOTIVATE
In studies ADVANCE and MOTIVATE, subjects were randomized to receive risankizumab at either 600 mg (recommended dose), 1 200 mg, or placebo, at Week 0, Week 4, and Week 8.
In ADVANCE, 58% (491/850) subjects had failed or were intolerant to treatment with one or more biologic therapies (prior biologic failure), and 42% (359/850) had failed or were intolerant to therapy with conventional therapies but not biologic therapies (without prior biologic failure). In ADVANCE, among the subjects without prior biologic failure, (87%) 314/359 were naïve to biologic therapy and the remaining 13% had received a biologic but never failed or demonstrated intolerance.
All patients in MOTIVATE had prior biologic failure.
The co-primary endpoints were clinical remission based on SF and APS (average daily SF ≤2.8 and not worse than baseline and average daily AP score ≤1 and not worse than baseline) at Week 12, and endoscopic response (greater than 50% decrease in SES-CD from baseline, or a decrease of at least 2 points for subjects with a baseline score of 4 and isolated ileal disease) at Week 12. In both studies, a greater proportion of subjects treated with Skyrizi achieved clinical remission at Week 12 and endoscopic response at Week 12 compared to placebo (Table 2). Enhanced SF/APS clinical response and clinical remission were significant as early as Week 4 in subjects treated with Skyrizi and continued to improve through Week 12.
Additional secondary endpoints measured at Week 12 included the proportion of subjects with enhanced SF/APS clinical response (with ≥60% decrease in average daily SF and/or ≥35% decrease in average daily AP score and both not worse than Baseline, and/or clinical remission), endoscopic remission (SES-CD ≤4 and at least a        2 point reduction versus Baseline and no subscore greater than 1 in any individual
SKY 360-600 API FEB24_CL                                                         Page 7 of 16 variable), mucosal healing (SES-CD ulcerated surface subscore of 0 in subjects with a subscore of >1 at Baseline), a decrease of least 100 points in baseline CDAI, and a CDAI <150 at Week 12.
Table 2. Efficacy results in ADVANCE and MOTIVATE
ADVANCE                               MOTIVATE
Placebo IV Skyrizi Treatment Placebo   Skyrizi Treatment
(N=175)            differencee IV             differencee
600 mg IV                  600 mg IV
%               (95% CI) (N=187)           (95% CI)
(N=336)                    (N=191)
%
%                          %

Clinical remission                                  22%                                      15% 22%          43%                       19%         35% at Week 12a                                     [14%, 30%]   b
[6%, 24%]c

Endoscopic                                                                                   18% 28% response at               12%          40%                       11%         29%            [10%, Week 12a                                        [21%, 35%]b
25%]b
Enhanced
SF/APS clinical                                     15%                                      14% 31%          46%                       32%         45% response at Week                                [6%, 23%]c                             [4%, 23%]d 4
Enhanced                                                                                     23% SF/APS clinical                                     21%
42%          63%                       39%         62%            [13%, response at Week                                [12%, 30%]b
12                                                                                          33%]b 
Mucosal healing                                     14%                                      9% 8%           21%                        4%         14% at Week 12                                      [8%, 19%]b                             [4%, 15%]c Endoscopic                                          15%                                      15% remission at              9%           24%                        4%         19% b
Week 12                                         [9%, 21%]                              [9%, 21%]b a
Co-primary endpoints.
b
Statistically significant under multiplicity-control for Skyrizi vs placebo comparison (p<0.001).
c
Statistically significant under multiplicity-control for Skyrizi vs placebo (p≤0.01).
d
Nominal p ≤ 0.01 SKYRIZI vs placebo comparison.
e
Adjusted treatment difference.


At Week 4, a higher proportion of subjects treated with Skyrizi achieved a CDAI <150 compared to placebo (ADVANCE, Skyrizi=18%, placebo=10%, p≤0.05; MOTIVATE, Skyrizi=21%, placebo=11%, p≤0.01).
At Week 12, a higher proportion of subjects treated with Skyrizi achieved a CDAI<150 compared to placebo (ADVANCE, Skyrizi=45%, placebo=25%, p<0.001; MOTIVATE, Skyrizi=42%, placebo=20%, p<0.001).
At Week 12, a higher proportion of subjects treated with Skyrizi achieved a decrease of at least 100 points in baseline CDAI compared to placebo (ADVANCE, Skyrizi=60%, placebo=37%, p<0.001; MOTIVATE, Skyrizi=60%, placebo=30%, p<0.001).

SKY 360-600 API FEB24_CL                                                            Page 8 of 16 At Week 12, a higher proportion of subjects treated with Skyrizi achieved both enhanced SF/APS clinical response and endoscopic response at Week 12 compared to placebo (ADVANCE, Skyrizi=31%, placebo=8%, p<0.001; MOTIVATE,
Skyrizi=21%, placebo=7%, p<0.001).
The results for the co-primary endpoints for subjects with and without prior biologic failure are presented in Table 3.
Table 3. Efficacy results at Week 12 in subjects with prior biologic treatment failure and subjects without prior biologic failure in ADVANCE
ADVANCE
Placebo IV                   Skyrizi 600 mg
Clinical remission per SF/AP Score
Prior biologic failure                  23% (N=97)                     41% (N=195) Without prior biologic failure          21% (N=78)                     48% (N=141) Endoscopic response
Prior biologic failure                  11% (N=97)                     33% (N=195) Without prior biologic failure          13% (N=78)                     50% (N=141) 

In ADVANCE, a higher proportion of subjects treated with Skyrizi with and without prior biologic failure achieved CDAI<150 compared to placebo (With prior biologic failure, Skyrizi=42%, placebo=26%; Without prior biologic failure, Skyrizi=49%, placebo=23%).
CD-related hospitalisations
Rates of CD-related hospitalisations through Week 12 were lower in subjects treated with Skyrizi compared to placebo (ADVANCE, Skyrizi=3%, placebo=12%, p<0.001; MOTIVATE, Skyrizi=3%, placebo=11%, p≤0.01).
FORTIFY
The maintenance study FORTIFY evaluated 462 subjects with SF/APS clinical response to 12 weeks of Skyrizi IV induction treatment in studies ADVANCE and MOTIVIATE. Subjects were randomized to continue to receive a maintenance regimen of Skyrizi 360 mg SC (recommended dose), or Skyrizi 180 mg SC every 8 weeks, or to withdraw from Skyrizi induction and receive placebo SC every 8 weeks for up to 52 weeks.
The co-primary endpoints were clinical remission at Week 52 and, endoscopic response at Week 52. Co-primary endpoints were also measured in subjects with and without prior biologic failure (see Table 4).
Secondary endpoints measured at Week 52 included enhanced SF/APS clinical response, maintenance of clinical remission (clinical remission at Week 52 in subjects with clinical remission at Week 0), mucosal healing, endoscopic remission, deep remission (clinical remission and endoscopic remission), and CDAI <150.
Table 4. Efficacy results in FORTIFY at Week 52 (64 weeks from initiation of induction dose)
FORTIFY


SKY 360-600 API FEB24_CL                                                        Page 9 of 16 Skyrizi IV induction/    Skyrizi IV           Treatment g
Placebo SC        induction/ Skyrizi difference (95% CI)
(N=164) %
360 mg SC
(N=141) %
Clinical remissiona                      40%                  52%           15% [5%, 25%]b,h Prior biologic failure             34% (N=123)           48% (N=102)          14% [1%,27%] Without prior biologic              56% (N=41)            62% (N=39)         5% [-16%,27%] failure
Endoscopic responsea                     22%                  47%           28% [19%, 37%]c,h Prior biologic failure             20% (N=123)            44% (N=102)        23% [11%, 35%] Without biologic failure            27% (N=41)            54% (N=39)         27% [6%, 48%] Enhanced SF/APS clinical
49%                  59%           13% [2%, 23%]f,h response

Maintenance of clinical                (N = 91)             (N = 72)
21% [6%, 35%]e,h remission                                51%                  69%
Endoscopic remission                     13%                  39%           28% [20%, 37%]d,h (N = 162)           (N = 141)
Mucosal healing                                                             22% [14%, 30%]d,h 10%                  31% a
Co-primary endpoints b
Statistically significant under multiplicity-control for Skyrizi vs placebo comparison (p≤0.01).
c
Statistically significant under multiplicity-control for Skyrizi vs placebo comparison (p≤0.001).
d
Nominal p<0.001 Skyrizi vs placebo comparison.
e
Nominal p≤0.01 Skyrizi vs placebo comparison.
f
Nominal p≤0.05 Skyrizi vs placebo comparison.
g
The induction-only group consisted of subjects who achieved clinical response to Skyrizi induction therapy and were randomized to receive placebo in the maintenance study (FORTIFY).
h
Adjusted treatment difference.


Deep remission at Week 52 was observed at higher rates in subjects treated with Skyrizi IV/Skyrizi SC compared to subjects who received Skyrizi IV/placebo SC (28% vs. 10%, respectively, p<0.001).
At Week 52, a higher proportion of subjects treated with Skyrizi IV/Skyrizi SC achieved CDAI < 150 compared to Skyrizi IV/placebo SC (52% vs. 41%,
respectively, p≤0.01). A higher proportion of subjects treated with Skyrizi IV/Skyrizi SC achieved a decrease of at least 100 points in baseline CDAI score compared to subjects treated with Skyrizi IV/placebo SC (62% vs. 48%, respectively, p≤ 0.01).
91 subjects who did not demonstrate SF/APS clinical response 12 weeks after Skyrizi induction in studies ADVANCE and MOTIVATE received subcutaneous 360 mg dose of Skyrizi at Week 12 and Week 20. Of these subjects, 64% (58/91) achieved 
SKY 360-600 API FEB24_CL                                                           Page 10 of 16 SF/APS clinical response at Week 24; 33 of the subjects achieving SF/APS clinical response enrolled in FORTIFY and continued receiving Skyrizi 360 mg SC every 8 weeks for up to 52 weeks. Among these subjects, 55% (18/33) achieved clinical remission and 45% (15/33) achieved endoscopic response at Week 52.
During FORTIFY, 30 subjects had loss of response to Skyrizi 360 mg SC treatment and received rescue treatment with Skyrizi (1 200 mg IV single dose, followed by 360 mg SC every 8 weeks). Of these subjects, 57% (17/30) achieved SF/APS clinical response at Week 52. In addition, 20% (6/30) and 34% (10/29) of subjects achieved clinical remission and endoscopic response at Week 52, respectively.
Health-related and quality of life outcomes
Health-related quality of life was assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ), 36-Item Short Form Health Survey (SF-36), and the European Quality of Life 5 Dimensions (EQ-5D). Improvement in fatigue was evaluated by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale.
At Week 12 of ADVANCE and MOTIVATE, subjects treated with Skyrizi achieved clinically meaningful improvements from baseline in IBDQ total score, all IBDQ domain scores (bowel symptoms, systemic function, emotional function, and social function), SF-36 Physical and Mental Component Summary Score, EQ-5D VAS, and FACIT-Fatigue compared to placebo.
Subjects treated with Skyrizi experienced more improvements in work productivity compared to placebo, as assessed by the WPAI-CD questionnaire at Week 12.
Specifically, greater reductions in impairment while working, overall work impairment, and activity impairment was demonstrated in ADVANCE; and greater reduction in activity impairment was demonstrated in MOTIVATE.
Compared to placebo, subjects treated with Skyrizi achieved clinically meaningful improvements from baseline in Crohn’s-related symptoms and sleep impact as assessed by Crohn’s Symptom Severity (CSS) questionnaire at Week 12. These improvements were maintained in subjects treated with Skyrizi IV/Skyrizi SC in FORTIFY through Week 52.
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with risankizumab in one or more subsets of the paediatric population in the treatment of Crohn’s disease (see section 4.2 for information on paediatric use).

Pharmacokinetic Properties

5.2    Pharmacokinetic properties
Absorption
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.


In subjects with Crohn’s disease treated with 600 mg IV induction dose at Weeks 0,        4, and 8 followed by 360 mg SC 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 
SKY 360-600 API FEB24_CL                                                       Page 11 of 16 state median peak and trough concentrations are estimated to be 28.0 and 8.13 ug/mL respectively during the maintenance period (Weeks 40-48).
Distribution
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.
Biotransformation
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.
Elimination
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.
Linearity/non-linearity
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 or Crohn’s disease.
Interactions
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 medications was observed based on population pharmacokinetic analyses in Crohn’s disease.
Special populations
Paediatric population
The pharmacokinetics of risankizumab in paediatric subjects under 16 years of age has not been established. 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.
Elderly


SKY 360-600 API FEB24_CL                                                          Page 12 of 16 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 1 574 subjects with Crohn’s disease exposed to risankizumab, 72 were 65 years or older. No overall differences in risankizumab exposure were observed between older and younger subjects who received risankizumab.
Patients with renal or hepatic impairment
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 psoriasis, or Crohn’s disease.
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.
Body weight
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. No dose adjustment based on body weight is currently recommended.
Gender or race
The clearance of risankizumab was not significantly influenced by gender or race in adult subjects with plaque psoriasis or Crohn’s disease. No clinically meaningful differences in risankizumab exposure were observed in Chinese or Japanese subjects compared to Caucasian subjects in clinical pharmacokinetic studies in healthy volunteers.