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

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.

Clinical efficacy and safety

Plaque Psoriasis
The efficacy and safety of risankizumab was assessed in 2,109 subjects with moderate to severe plaque psoriasis in four multicentre, randomised, double-blind studies (ULTIMMA-1, ULTIMMA-2, IMMHANCE, and IMMVENT). Enrolled subjects were 18 years of age and older with plaque psoriasis who had a body surface area (BSA) involvement of ≥10%, a static Physician Global Assessment (sPGA) score of ≥3 in the overall assessment (plaque thickness/induration, erythema, and scaling) of psoriasis on a severity scale of 0 to 4, a Psoriasis Area and Severity Index (PASI) score ≥12, and who were candidates for systemic therapy or phototherapy.

Overall, subjects had a median baseline PASI score of 17.8, a median BSA of 20.0%, and a median baseline DLQI score of 13.0. Baseline sPGA score was severe in 19.3% of subjects and moderate in 80.7% of subjects. A total of 9.8% of study subjects had a history of diagnosed psoriatic arthritis.

Across all studies, 30.9% of subjects were naïve to any systemic therapy (including non-biologic and biologic), 38.1% had received prior phototherapy or photochemotherapy, 48.3% had received prior non biologic systemic therapy, 42.1% had received prior biologic therapy, and 23.7% had received at least one anti-TNF alpha agent for the treatment of psoriasis.

ULTIMMA-1 and ULTIMMA-2

ULTIMMA-1 and ULTIMMA-2 enrolled 997 subjects (598 randomised to risankizumab 150 mg, 199 to ustekinumab 45 mg or 90 mg [according to baseline weight], and 200 to placebo). Subjects received treatment at week 0, week 4, and every 12 weeks thereafter. The two co-primary endpoints in ULTIMMA-1 and ULTIMMA-2 were the proportion of subjects who achieved 1) PASI 90 response and 2) sPGA score of clear or almost clear (sPGA 0 or 1) at week 16 versus placebo. The results for the co-primary and other endpoints are presented in Table 2 and Figure 1.



Table 2: Efficacy and quality of life results in adults with plaque psoriasis in ULTIMMA-1 and ULTIMMA-2
ULTIMMA-1                                       ULTIMMA-2
Risankizumab Ustekinumab          Placebo      Risankizumab   Ustekinumab         Placebo (N=304)     (N=100)            (N=102)         (N=294)        (N=99)           (N=98) n (%)       n (%)              n (%)           n (%)          n (%)            n (%) sPGA of clear or almost clear (0 or 1)

Week 16a        267 (87.8)     63 (63.0)       8 (7.8)       246 (83.7)        61 (61.6)      5 (5.1) 
Week 52        262 (86.2)        54 (54.0)       --        245 (83.3)          54 (54.5)         -- sPGA of clear (0)
Week 16        112 (36.8)        14 (14.0)    2 (2.0)      150 (51.0)          25 (25.3)      3 (3.1) Week 52        175 (57.6)        21 (21.0)       --        175 (59.5)          30 (30.3)         -- PASI 75
Week 12        264 (86.8)        70 (70.0)    10 (9.8)     261 (88.8)          69 (69.7)      8 (8.2) Week 52        279 (91.8)        70 (70.0)       --        269 (91.5)          76 (76.8)         -- PASI 90
Week 16a       229 (75.3)        42 (42.0)    5 (4.9)      220 (74.8)          47 (47.5)      2 (2.0) Week 52        249 (81.9)        44 (44.0)       --        237 (80.6)          50 (50.5)         -- PASI 100
Week 16        109 (35.9)        12 (12.0)    0 (0.0)      149 (50.7)          24 (24.2)      2 (2.0) Week 52        171 (56.3)        21 (21.0)       --        175 (59.5)          30 (30.3)         -- DLQI 0 or 1b
Week 16        200 (65.8)        43 (43.0)    8 (7.8)      196 (66.7)          46 (46.5)      4 (4.1) Week 52        229 (75.3)        47 (47.0)       --        208 (70.7)          44 (44.4)         -- PSS 0 (symptom-free)c
Week 16        89 (29.3)         15 (15.0)    2 (2.0)       92 (31.3)          15 (15.2)      0 (0.0) Week 52        173 (56.9)        30 (30.0)       --        160 (54.4)          30 (30.3)         -- All comparisons of risankizumab versus ustekinumab and placebo achieved p<0.001 except for PASI 75 at week 52 in ULTIMMA-2 where p=0.001
a
Co-primary endpoints versus placebo
b
No impact on health-related quality of life
c
Psoriasis Symptom Scale (PSS) of 0 means no symptoms of pain, itching, redness, and burning during the last 24 hours



Figure 1: Time course of mean percent change from baseline of PASI in ULTIMMA-1 and ULTIMMA-2
0

-10

-20
PASI Percent Change from Baseline


-30
RZB
-40
UST
-50
PBO
-60

-70

-80
-90

-100
0      4          8   12   16      22   28   34   40   46     52

Weeks
RZB = risankizumab
UST = ustekinumab
PBO = placebo
p<0.001 at each time point

Examination of age, gender, race, body weight ≤130 kg, baseline PASI score, concurrent psoriatic arthritis, previous non-biologic systemic treatment, previous biologic treatment, and previous failure of a biologic did not identify differences in response to risankizumab among these subgroups.

Improvements were observed in psoriasis involving the scalp, the nails, and the palms and soles at week 16 and week 52 in subjects treated with risankizumab.



Table 3: Mean changes from baseline in NAPSI, PPASI, and PSSI
ULTIMMA-1                   ULTIMMA-2                      IMMHANCE
Risankizumab Placebo Risankizumab Placebo                   Risankizumab Placebo NAPSI:                                                                                    N=58; N=56;                        N=49;
Change           N=178;                       N=177;                         N=235;         2.5 2.1 (1.86)                  3.0 (1.76)
at Week        -9.0 (1.17)                  -7.5 (1.03)                    -7.5 (0.89)    (1.70) ***                          ***
16 (SE)                                                                                    *** PPASI:                          N=34;                        N=23;                        N=26; N=95;                                                       N=113;
Change                          -3.17         N=86;          -3.74                        -0.27 -5.93 (0.324)                                               -7.39 (0.654) at Week                        (0.445)    -7.24 (0.558)     (1.025)                      (1.339) 16 (SE)                          ***                           **                          *** PSSI:                           N=92;                        N=83;                        N=88; Change           N=267;          -2.9         N=252;          -4.6           N=357;        -5.5 at Week       -17.6 (0.47)      (0.69)     -18.4 (0.52)      (0.82)       -20.1 (0.40)    (0.77) 16 (SE)                          ***                          ***                          *** NAPSI:
Change           N=178;                       N=183;
-                            -               -            -
at Week       -15.7 (0.94)                 -16.7 (0.85)
52 (SE)
PPASI:
N=95;
Change                                        N=89;
-6.16 (0.296)         -                            -               -            - at Week                                   -8.35 (0.274)
52 (SE)
PSSI:
Change           N=269;                       N=259;
-                            -               -            -
at Week       -17.9 (0.34)                 -18.8 (0.24)
52 (SE)
Nail Psoriasis Severity Index (NAPSI), Palmoplantar Psoriasis Severity Index (PPASI), Psoriasis Scalp Severity Index (PSSI), and Standard Error (SE)
** P < 0.01 comparing to risankizumab
*** P < 0.001 comparing to risankizumab

Anxiety and depression, as measured by the Hospital Anxiety and Depression Scale (HADS), improved in the risankizumab group at week 16 compared with the placebo group.

Maintenance of response

In an integrated analysis of subjects receiving risankizumab in ULTIMMA-1 and ULTIMMA-2 for PASI 100 responders at week 16, 79.8% (206/258) of the subjects who continued on risankizumab maintained the response at week 52. For PASI 90 responders at week 16, 88.4% (398/450) of subjects maintained the response at week 52.

The safety profile of risankizumab with up to 77 weeks of exposure was consistent with the profile observed up to 16 weeks.

IMMHANCE

IMMHANCE enrolled 507 subjects (407 randomised to risankizumab 150 mg and 100 to placebo).
Subjects received treatment at week 0, week 4, and every 12 weeks thereafter. Subjects who were originally on risankizumab and had a sPGA response of clear or almost clear at week 28 were re- randomised to continue risankizumab every 12 weeks through week 88 (with follow-up 16 weeks after last risankizumab dose) or have treatment withdrawn.



At week 16, risankizumab was superior to placebo on the co-primary endpoints of sPGA of clear or almost clear (83.5% risankizumab vs 7.0% placebo) and PASI 90 (73.2% risankizumab vs 2.0% placebo).

Of the 31 subjects from the IMMHANCE study with latent tuberculosis (TB) who did not receive prophylaxis during the study, none developed active TB during the mean follow-up of 55 weeks on risankizumab.

Among subjects with sPGA of clear or almost clear at week 28 in IMMHANCE, 81.1% (90/111) of subjects re-randomised to continued treatment with risankizumab maintained this response at week 104 compared with 7.1% (16/225) who were re-randomised to withdrawal from risankizumab. Of these subjects, 63.1% (70/111) of subjects re-randomised to continued treatment with risankizumab achieved a sPGA clear response at week 104 compared with 2.2% (5/225) who were re-randomised to withdrawal from risankizumab.

Among subjects who achieved sPGA of clear or almost clear at week 28 and relapsed to sPGA of moderate or severe following withdrawal from risankizumab, 83.7% (128/153) regained sPGA of clear or almost clear after 16 weeks of retreatment. Loss of sPGA of clear or almost clear was observed as early as 12 weeks after a missed dose. Of those subjects who were re-randomised to withdraw from treatment, 80.9% (182/225) relapsed, and the median time to relapse was 295 days. No characteristics were identified to predict the time to loss of response or likelihood of regaining response at the individual patient level.

IMMVENT

IMMVENT enrolled 605 subjects (301 randomised to risankizumab and 304 to adalimumab). Subjects randomised to risankizumab received 150 mg of treatment at week 0, week 4, and every 12 weeks thereafter. Subjects randomised to adalimumab received 80 mg at week 0, 40 mg at week 1, and 40 mg every other week through week 15. Starting at week 16, subjects who were receiving adalimumab continued or switched treatment based on response:
•     0.

e.
Summarized from pooled data from KEEPSAKE1 and KEEPSAKE2 for subjects with baseline LDI >0.

Response over time

In KEEPSAKE1, a greater ACR20 response was observed in the risankizumab group compared to placebo as early as week 4 (25.7%) and the treatment difference continued over time to week 24 (Figure 3).

Figure 3. Percent of subjects achieving ACR20 responses in study KEEPSAKE1 through week 24
ACR20 response rate (%)



Baseline   Week 4        Week 8        Week 12        Week 16              Week 24 Visit
○ Placebo (N=481) ──■── Risankizumab (N=483) 

A greater ACR20 response for risankizumab versus placebo was seen as early as week 4 in 19.6% of subjects in KEEPSAKE2.

Responses observed in risankizumab groups were similar regardless of concomitant non-biologic DMARD use, number of prior non-biologic DMARDs, age, gender, race, and BMI. In KEEPSAKE2, responses were seen regardless of prior biologic therapy.

The safety profile of risankizumab with up to 52 weeks of exposure was consistent with the profile observed up to 24 weeks.

In both studies, the proportion of subjects achieving modified PsA Response Criteria (PsARC) at week 24 was higher in subjects receiving risankizumab compared with placebo. In addition, subjects
receiving risankizumab achieved greater improvement in Disease Activity Score (28 joints) using CRP (DAS28-CRP) compared with placebo at week 24. Improvements were maintained through week 52 for PsARC and DAS28-CRP.

Treatment with risankizumab resulted in improvements in individual ACR components, Health Assessment Questionnaire-Disability Index (HAQ-DI), pain assessment, and high-sensitivity C- reactive protein (hsCRP) compared with placebo.

Treatment with risankizumab resulted in statistically significant improvement in the skin manifestations of psoriasis in subjects with PsA.

Treatment with risankizumab resulted in statistically significant improvement in the modified Nail Psoriasis Severity Index (mNAPSI) and the 5-point Physician’s Global Assessment of Fingernail Psoriasis (PGA-F) scores in subjects with nail psoriasis at baseline (67.3%) in KEEPSAKE1. This improvement was maintained through week 52 (see Table 7).

Table 7. Nail psoriasis efficacy results in KEEPSAKE1
Placebo                       Risankizumab
N=338                            N=309
mNAPSI change from baseline a
Week 24                               -5.57                          -9.76 b Week 52                                 -                            -13.64 PGA-F change from baseline a
Week 24                                -0.4                           -0.8 b Week 52                                 -                              -1.2 PGA-F clear/minimal and ≥2-grade improvement c
Week 24 n (%)                       30 (15.9)                         71 (37.8) d
Week 52 n (%)                           -                          105 (58.0) a.
Summarized for subjects with baseline nail psoriasis (Placebo N=338; risankizumab N=309; at week 52, for mNAPSI, observed risankizumab N=290, for PGA-F, observed risankizumab N=291).
b.
Multiplicity-controlled p≤0.001 risankizumab vs placebo comparison.
c.
Summarized for subjects with nail psoriasis and a PGA-F overall global assessment score of ‘Mild’, ‘Moderate’ or ‘Severe’ at Baseline (Placebo N=190; risankizumab N=188, at week 52 observed risankizumab N=181).
d.
Nominal p≤0.001 risankizumab vs placebo comparison.

Radiographic Response

In KEEPSAKE1, inhibition of progression of structural damage was assessed radiographically and expressed as the change in modified Total Sharp Score (mTSS) at week 24, compared with baseline.
The mTSS score was modified for PsA by addition of hand distal interphalangeal (DIP) joints. At week 24, the mean progression of structural damage with risankizumab (mean mTSS 0.23) compared with placebo (mean mTSS 0.32) was not statistically significant. At week 24, the proportion of subjects with no radiographic progression (defined as a change from baseline in mTSS ≤ 0) was higher with risankizumab (92.4%) compared with placebo (87.7%). This response was maintained through week 52.

Physical Function and Health Related Quality of Life

In both studies, subjects treated with risankizumab showed statistically significant improvement from baseline in physical function as assessed by HAQ-DI at week 24 (KEEPSAKE1 (-0.31) compared with placebo (-0.11) (p ≤0.001)), (KEEPSAKE2 (-0.22) compared with placebo (-0.05) (p ≤0.001)).
At week 24, a greater proportion of subjects achieved a clinically meaningful reduction of at least 0.35 in HAQ-DI score from baseline in the risankizumab group compared with placebo. Improvements in physical function were maintained through week 52.

In both studies, subjects treated with risankizumab demonstrated significant improvements in the SF-36 V2 physical component summary scores and in FACIT-Fatigue scores at week 24, compared with placebo, with improvements maintained through week 52.


At baseline, psoriatic spondylitis was reported in 19.6% (7.9% diagnosed by radiograph or MRI) of subjects in KEEPSAKE1 and 19.6% (5% diagnosed by radiograph or MRI) of subjects in KEEPSAKE2. Subjects with clinically assessed psoriatic spondylitis who were treated with risankizumab showed improvements from baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores compared with placebo at week 24. Improvements were maintained through week 52. There is insufficient evidence of the efficacy of risankizumab in subjects with radiograph- or MRI-confirmed ankylosing spondylitis-like psoriatic arthropathy due to the small number of subjects studied.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

The pharmacokinetics of risankizumab was similar between subjects with plaque psoriasis and subjects with psoriatic arthritis.

Absorption

Risankizumab exhibited linear pharmacokinetics with dose-proportional increase in exposure across dose ranges of 18 to 300 mg and 0.25 to 1 mg/kg administered subcutaneously, and 200 to 1,200 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 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.

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.

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.

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 300 mg or 0.25 to 1 mg/kg subcutaneous administration in healthy subjects or subjects with psoriasis.

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 treatment used by some subjects with plaque psoriasis or psoriatic arthritis during the clinical studies.

Special populations

Paediatric population
The pharmacokinetics of risankizumab in paediatric subjects has not been established.

Elderly

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. 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 plaque psoriasis or psoriatic arthritis.

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. 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 psoriatic arthritis. No clinically meaningful differences in risankizumab exposure were observed in Chinese or Japanese subjects compared with Caucasian subjects in a clinical pharmacokinetic study.