Risankizumab exhibits typical immunoglobulin (Ig) G1 monoclonal antibody pharmacokinetic characteristics with bi-exponential disposition, long elimination half-life (approximately 28 days), and linear pharmacokinetics when administered intravenously (0.01 mg/kg–1200 mg) or subcutaneously (0.25 mg/kg–300 mg). |
Bodyweight, high titers of antidrug antibodies, baseline serum albumin, baseline high-sensitivity C-reactive protein, and baseline serum creatinine were statistically correlated with risankizumab clearance in population pharmacokinetic analyses; however, exposure–response analyses demonstrated that these covariates had no clinically meaningful impact on risankizumab efficacy in psoriasis patients with the clinical dosing regimen of 150 mg administered at weeks 0 and 4, and every 12 weeks thereafter. |
The risankizumab clinical dosing regimen maximized efficacy as assessed by the Psoriasis Area and Severity Index (PASI) 90, PASI 100, and static Physicians Global Assessment 0/1 responses, with no apparent correlation between exposure and safety in patients with plaque psoriasis. |
A therapeutic protein drug interaction study and population pharmacokinetic analyses confirmed the expected lack of drug interaction potential for risankizumab as a perpetrator or a victim. |
1 Introduction
2 Clinical Studies
Study | Objective(s) | Study design | Dosage regimen and route of administration | Treatment duration | No. of subjects | Analyses |
---|---|---|---|---|---|---|
1 | To assess the safety, tolerability, and pharmacokinetics of risankizumab in healthy Caucasian, Chinese, and Japanese male subjects following single rising SC (Stage 1) and IV (Stage 2) doses of risankizumab | Phase I randomized, double-blind, placebo-controlled, two-center study consisting of two stages: Stage 1: SC dosing Stage 2: IV dosing Active: placebo randomization 6:2 in Stages 1 and 2 | Risankizumab doses: 18 mg SC: Caucasian (n = 6), Japanese (n = 6), and Chinese (n = 6) 90 mg SC: Japanese (n = 6), Chinese (n = 7) 300 mg SC: Caucasian (n = 6), Japanese (n = 6), Chinese (n = 6) Placebo SC (n = 16) 200 mg IV: Japanese (n = 6) 600 mg IV: Japanese (n = 6) 1200 mg IV: Japanese (n = 6) Placebo IV (n = 6) | Single dose | 89 Treated 85 Completed | NCA, PopPK, IIA |
2 | To assess the safety, tolerability, clinical efficacy, and pharmacokinetics of risankizumab in subjects with moderate-to-severe chronic plaque psoriasis following single IV (Stage 1) and SC doses (Stage 2) | Randomized, double-blind, multicenter, placebo-controlled, ascending dose study consisting of two stages: Stage 1: IV dosing (3:1 active:placebo) Stage 2: SC dosing (6:1 active:placebo) | Risankizumab doses: 0.01 mg/kg IV (n = 3) 0.05 mg/kg IV (n = 3) 0.25 mg/kg IV (n = 3) 1 mg/kg IV (n = 3) 3 mg/kg IV (n = 3) 5 mg/kg IV (n = 3) Placebo IV (n = 6) 0.25 mg/kg SC (n = 7) 1 mg/kg SC (n = 6) Placebo SC (n = 2) | Single dose | 39 Treated 38 Completed | NCA, PopPK, IIA |
8 | To assess the effect of risankizumab on the pharmacokinetics of CYP probe substrates, caffeine (for CYP1A2), warfarin (for CYP2C9), omeprazole (for CYP2C19), metoprolol (for CYP2D6), and midazolam (for CYP3A). | Open-label, one-sequence study in subjects with moderate-to-severe chronic plaque psoriasis with or without concomitant psoriatic arthritis | Caffeine 100 mg, warfarin 10 mg, omeprazole 20 mg, metoprolol 50 mg, midazolam 2 mg as a single dose, as a cocktail, on days 1 and 98 Risankizumab 150 mg SC every 4 weeks on days 8, 36, 64, and 92 | Two single doses (CYP cocktail); multiple doses every 4 weeks (risankizumab) | 21 Treated 21 Completed | NCA |
Study (phase) | Objective(s) | Study design | Dosage regimen and route of administration | Duration of dosing (study duration) | No. of subjects | Analyses |
---|---|---|---|---|---|---|
3 (phase II) | To assess the efficacy of risankizumab compared with ustekinumab in patients with moderate-to-severe chronic plaque psoriasis To assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of risankizumab | A randomized, parallel-arm, dose-ranging, multiple-dose, active comparator-controlled, double-blind study in psoriasis patients | Subjects were randomized 1:1:1:1 into the following dose groups: Risankizumab 18 mg SC (18 mg × one injection) at week 0 (n = 43) Risankizumab 90 mg SC (90 mg × 1 injection) at weeks 0, 4, and 16 (n = 41) Risankizumab 180 mg SC (90 mg × two injections) at weeks 0, 4. and 16 (n = 42) Ustekinumab 45 or 90 mg SC at weeks 0, 4, and 16 (n = 40) | Up to 16 weeks (48 weeks for subjects not enrolling in OLE) | 166 Treated; 157 completed | PopPK, ER, IIA |
UltIMMa-1 (4, phase III) | To assess the efficacy and safety of risankizumab compared with ustekinumab and placebo in patients with moderate-to-severe chronic plaque psoriasis | Placebo and active-controlled, confirmatory, double-blind, double-dummy, randomized, parallel design comparison of risankizumab with ustekinumab and placebo over 52 weeks in psoriasis patients | Subjects were randomized at a ratio of 3:1:1 to one of three treatment arms: Risankizumab 150 mg (75 mg × two injections) SC at weeks 0 and 4, and every 12 weeks thereafter (n = 304) Ustekinumab 45 or 90 mg SC at weeks 0 and 4, and every 12 weeks thereafter (n = 100) Placebo SC at weeks 0 and 4, followed by risankizumab 150 mg SC every 12 weeks thereafter (n = 102) | 40 weeks (52 weeks; 56 weeks for subjects not enrolling in OLE]) | 506 Treated; 478 completed | PopPK, ER, IIA |
UltIMMa-2 (5, phase III) | To assess the efficacy and safety of risankizumab compared with ustekinumab and placebo in patients with moderate-to-severe chronic plaque psoriasis | Placebo and active-controlled, confirmatory, double-blind, double-dummy, randomized, parallel design comparison of risankizumab and ustekinumab and placebo over 52 weeks in psoriasis patients | Subjects were randomized at a ratio of 3:1:1 to one of three treatment arms: Risankizumab 150 mg (75 mg × two injections) SC at week 0 and 4, and every 12 weeks thereafter (n = 294) Ustekinumab 45 or 90 mg SC at weeks 0 and 4, then every 12 weeks thereafter (n = 99) Placebo SC at weeks 0 and 4, followed by risankizumab 150 mg SC every 12 weeks thereafter (N = 98) | 40 weeks (52 weeks; 56 weeks for subjects not enrolling in OLE) | 491 Treated; 459 completed | PopPK, ER, IIA |
IMMhance (6, phase III) | To assess the safety and efficacy of risankizumab in comparison with placebo in patients with moderate-to-severe chronic plaque psoriasis. To assess the maintenance of response following drug withdrawal and the response after retreatment in subjects who experience relapse after drug withdrawal | Placebo-controlled, confirmatory, double-blind, randomized withdrawal and retreatment study | Subjects were randomized at a ratio of 4:1 to one of two treatment arms: Risankizumab 150 mg (75 mg × two injections) SC at weeks 0 and 4, and every 12 weeks thereafter (n = 407) Placebo SC at weeks 0 and 4 followed by risankizumab 150 mg SC every 12 weeks thereafter (n = 100) | 88 weeks (104 weeks) | 507 Treated; ongoing | PopPK, ER, IIA |
IMMvent (7, phase III) | To assess the efficacy and safety of risankizumab compared with adalimumab in patients with moderate-to-severe chronic plaque psoriasis | Active-controlled, double-blind, double-dummy, randomized, parallel design comparison of risankizumab and adalimumab over 44 weeks in psoriasis patients | Subjects were randomized at a ratio of 1:1 to one of two treatment arms: Risankizumab 150 mg (75 mg × two injections) SC at weeks 0 and 4, and every 12 weeks thereafter (n = 301) Adalimumab 80 mg SC at randomization; then 40 mg SC at week 1, and thereafter every other week (n = 304) | 32 weeks for risankizumab and 41 weeks for adalimumab (44 weeks; 48 weeks for subjects not enrolling in OLE) | 605 Treated; 550 completed | PopPK, ER, IIA |
9 (phase II/III; Japan) | To assess the efficacy and safety of two different dose regimens of risankizumab compared with placebo in Japanese subjects with moderate-to-severe chronic plaque psoriasis (with or without psoriatic arthritis) | Randomized, double-blind, double-dummy, placebo-controlled, parallel design study comparing two different dose regimens of risankizumab with placebo | Subjects were randomized at a ratio of 2:2:1:1 to one of four treatment arms: Risankizumab 75 mg (75 mg × one injection) SC at weeks 0 and 4, and every 12 weeks thereafter (n = 58) Risankizumab 150 mg (75 mg × two injections) SC at weeks 0 and 4, and every 12 weeks thereafter (n = 55) Placebo with risankizumab 75 mg (75 mg × one injection) SC at week 16 and every 12 weeks thereafter (n = 27) Placebo with risankizumab 150 mg (75 mg × two injections) SC at week 16 and every 12 weeks thereafter (n = 27) | 40 weeks (52 weeks; 56 weeks for subjects not enrolling in OLE) | 171 Treated; ongoing | PopPK (Japan only)a, ER (Japan only)a, IIA (Japan only)a |
10 (phase III; Japan) | To assess the safety and efficacy of two different dose regimens of risankizumab for Japanese subjects with GPP or EP | Randomized, open-label study of two different dose regimens of risankizumab in subjects with GPP or EP | Subjects were randomized at a ratio of 1:1 to one of two treatment arms: Risankizumab 75 mg (75 mg × one injection) SC at weeks 0 and 4, and every 12 weeks thereafter (n = 9) Risankizumab 150 mg (75 mg × two injections) SC at weeks 0 and 4, and every 12 weeks thereafter (n = 8) | 172 weeks (188 weeks) | 17 Treated; ongoing | PopPK (Japan)a, ER for safety only (Japan)a, IIA (Japan)a |
3 Clinical Pharmacokinetics of Risankizumab
3.1 Single-Dose Pharmacokinetics
Parameter | Unit | IV dose of risankizumab | SC dose of risankizumab | ||||||
---|---|---|---|---|---|---|---|---|---|
0.01 mg/kg | 0.05 mg/kg | 0.25 mg/kg | 1 mg/kg | 3 mg/kg | 5 mg/kg | 0.25 mg/kg | 1.0 mg/kg | ||
[n = 3] | [n = 3] | [n = 3] | [n = 3] | [n = 3] | [n = 3] | [n = 6] | [n = 7] | ||
Cmax | µg/mL | 0.311 (0.311, 9) | 1.36 (1.4, 27) | 5.95 (5.97, 11) | 12.3 (16.9, 71) | 66.2 (66.4, 9) | 110 (110, 9) | 0.886 (0.972, 47) | 4.76 (5.20, 35) |
Tmaxa | day | 0.083 (0.067–0.083) | 0.043 (0.042–0.083) | 0.094 (0.083–0.17) | 0.042 (0.042–0.17) | 0.083 (0.042–0.083) | 0.083 (0.042–0.083) | 13.5 (7.00–14.1) | 3.00 (2.00–10.0) |
AUC∞ | µg day/mL | 2.93 (2.99, 25) | 15.7 (17.0, 43) | 85.1 (85.6, 13) | 167 (224, 68) | 952 (955, 9) | 1650 (1680, 23) | 40.4 (44.8, 46) | 177 (201, 45) |
t½ | day | 19.4 (19.6, 17) | 22.5 (22.8, 20) | 22.0 (22.8, 30) | 27.7 (27.8, 12) | 17.9 (19.0, 38) | 22.8 (23.7, 34) | 23.0 (24.3, 33) | 26.1 (26.5, 19) |
CL or CL/Fb | L/day | 0.325 (0.346, 42) | 0.328 (0.347, 44) | 0.280 (0.282, 16) | 0.557 (0.829, 110) | 0.273 (0.273, 2) | 0.231 (0.237, 30) | 0.534 (0.612, 57) | 0.367 (0.390, 35) |
AUC∞/dose | µg day/mL/mg | 3.08 (3.28, 43) | 3.05 (3.21, 35) | 3.57 (3.60, 16) | 1.79 (2.38, 67) | 3.67 (3.67, 2) | 4.34 (4.44, 25) | 1.87 (2.15, 58) | 2.73 (2.92, 43) |
3.2 Multiple-Dose Pharmacokinetics
Risankizumab 150 mg SC groupa | Geometric mean (arithmetic mean, %CV) | ||||
---|---|---|---|---|---|
Week 4 | Week 16 | Week 28 | Week 40 | Week 52 | |
[n = 1065] | [n = 1057] | [n = 1038] | [n = 750] | [n = 721] | |
Total across phase III studies | 5.47 (5.89, 38) | 1.84 (2.27, 60) | 1.60 (1.98, 60) | 1.57 (2.00, 75) | 1.52 (1.94, 65) |
[n = 177] | [n = 175] | [n = 173] | [n = 166] | [n = 156] | |
Japanese patients only across phase III studies | 5.23 (5.65, 38) | 1.70 (2.16, 71) | 1.39 (1.78, 65) | 1.46 (1.94, 89) | 1.42 (1.85, 66) |
3.3 Population Pharmacokinetics
Parameter | Population | |
---|---|---|
Non-Japanese (phase III) [n = 1130] | Japanese [n = 102] | |
Cmax (µg/mL) | 12.4 (3.29) 12.2 | 14.5 (3.44) 14.5 |
AUCτ (µg·day/mL) | 494 (176) 481 | 559 (194) 522 |
Ctrough (µg/mL) | 2.02 (1.18) 1.82 | 2.22 (1.26) 1.90 |
3.4 Bioavailability of Subcutaneous Risankizumab
3.5 Effect of Intrinsic Factors
3.5.1 Renal and Hepatic Impairment
3.5.2 Psoriasis Disease (Disease State)
3.5.3 Race/Ethnicity
3.5.4 Age and Sex
3.5.5 Body Weight
3.5.6 Antidrug Antibodies and Neutralizing Antibodies
3.6 Effect of Extrinsic Factors
3.6.1 Risankizumab as a Perpetrator for Drug–Drug Interaction (DDI)
3.6.2 Risankizumab as a Victim for DDIs
4 Exposure Response Analyses for Efficacy
4.1 Phase I and II Studies
4.2 Phase II and III Studies
4.3 Exposure–Response Analyses for Safety
5 Immunogenicity
Population | Japanese subjects who received at least one dose of risankizumab 75–150 mg SC | Non-Japanese subjects who received at least one dose of risankizumab 75–150 mg SC | ||
---|---|---|---|---|
Plaque psoriasis, GPP, or EP | Psoriatic arthritis | Plaque psoriasis | Psoriatic arthritis | |
Evaluable subjects (n) | 228 | 11 | 1322 | 129 |
ADA incidence (treatment-emergent) [n (%)] | 54 (23.7) | 1 (9.1) | 296 (22.4) | 16 (12.4) |
NAb incidence (treatment-emergent) [n (%)] | 23 (10.9)a | 0 (0) | 177 (13.4) | 0 (0) |
5.1 Assessment of the Effect of Immunogenicity on Risankizumab Plasma Exposures
5.2 Assessment of the Effect of Immunogenicity on Risankizumab Efficacy
Efficacy response (NRI) | Week 16 (placebo-controlled) [n = 1000] | Week 52 (ustekinumab-controlled) [n = 598] | ||||
---|---|---|---|---|---|---|
ADA-negative [n = 819] | ADA-positive with ADA titer < 128 [n = 174] | ADA-positive with ADA titer ≥128 [n = 7] | ADA-negative [n = 456] | ADA-positive with ADA titer < 128 [n = 136] | ADA-positive with ADA titer ≥128 [N = 6] | |
PASI 75 | 735 (89.7) | 155 (89.1) | 5 (71.4) | 414 (90.8) | 130 (95.6) | 4 (66.7) |
PASI 90 | 610 (74.5) | 131 (75.3) | 2 (28.6) | 377 (82.7) | 106 (77.9) | 3 (50.0) |
PASI 100 | 372 (45.4) | 76 (43.7) | 1 (14.3) | 270 (59.2) | 75 (55.1) | 1 (16.7) |
sPGA 0/1 | 695 (84.9) | 150 (86.2) | 4 (57.1) | 385 (84.4) | 120 (88.2) | 2 (33.3) |
5.3 Effect of Immunogenicity on Risankizumab Safety
Primary safety pool analysis set [N = 1384] (16 weeks) | All risankizumab doses [N = 1807] ADA subset of all risankizumab psoriasis analysis sets (52 weeks) | |||
---|---|---|---|---|
ADA-positive [n = 256] | ADA-negative [n = 1128] | ADA-positive [n = 420] | ADA-negative [n = 1387] | |
Hypersensitivity reaction (per SMQ) [n (%)] | 6 (2.3) | 34 (3.0) | 32 (7.6) | 97 (7.0) |
Injection site reaction (per CMQ) [n (%)] | 7 (2.7) | 15 (1.3) | 21 (5.0) | 46 (3.3) |