Efficacy and Safety of Continuous Risankizumab Therapy vs Treatment Withdrawal in Patients With Moderate to Severe Plaque Psoriasis: A Phase 3 Randomized Clinical Trial

Abstract

Importance: Risankizumab selectively inhibits interleukin 23, a cytokine that contributes to psoriatic inflammation.

Objective: To evaluate the efficacy and safety of risankizumab vs placebo and continuous treatment vs withdrawal in adults with moderate to severe plaque psoriasis.

Design, setting, and participants: Multinational, phase 3, randomized, double-blind, placebo-controlled trial conducted from March 6, 2016, to July 26, 2018. A total of 507 eligible patients had stable moderate to severe chronic plaque psoriasis for 6 months or longer, body surface area involvement greater than or equal to 10%, Psoriasis Area and Severity Index (PASI) greater than or equal to 12, and a static Physician's Global Assessment (sPGA) score greater than or equal to 3. Intention-to-treat analysis was conducted.

Interventions: Patients were randomized (4:1, interactive response technology) to risankizumab, 150 mg, subcutaneously, or placebo at weeks 0 and 4 (part A1). All patients received risankizumab at week 16. At week 28, patients randomized to risankizumab who achieved an sPGA score of 0/1 were rerandomized 1:2 to risankizumab or placebo every 12 weeks (part B).

Main outcomes and measures: Co-primary end points for the part A1 phase included proportions of patients achieving greater than or equal to 90% improvement in PASI (PASI 90) and sPGA score of 0/1 at week 16. The PASI measures severity of erythema, infiltration, and desquamation weighted by area of skin involvement over the head, trunk, upper extremities, and lower extremities; scores range from 0 (no disease) to 72 (maximal disease activity). The sPGA assesses average thickness, erythema, and scaling of all psoriatic lesions; scores range from 0 (clear) to 4 (severe), with 0/1 indicating clear or almost clear. Primary and secondary end points in part B included proportion of rerandomized patients achieving an sPGA score of 0/1 at week 52 (primary) and week 104 (secondary).

Results: Of 563 patients screened, 507 were randomized to risankizumab (n = 407) or placebo (n = 100). Most patients were men (356 [70.2%]); median age was 51 years (interquartile range, 38-60 years). At week 16, 298 patients (73.2%) in the treatment group vs 2 patients (2.0%) receiving placebo achieved a PASI 90 response, and 340 patients (83.5%) receiving risankizumab vs 7 patients (7.0%) receiving placebo achieved sPGA 0/1 scores (placebo-adjusted differences: PASI 90: 70.8%; 95% CI, 65.7%-76.0%; sPGA 0/1: 76.5%; 95% CI, 70.4%-82.5%; P < .001 for both). At week 28, 336 responders were rerandomized to risankizumab (n = 111) or treatment withdrawal (n = 225). At week 52, the sPGA 0/1 score was achieved by 97 patients (87.4%) receiving risankizumab vs 138 patients (61.3%) receiving placebo. At week 104, the sPGA 0/1 score was achieved by 90 patients (81.1%) receiving risankizumab vs 16 patients (7.1%) receiving placebo (placebo-adjusted differences: week 52: 25.9%; 95% CI, 17.3%-34.6%; week 104: 73.9%; 95% CI, 66.0%-81.9%; P < .001 for both). Rates of treatment-emergent adverse events were similar between risankizumab (186 [45.7%]) and placebo (49 [49.0%]) in part A1 and remained stable over time.

Conclusions and relevance: Risankizumab showed superior efficacy compared with placebo through 16 weeks and treatment withdrawal through 2 years. Risankizumab was well tolerated, with no unexpected safety findings during the 2-year trial.

Trial registration: ClinicalTrials.gov Identifier: NCT02672852.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Blauvelt has served as a scientific adviser and/or clinical study investigator for AbbVie, Aclaris, Almirall, Arena, Athenex, Boehringer Ingelheim, Bristol-Myers Squibb, Dermavant, Dermira, Eli Lilly and Company, FLX Bio, Forte, Galderma, Janssen, Leo, Novartis, Ortho, Pfizer, Regeneron, Sandoz, Sanofi Genzyme, Sun Pharma, and UCB Pharma, and as a paid speaker for AbbVie. Dr Leonardi has received honoraria or fees for serving on advisory boards, as a speaker, and as a consultant, as well as grants as an investigator from AbbVie, Actavis, Amgen, Celgene, Coherus, Dermira, Eli Lilly, Galderma, Janssen, Leo, Merck, Novartis, Pfizer, Sandoz, Stiefel, UCB, and Wyeth. Dr Gooderham has received honoraria or fees for serving on advisory boards, as a speaker, and as a consultant, as well as grants as an investigator from AbbVie, Amgen, Akros, Arcutis, Boehringer Ingelheim, BMS, Celgene, Coherus, Dermavant, Dermira, Eli Lilly, Galderma, GSK, Janssen, Kyowa Hakko Kirin Pharma, Leo Pharma, MedImmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sun Pharma, Takeda, UCB, and Valeant. Dr Papp has received honoraria or fees for serving on advisory boards, as a speaker, and as a consultant, as well as grants as principal investigator from AbbVie, Amgen, Astellas, Baxalta, Baxter, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Coherus, Dermira, Eli Lilly, Forward Pharma, Galderma, Genentech, GlaxoSmithKline, Janssen, Kyowa-Hakko Kirin, Leo Pharma, MedImmune, Merck-Serono, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Stiefel, Sun Pharma, Takeda, UCB, and Valeant. Dr Philipp has received honoraria or fees for serving on advisory boards, as a speaker, and as a consultant, as well as grants as an investigator from AbbVie, Almirall, Amgen, Biogen, BMS GmbH, Boehringer Ingelheim, Celgene, Dermira, Eli Lilly, GSK, Hexal, Janssen Cilag, Leo Pharma, Maruho, MSD, Merck, Mundipharma, Novartis, Pfizer, UCB Pharma, and VBL Therapeutics. Dr J. J. Wu has been an investigator for AbbVie, Amgen, Eli Lilly, Janssen, and Novartis; a paid consultant for AbbVie, Almirall, Amgen, Bristol-Myers Squibb, Celgene, Dermira, Dr Reddy’s Laboratories, Eli Lilly, Janssen, LEO Pharma, Novartis, Promius Pharma, Regeneron, Sun Pharmaceutical, UCB, and Valeant Pharmaceuticals North America LLC; and a speaker for AbbVie, Amgen, Celgene, Novartis, Regeneron, Sanofi Genzyme, Sun Pharmaceutical, UCB, and Valeant Pharmaceuticals North America LLC. Dr Igarashi has received honoraria or fees for serving on advisory boards, as a speaker, and as a consultant, as well as grants as an investigator from AbbVie, Celgene, Eli Lilly, Kyowa Kirin, Janssen, Maruho and Novartis. Dr Flack is a full-time employee of Boehringer Ingelheim. Drs Geng, T. Wu, and Williams are full-time employees of AbbVie and may own stock/options. Dr Camez is a former full-time employee of AbbVie and may own stock/options. Dr Langley has served as principal investigator for and is a paid member of the scientific advisory board or served as a speaker for AbbVie, Amgen, Celgene, Janssen, Leo, Lilly, Merck, Novartis, Pfizer, and Boehringer Ingelheim.

Figures

Figure 1.. Trial Profile

Number of patients represents those in intention-to-treat analysis. sPGA indicates static Physician’s Global Assessment.

Figure 2.. Patients Response With Nonresponder Imputation After Rerandomization in Part B

Proportion of patients achieving static Physician’s Global Assessment (sPGA) 0/1, indicating clear or almost clear (A), Psoriasis Area and Severity Index (PASI) 90, indicating greater than or equal to 90% improvement in the PASI from baseline (B), sPGA 0, indicating clear (C), and PASI 100, indicating 100% improvement in the PASI from baseline (D). aP = .005 vs placebo based on nominal P value. bP < .001 vs placebo based on nominal P value except for sPGA 0/1 at weeks 52 and 104. cP < .002 vs placebo based on nominal P value.