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Clinical Trial

Risankizumab for Ulcerative Colitis: Two Randomized Clinical Trials

Edouard Louis et al. JAMA. .

Erratum in

Abstract

Importance: The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit of IL-23) for the treatment of ulcerative colitis are unknown.

Objective: To evaluate the efficacy and safety of risankizumab when administered as an induction and a maintenance therapy for patients with ulcerative colitis.

Design, setting, and participants: Two phase 3 randomized clinical trials were conducted. The induction trial was conducted at 261 clinical centers (in 41 countries) and enrolled 977 patients from November 5, 2020, to August 4, 2022 (final follow-up on May 16, 2023). The maintenance trial was conducted at 238 clinical centers (in 37 countries) and enrolled 754 patients from August 28, 2018, to March 30, 2022 (final follow-up on April 11, 2023). Eligible patients had moderately to severely active ulcerative colitis; a history of intolerance or inadequate response to 1 or more conventional therapies, advanced therapies, or both types of therapies; and no prior exposure to risankizumab.

Interventions: For the induction trial, patients were randomized 2:1 to receive 1200 mg of risankizumab or placebo administered intravenously at weeks 0, 4, and 8. For the maintenance trial, patients with a clinical response (determined using the adapted Mayo score) after intravenous treatment with risankizumab were randomized 1:1:1 to receive subcutaneous treatment with 180 mg or 360 mg of risankizumab or placebo (no longer receiving risankizumab) every 8 weeks for 52 weeks.

Main outcomes and measures: The primary outcome was clinical remission (stool frequency score ≤1 and not greater than baseline, rectal bleeding score of 0, and endoscopic subscore ≤1 without friability) at week 12 for the induction trial and at week 52 for the maintenance trial.

Results: Among the 975 patients analyzed in the induction trial (aged 42.1 [SD, 13.8] years; 586/973 [60.1%] were male; and 677 [69.6%] were White), the clinical remission rates at week 12 were 132/650 (20.3%) for 1200 mg of risankizumab and 20/325 (6.2%) for placebo (adjusted between-group difference, 14.0% [95% CI, 10.0%-18.0%], P < .001). Among the 548 patients analyzed in the maintenance trial (aged 40.9 [SD, 14.0] years; 313 [57.1%] were male; and 407 [74.3%] were White), the clinical remission rates at week 52 were 72/179 (40.2%) for 180 mg of risankizumab, 70/186 (37.6%) for 360 mg of risankizumab, and 46/183 (25.1%) for placebo (adjusted between-group difference for 180 mg of risankizumab vs placebo, 16.3% [97.5% CI, 6.1%-26.6%], P < .001; adjusted between-group difference for 360 mg of risankizumab vs placebo, 14.2% [97.5% CI, 4.0%-24.5%], P = .002). No new safety risks were detected in the treatment groups.

Conclusion and relevance: Compared with placebo, risankizumab improved clinical remission rates in an induction trial and in a maintenance trial for patients with moderately to severely active ulcerative colitis. Further study is needed to identify benefits beyond the 52-week follow-up.

Trial registration: ClinicalTrials.gov Identifiers: NCT03398148 and NCT03398135.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Louis reported receiving research grants from Janssen, Pfizer, and Takeda; receiving educational grants from AbbVie, Janssen, MSD (Merck Sharp & Dohme), and Takeda; receiving speaker fees from AbbVie, Falk, Ferring, Hospira, Janssen, MSD, Pfizer, and Takeda; serving on advisory boards for AbbVie, Arena, Celgene, Ferring, Galapagos, Gilead, Hospira, Janssen, MSD, Pfizer, and Takeda; and serving as a consultant for AbbVie. Dr Schreiber reported receiving consulting fees from AbbVie, Amgen, Arena, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Falk Pharma, Ferring, Galapagos/Gilead, Genentech/Roche, GSK (GlaxoSmithKline), IMAB Biophatrma, Lilly, MSD, Morphic, Novartis, Pfizer, Shire, Takeda, and Ventyx and receiving speaker fees from Ferring, Galapagos/Gilead, MSD, Pfizer, and Takeda. Dr Panaccione reported receiving consulting fees, speaker fees, and research support from Abbott, AbbVie, Abbivax, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, GSK, BIOJAMP, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Sublimity Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Viatris, Ventyx, and UCB. Dr Bossuyt reported receiving research grants from AbbVie, Amgen, Janssen, Mundipharma, Mylan, Pfizer, and Viatris; receiving lecture fees from AbbVie, Janssen, Pfizer, and Takeda; receiving advisory board fees from AbbVie, Arena Pharmaceuticals, Bristol Myers Squibb, Hospira, Janssen, Merck, Mundipharma, Pentax Medical, Pfizer, PSI contract research organization, Roche, Sandoz, and Takeda; and receiving personal fees from AbbVie, Bristol Myers Squibb, Clinical Academic Group, Celltrion, Falk, European Pharma Group, Galapagos, Janssen, Lilly, Materia Prima, Pentax, Pfizer, Scope, Takeda, Arena, Circle Pharma Inc, Globalport, PSI contract research organization, Roche, and Tetrameros. Dr Biedermann reported receiving lecture and consulting fees from Takeda, Sanofi, AbbVie, Falk, Bristol Myers Squibb, Janssen, Lilly, and Pfizer and serving on advisory boards for AbbVie, Amgen, Aquilion, Bristol Myers Squibb, Esocap, Falk, Janssen, Pfizer, Takeda, and Sanofi. Dr Colombel reported receiving consulting fees from AbbVie, Amgen, AnaptysBio, Allergan, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Celltrion, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, GSK, Genentech (Roche), Immunic, Janssen Pharmaceuticals, Kaleido Biosciences, Immunic, Invea, Iterative Scopes, Merck, Landos, Microba Life Science, Novartis, Otsuka Pharmaceutical, Pfizer, Protagonist Therapeutics, Prometheus, Sanofi, Seres, Sun, Takeda, Teva, TiGenix, Union, and Vifor; receiving grants, lecture fees, and other personal fees from Amgen, Celgene Corporation, Kaleido Biosciences, and TiGenix; receiving received research grants from AbbVie, Janssen Pharmaceuticals, Takeda, and Bristol Myers Squibb; receiving payment for lectures from AbbVie and Takeda; and having stock options in Intestinal Biotech Development. Dr Parkes reported receiving personal fees from AbbVie, Allergan, Bristol Myers Squibb, Celltrion, Ferring, Galapagos, Janssen, Napp Pharmaceuticals, Pfizer, Sorriso Pharmaceuticals, Takeda, and Tillotts; receiving research funding from AbbVie and Takeda; and serving as the director and being a shareholder in Ampersand Health. Dr Peyrin-Biroulet reported receiving personal fees from AbbVie, Abivax, Adacyte, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, Bristol Myers Squibb, Celltrion, CONNECT Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, HAC-Pharma, IAG Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Nordic Pharma, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par’Immune, Pfizer, Prometheus, Protagonist, Roche, Roivant, Sanofi, Sandoz, Takeda, Theravance, Thermo Fisher, Tigenix, Tillots, Viatris, Vifor, Ysopia, Abivax, Samsung, Ventyx, Roivant, and Vectivbio and receiving grants from Celltrion and Fresenius Kabi. Dr D’Haens reported receiving personal fees from AbbVie, Alimentiv, AstraZeneca, Pfizer, Johnson & Johnson, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, GSK, Immunc, Polpharm, Takeda, and Ventyx; receiving grants from Pfizer, Takeda, and Tillotts; serving as an adviser to AbbVie, Alimentiv, AstraZeneca, Bristol Meyers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Galapagos, Pfizer, Immunic, Johnson & Johnson, Takeda, Tillotts, Ventyx, and Vifor Pharma; and receiving speaker fees from AbbVie, Johnson & Johnson, Pfizer, Takeda, and Tillotts. Dr Hisamatsu reported receiving research grants from AbbVie, Alfresa Pharma, Boston Scientific, Daiichi Sankyo, EA Pharma, Janssen, JIMRO, Kissei Pharmaceutical Co, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, and Zeria Pharmaceutical; receiving consulting fees from AbbVie, Boston Scientific, Bristol Myers Squibb, EA Pharma, Janssen, Nichi-Iko, Gilead Sciences, Eli Lilly, Takeda, Bristol Myers Squibb, Mitsubishi Tanabe Mochida Pharmaceutical, Nichi-Iko Pharmaceutical Co, and Pfizer; and receiving lecture fees from AbbVie, Boston Scientific, Bristol Myers Squibb, EA Pharma, Gilead Sciences, Janssen, JIMRO, Lilly, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Kissei Pharmaceutical, Pfizer, and Takeda. Dr Siegmund reported serving as a consultant to AbbVie, Abivax, Arena, Bristol Myers Squibb, Boehringer Ingelheim, CED Service GmbH, Celgene, CT Scout, Endpoint Health, Falk, Forga Software, Galapagos, Janssen, Eli Lilly, Materia Prima, Pfizer, Takeda, Pharma Insight, Predictimmune, and PsiCro; receiving speaker fees from AbbVie, Bristol Myers Squibb, CED Service GmbH, Chiesi, Falk, Ferring, Gilead, Janssen, Lilly, Materia Prima, Takeda, and Pfizer; and receiving grants from Arena/Pfizer. Dr Boland reported receiving grants from Merck, Prometheus Biosciences, Merck, Bristol Myers Squibb, and Gilead and receiving personal fees from Gilead, Pfizer, Merck, and Bristol Myers Squibb for serving on advisory boards and consulting. Dr Melmed reported serving as a consultant to AbbVie, Arena, Boeringer Ingelheim, Bristol Myers Squibb, Dieta, Ferring, Fresenius Kalbi, Genentech, Gilead, Iterative Scopes, Lilly, Janssen, Oshi Health, Pfizer, Prometheus Labs, Samsung Bioepis, Takeda, Techlab, and Viatris; receiving grants from Pfizer; having equity in Dieta; receiving personal fees from OptionCare and Verantos; having a patent issued for treating inflammatory bowel disease using ultraviolet light; and having a patent pending for treating inflammatory bowel disease with antifungal therapy. Dr Armuzzi reported receiving personal fees from AbbVie, Allergan, Amgen, Arena, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Eli Lilly, Falk, Ferring, Galapagos, Gilead, Janssen, Lionhealth, MSD, Mylan, Nestlé, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, Takeda, Teva Pharmaceuticals, and Tillots Pharma; receiving speaker fees from AbbVie, Amgen, Biogen, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead, Janssen, Merck & Co, Mitsubishi Tanabe, Novartis, Pfizer, Roche, Samsung Bioepis, Sandoz, Takeda, and Tigenix; and receiving research grants from Biogen, Merck & Co, Pfizer, and Takeda. Dr Levine reported being a former AbbVie employee (at the time the study was conducted) and owning stock in AbbVie. Dr Kalabic reported having a patent pending for risankizumab to treat Crohn disease and ulcerative colitis. Drs Kalabic, Chen, Cheng, Shu, Duan, Pivorunas, Sanchez Gonzalez, D’Cunha, Neimark, and Wallace are employees of AbbVie. In addition, Dr Wallace reported having a patent pending for use of risankizumab to treat Crohn disease and ulcerative colitis. Dr Atreya reported receiving personal fees from AbbVie, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion Healthcare, the Falk Foundation, Ferring, Fresenius Kabi, Galapagos, Gilead, InDex Pharmaceuticals, Janssen-Cilag, Kliniksa Pharmaceuticals, Lilly, MSD, Novartis, Pfizer, Roche, Samsung Bioepsis, Stelic Institute, Takeda Pharma, Tillotts Pharma AG, and Viatris and receiving research/educational support from AbbVie, Biogen, InDex Pharmaceuticals, Takeda Pharma, and Tillotts Pharma AG. Dr Ferrante reported receiving personal fees from AbbVie, AgomAb Therapeutics, Biogen, Boehringer Ingelheim, Celgene, Celltrion, the Falk Foundation, Eli Lilly, Ferring, Janssen-Cilag, MRM Health, MSD, Pfizer, Regeneron, Takeda, Thermo Fisher, Truvion Healthcare, and Viatris; receiving research grants from AbbVie, Biogen, Exempli Gratia Pharmaceuticals, Janssen, Pfizer, Takeda, and Viatris; and receiving fees for speaking from Biogen, Boehringer Ingelheim, the Falk Foundation, Ferring, Janssen-Cilag, MSD, Pfizer, Takeda, Truvion Healthcare, and Viatris. Dr Loftus reported receiving consulting fees from AbbVie, Alvotech, Amgen, Arena, Astellas, Avalo, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion Healthcare, Eli Lilly, Fresenius Kabi, Genentech, Gilead Sciences, GSK, Gossamer Bio, Iota Biosciences, Iterative Health, Janssen, Morphic Therapeutic, Ono Pharma, Protagonist, Sun Pharma, Surrozen, Takeda, TR1X, and UCB Pharma; receiving research support from AbbVie, AstraZeneca, Bristol Myers Squibb, Celgene/Receptos, Genentech, Gilead Sciences, Gossamer Bio, Janssen, Pfizer, Receptos, Takeda, Theravance, and UCB Pharma; and being a shareholder of Exact Sciences. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow of Patients in the Induction Trial
aDetermination of eligibility was made at the clinical sites at the time of enrollment. The specific reasons for not meeting screening criteria were not collected. bThe 2:1 randomization was stratified by the number of prior biological drugs (0 or 1 vs >1) each patient received that produced an inadequate response, current use of steroids (yes vs no), and adapted Mayo score (≤7 vs >7). cThe patients included in the primary efficacy analysis received at least 1 dose of study drug during the 12-week, double-blind induction period.
Figure 2.
Figure 2.. Flow of Patients in the Maintenance Trial
aThe patients with an inadequate response to risankizumab could receive an additional 12 weeks of therapy with risankizumab (during an extended period of induction therapy in the phase 3 substudy; data not shown). bIncluded in the safety analysis. cReceived 1800-mg intravenous dose in phase 2b study or 1200-mg intravenous dose in phase 3 study. These individuals were included in the safety analysis only (not included in the primary efficacy analysis).
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