Risankizumab as induction therapy for Crohn's disease: results from the phase 3 ADVANCE and MOTIVATE induction trials

doi:10.1016/S0140-6736(22)00467-6

The Lancet

Volume 399, Issue 10340, 28 May–3 June 2022, Pages 2015-2030

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https://doi.org/10.1016/S0140-6736(22)00467-6 Get rights and content

Summary

Background

Risankizumab, an interleukin (IL)-23 p19 inhibitor, was evaluated for safety and efficacy as induction therapy in patients with moderately to severely active Crohn's disease.

Methods

ADVANCE and MOTIVATE were randomised, double-masked, placebo-controlled, phase 3 induction studies. Eligible patients aged 16–80 years with moderately to severely active Crohn's disease, previously showing intolerance or inadequate response to one or more approved biologics or conventional therapy (ADVANCE) or to biologics (MOTIVATE), were randomly assigned to receive a single dose of intravenous risankizumab (600 mg or 1200 mg) or placebo (2:2:1 in ADVANCE, 1:1:1 in MOTIVATE) at weeks 0, 4, and 8. We used interactive response technology for random assignment, with stratification by number of previous failed biologics, corticosteroid use at baseline, and Simple Endoscopic Score for Crohn's disease (SES-CD). All patients and study personnel (excluding pharmacists who prepared intravenous solutions) were masked to treatment allocation throughout the study. Coprimary endpoints were clinical remission (defined by Crohn's disease activity index [CDAI] or patient-reported outcome criteria [average daily stool frequency and abdominal pain score]) and endoscopic response at week 12. The intention-to-treat population (all eligible patients who received at least one dose of study drug in the 12-week induction period) was analysed for efficacy outcomes. Safety was assessed in all patients who received at least one dose of study drug. Both trials were registered on ClinicalTrials.gov, NCT03105128 (ADVANCE) and NCT03104413 (MOTIVATE), and are now complete.

Findings

Participants were enrolled between May 10, 2017, and Aug 24, 2020 (ADVANCE trial), and Dec 18, 2017 and Sept 9, 2020 (MOTIVATE trial). In ADVANCE, 931 patients were assigned to either risankizumab 600 mg (n=373), risankizumab 1200 mg (n=372), or placebo (n=186). In MOTIVATE, 618 patients were assigned to risankizumab 600 mg (n=206), risankizumab 1200 mg (n=205), or placebo (n=207). The primary analysis population comprised 850 participants in ADVANCE and 569 participants in MOTIVATE. All coprimary endpoints at week 12 were met in both trials with both doses of risankizumab (p values ≤0·0001). In ADVANCE, CDAI clinical remission rate was 45% (adjusted difference 21%, 95% CI 12–29; 152/336) with risankizumab 600 mg and 42% (17%, 8–25; 141/339) with risankizumab 1200 mg versus 25% (43/175) with placebo; stool frequency and abdominal pain score clinical remission rate was 43% (22%, 14–30; 146/336) with risankizumab 600 mg and 41% (19%, 11–27; 139/339) with risankizumab 1200 mg versus 22% (38/175) with placebo; and endoscopic response rate was 40% (28%, 21–35; 135/336) with risankizumab 600 mg and 32% (20%, 14–27; 109/339) with risankizumab 1200 mg versus 12% (21/175) with placebo. In MOTIVATE, CDAI clinical remission rate was 42% (22%, 13–31; 80/191) with risankizumab 600 mg and 40% (21%, 12–29; 77/191) with risankizumab 1200 mg versus 20% (37/187) with placebo; stool frequency and abdominal pain score clinical remission rate was 35% (15%, 6–24; 66/191) with risankizumab 600 mg and 40% (20%, 12–29; 76/191) with risankizumab 1200 mg versus 19% (36/187) with placebo; and endoscopic response rate was 29% (18%, 10–25; 55/191) with risankizumab 600 mg and 34% (23%, 15–31; 65/191) with risankizumab 1200 mg versus 11% (21/187) with placebo. The overall incidence of treatment-emergent adverse events was similar among the treatment groups in both trials. Three deaths occurred during induction (two in the placebo group [ADVANCE] and one in the risankizumab 1200 mg group [MOTIVATE]). The death in the risankizumab-treated patient was deemed unrelated to the study drug.

Interpretation

Risankizumab was effective and well tolerated as induction therapy in patients with moderately to severely active Crohn's disease.

Funding

AbbVie.

Introduction

Interleukin (IL)-23 inhibition is a promising therapeutic approach to treat Crohn's disease. IL-23 is an inflammatory cytokine comprising a distinct p19 subunit and a p40 subunit shared with IL-12.¹ IL-23 modulates intestinal inflammation through effector cytokines that include IL-22.² Elevated concentrations of IL-23 are present in the mucosa of patients with Crohn's disease, and genome-wide association studies have shown a strong correlation between polymorphisms of the IL-23 or IL-23 receptor (IL-23R) gene and inflammatory bowel diseases.3, 4, 5, 6 IL-23R gene variants have been shown to modulate IL-22 serum concentrations, which, in turn, have been shown to correlate with disease activity.7, 8, 9 A phase 2a study examining anti-IL-23 therapy in patients with Crohn's disease identified a decrease in serum IL-22 concentrations after treatment, with greater clinical remission and response rates in patients with higher baseline serum IL-22.¹⁰ Therefore, IL-22 might be clinically useful both as a downstream biomarker of Crohn's disease activity and as a pharmacodynamic biomarker of IL-23 activity.

Risankizumab is a monoclonal antibody that selectively binds to the IL-23 p19 subunit, inhibiting its interaction with the IL-23R complex, and is currently approved for the treatment of plaque psoriasis and psoriatic arthritis. In a randomised, double-masked, phase 2 study in patients with moderately to severely active Crohn's disease, intravenous induction therapy with risankizumab was well tolerated and efficacious at doses of 200 mg and 600 mg in patients who were naive to, or previously treated with, tumour necrosis factor (TNF) antagonist therapy or vedolizumab.¹¹ Higher efficacy was observed with the 600 mg dose; however, because a plateau of response was not reached, it was unknown if a dose higher than 600 mg would provide greater efficacy. Here, we report the primary results from the first 12 weeks of two phase 3 studies, ADVANCE and MOTIVATE. These trials evaluated the efficacy and safety of 600 mg and 1200 mg intravenous risankizumab as induction therapy in patients with moderately to severely active Crohn's disease who had previously shown intolerance or inadequate response to conventional or biologic therapies.

Section snippets

Study design and participants

ADVANCE and MOTIVATE were phase 3, multicentre, double-masked, randomised, placebo-controlled induction trials performed globally at 297 sites in 39 countries (ADVANCE) and 214 sites in 40 countries (MOTIVATE; appendix p 34). Sites included hospitals, academic medical centres, clinical research units, and private practices. Each study included a screening period of up to 35 days, a 12-week induction period (induction period 1), an additional exploratory 12-week prolonged induction period

Results

In the ADVANCE trial, 931 patients were randomly assigned to receive intravenous risankizumab 600 mg (n=373), intravenous risankizumab 1200 mg (n=372), or intravenous placebo (n=186) between May 10, 2017, and Aug 24, 2020. 850 participants were included in the primary efficacy analysis (figure 1). In MOTIVATE, 618 patients were randomly assigned to receive intravenous risankizumab 600 mg (n=206), intravenous risankizumab 1200 mg (n=205), or placebo (n=207) between Dec 18, 2017, and Sept 9,

Discussion

In patients with moderately to severely active Crohn's disease, a significantly greater proportion achieved the coprimary endpoints of clinical remission and endoscopic response with risankizumab treatment than with placebo treatment at week 12. Symptomatic improvement was evident at week 4, and endoscopic improvement was observed at week 12. Treatment effects of risankizumab were observed in patients with and without previous bio-failure. Considering these strong results, risankizumab could be

Data sharing

AbbVie is committed to responsible data sharing regarding the clinical trials it sponsors. This includes access to anonymised, individual, and trial-level data (analysis datasets), and other information (eg, protocols and clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. These clinical trial data can be requested by any qualified researchers who

Declaration of interests

GD’H reports being a consultant or speaker for AbbVie, ActoGeniX, AIM, Allergan, Amgen, Arena, Boehringer Ingelheim, Celgene (formerly Receptos), Celltrion, Cosmo Technologies, Elan, Eli Lilly, enGene, Dr Falk Pharma, Ferring, Galapagos, Genentech, Gilead Sciences, Giuliani, Given Imaging, GlaxoSmithKline (GSK), Gossamer Bio, Janssen Biologics, Merck, Sharp & Dohme (MSD), Neovacs, Norgine, Novo Nordisk, Otsuka, PDL BioPharma, Prometheus Laboratories, Progenity, Pfizer, Alimentiv (formerly

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ArticlesRisankizumab as induction therapy for Crohn's disease: results from the phase 3 ADVANCE and MOTIVATE induction trials

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Data sharing

Declaration of interests

Immunity

Clin Res Hepatol Gastroenterol

Gastroenterology

Lancet

Lancet

Gastroenterology

Gastroenterology

Lancet

IL-23–responsive innate lymphoid cells are increased in inflammatory bowel disease

J Exp Med

IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease

J Exp Med

A genome-wide association study identifies IL23R as an inflammatory bowel disease gene

Science

Articles
Risankizumab as induction therapy for Crohn's disease: results from the phase 3 ADVANCE and MOTIVATE induction trials