Risankizumab for Maintenance Treatment of Moderate-to-Severe Active Crohn’s Disease: Results from the Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 FORTIFY Maintenance Trial

Background

There is a great unmet need for new therapies with new mechanisms of action for patients with Crohn’s disease. The ADVANCE and MOTIVATE studies showed that intravenous risankizumab, a selective p19 anti-interleukin (IL)-23 antibody, was effective and well tolerated as an induction therapy. Here we report the efficacy and safety of subcutaneous risankizumab as maintenance therapy.

Methods

FORTIFY is a phase 3, multicenter, randomized, double-blind, placebo-controlled, maintenance withdrawal study in 273 clinical centers in 44 countries in North and South America, Europe, Oceania, Africa and the Asia-Pacific region which recruited participants with clinical response to risankizumab in the ADVANCE or MOTIVATE induction studies. Patients in the ADVANCE or MOTIVATE studies were between 16 and 80 years old and had moderate to severe active Crohn’s disease. Patients in the FORTIFY 1 substudy were re-randomised (1:1:1) to receive either subcutaneous risankizumab 180 mg, subcutaneous risankizumab 360 mg, or risankizumab withdrawal to receive a subcutaneous placebo (hereinafter referred to as withdrawal [subcutaneous placebo]). Treatment was administered every 8 weeks. Patients were stratified by induction dose, post-induction endoscopic response, and clinical remission status. Patients, investigators, and study staff were masked for treatment assignments. Co-primary endpoints at week 52 were clinical remission (Crohn’s Disease Activity Index [CDAI] in the US protocol, or stool frequency and abdominal pain score in the non-US protocol) and endoscopic response in patients who received at least one dose of study drug during the maintenance period of 52 weeks. Safety was assessed in patients receiving at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03105102.

Results

712 patients were initially evaluated and, between April 9, 2018 and April 24, 2020, 542 patients were randomized either to the risankizumab 180 mg group (n=179) or to the risankizumab 360 mg group (n=179), or in the placebo group (n = 184). Greater clinical remission and endoscopic response rates were achieved with risankizumab 360 mg compared to placebo (clinical CDAI remission was achieved in 74 (52%) of 141 patients vs. 67 (41%) of 164 patients, adjusted difference 15% [95% CI 5–24]; stool frequency and abdominal pain score, clinical remission was achieved in 73 (52%) of 141 vs. 65 (40%) of 164, adjusted difference 15% [5–25]; endoscopic response 66 (47%) of 141 patients vs. 36 (22%) of 164 patients, adjusted difference 28% [19–37]). Higher rates of CDAI clinical remission and endoscopic response (but not stool frequency and abdominal pain score) clinical remission [p=0·124]) were also achieved with risankizumab 180 mg versus withdrawal (subcutaneous placebo; CDAI clinical remission achieved in 87 [55%]
of 157 patients, adjusted difference 15% [95% CI 5–24]; endoscopic response 74 [47%]
of 157, adjusted difference 26% [17–35]). Results for more stringent endoscopic and composite parameters and inflammatory biomarkers were consistent with a dose-response relationship. Maintenance treatment was well tolerated. Adverse event rates were similar between groups, and the most commonly reported adverse events across all treatment groups were worsening of Crohn’s disease, arthralgia, and headache.

Interpretation

Subcutaneous risankizumab is a safe and effective treatment for maintaining remission in patients with moderately to severely active Crohn’s disease and offers a new treatment option for a wide range of patients by meeting endpoints likely to modify the future course of the disease.

Funding

AbbVie.

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