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Risankizumab Induction Therapy in Patients With Moderately to Severely Active Ulcerative Colitis: Efficacy and Safety in the Randomized Phase 3 INSPIRE Study
AIBD 2023
Background:
Risankizumab (RZB), a monoclonal antibody neutralizing interleukin (IL)-23p19, was evaluated for efficacy and safety of induction therapy in patients with moderately to severely active ulcerative colitis (UC) in the phase 3 trial, INSPIRE (NCT03398148).
Methods:
Eligible patients (18-80 years) with moderately to severely active UC (Adapted Mayo score of 5 – 9 points) and an endoscopic subscore of 2-3 (per central review) were enrolled. Patients were required to have demonstrated intolerance or inadequate response to conventional and/or advanced therapies (biologics, JAK inhibitors, and S1P receptor modulators). Patients (N=975) were randomized 2:1 to receive either RZB 1200 mg intravenously or placebo (PBO) at Weeks 0, 4, and 8, stratified by baseline corticosteroid use (yes vs no), baseline adapted Mayo Score (≤ 7 vs > 7), and number of advanced therapy failures (0, 1, >1). The primary endpoint was clinical remission (per Adapted Mayo Score defined as stool frequency subscore ≤ 1 and not greater than baseline, rectal bleeding subscore of 0, and endoscopic subscore ≤ 1 without friability) at Week 12. Key, ranked secondary endpoints included clinical response, endoscopic improvement, endoscopic remission, histologic-endoscopic mucosal improvement (HEMI), histologic-endoscopic mucosal remission (HEMR) at Week 12, unless otherwise noted.
Results:
Baseline characteristics were similar between treatment groups. A significantly greater proportion of patients receiving RZB (n=650) vs. PBO (n=325) achieved clinical remission (20.3% vs. 6.2%, adjusted treatment difference 14.0% [95% CI, 10.0%-18.0%], p < .00001). A greater proportion of patients achieved clinical remission for RZB vs. PBO in the advanced therapy-naïve (29.7% [n=317] vs. 8.4% [n=155], adjusted treatment difference 21.3% [95% CI, 14.6%-27.9%]) and advanced therapy-IR (11.4% [n=333] vs. 4.3% [n=170], adjusted treatment difference 7.2% [95% CI, 2.6%-11.8%]) subpopulations. All ranked secondary endpoints were met. Significantly higher clinical response rates (per Adapted Mayo Score at week 12: 64.3% vs. 35.7%, adjusted treatment difference 28.6% [95% CI, 22.3%-34.8%]; per partial Adapted Mayo Score at Week 4: 52.2% vs. 30.5%, adjusted treatment difference 21.8% [95% CI, 15.6%-28.1%]), endoscopic improvement (36.5% vs. 12.1%, adjusted treatment difference 24.3% [95% CI, 19.3%-29.4%]), endoscopic remission (10.6% vs. 3.4%, adjusted treatment difference 7.2% [95% CI, 4.2%-10.2%]), HEMI (24.5% vs. 7.7%, adjusted treatment difference 16.6% [95% CI, 12.3%-21.0%]), and HEMR (6.3% vs. 0.6%, adjusted treatment difference 5.6% [95% CI, 3.5%-7.7%]) were met for RZB vs. PBO, respectively (p < .00001 for all endpoints). Adverse event (AE) rates were 42.1% in RZB vs 49.7% in PBO, serious AEs (2.3% vs 10.2%), severe AEs (2.5% vs 10.2%), AEs leading to discontinuation of study drug (0.6% vs 3.7%), and serious infections (0.6% vs 1.2%), all numerically lower in the RZB arm. No adjudicated major adverse cardiovascular events, adjudicated anaphylaxis, or serious hepatic events reported. One death occurred in the RZB group due to covid-19 pneumonia, with no possibility of being related to study drug according to the investigator.
Conclusions:
RZB was superior to PBO as an induction therapy in patients with moderately to severely active UC for clinical remission and all secondary clinical, endoscopic, and endoscopic-histologic endpoints. RZB was well-tolerated, and no new safety risks were observed.
