S1 Risankizumab Versus Ustekinumab in Patients With Moderate to Severe Crohn’s Disease: Results From the Phase 3B SEQUENCE Trial

Background: Risankizumab (RZB) is a safe and effective treatment for Crohn’s disease (CD). The phase 3b SEQUENCE study directly compared the efficacy and safety of RZB, a selective IL-23 p19 inhibitor, and ustekinumab (UST), an IL-12/IL-23 p40 inhibitor. Methods: SEQUENCE was an open-label, multicenter, randomized, efficacy assessment-blinded study in patients with moderate to severe CD (CD activity index [CDAI] of 220-450, endoscopic evidence of mucosal inflammation, and average daily stool frequency ≥4 and/or average daily abdominal pain score ≥2) who previously failed ≥1 anti-TNF therapies. In Part 1 of the trial, patients were randomized 1:1 to receive RZB or UST for 48 weeks (wks). Randomization was stratified by number of anti-tumor necrosis factor (TNF) therapies failed (1/>1) and baseline steroid use (Yes/No). A mandatory steroid taper started at wk2. Primary endpoints were clinical remission (CDAI <150) at wk24 (non-inferiority of RZB vs UST in 50% of planned patients) and endoscopic remission (Simple Endoscopic Score for CD ≤4 and at least 2-point reduction vs baseline and no subscore >1 in any individual variable) at wk48 (superiority of RZB vs UST). Other clinical, endoscopic, and quality of life (QoL) outcomes, as well as adverse events (AEs), were assessed. Results: Five hundred twenty-seven patients were randomized; 520 were assessed for efficacy (RZB, N=255; UST, N=265). A higher proportion of patients completed the study with RZB (89.4%) versus UST (74.0%). Both primary endpoints of the study were met. At wk24, clinical remission rates were 58.6% (75/128) for RZB and 39.5% (54/137) for UST (Δ18.4 [95% CI, 6.6-30.3], non-inferiority met with the pre-defined margin of 10%); this endpoint was also analyzed post-hoc to test for superiority and achieved nominal P< 0.01. At wk48, endoscopic remission rates were 31.8% (81/255) for RZB and 16.2% (43/265) for UST (Δ15.6% [8.4-22.9], P< 0.0001 for superiority). RZB was superior to UST for all secondary endpoints: clinical remission at wk48 (60.8% vs 40.8%, Δ19.7% [11.3-28.1]), endoscopic response at wk48 (45.1% vs 21.9%, Δ23.3% [15.4-31.2]) and wk24 (45.2% vs 26.4%, Δ18.9% [10.9-26.9]), steroid-free (SF) endoscopic remission at wk48 (31.4% vs 15.5%, Δ15.9 [8.8-23.1]), and SF clinical remission at wk48 (60.8% vs 40.4%, Δ20.1% [11.7-28.4]) (all P< 0.0001 for superiority). Mean change from baseline in Inflammatory Bowel Disease Questionnaire total score was significantly greater with RZB versus UST at wk24 (52.4 vs 40.2, Δ12.2 [6.6-17.8]) and wk48 (56.5 vs 42.4, Δ14.1 [8.2-20.0]) (all P< 0.0001). Exposure-adjusted AE rates (Events/100 Patient Years) were comparable between RZB (341.2) and UST (282.7). Rates of serious AEs and AEs leading to study drug discontinuation were numerically lower with RZB than UST. Serious infection and hepatic event rates were similar between treatment groups with no serious hepatic events within the RZB arm. Two cases of malignancy were reported (one per treatment arm). There was one adjudicated major adverse cardiovascular event with UST. There were no deaths. Conclusions: In patients with moderate to severe CD who failed anti-TNF therapy, RZB demonstrated non-inferiority to UST in achieving wk24 clinical remission, superiority in achieving wk48 endoscopic remission, and superiority in other clinical, endoscopic, and QoL outcomes. The safety profiles of RZB and UST were consistent with previously published results.

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