RISANKIZUMAB VERSUS USTEKINUMAB FOR THE ACHIEVEMENT OF CLINICAL REMISSION AND REDUCTION IN INFLAMMATORY BIOMARKERS IN PATIENTS WITH MODERATE-TO-SEVERE CROHN’S DISEASE: RESULTS FROM THE PHASE 3B SEQUENCE TRIAL

Improved clinical outcomes and normalization of objective markers of inflammation are important treatment targets per STRIDE-II consensus for patients (pts) with Crohn’s disease (CD). In SEQUENCE, a head-to-head trial comparing the efficacy and safety of risankizumab (RZB), an interleukin (IL)-23 p19 inhibitor, and ustekinumab (UST), an IL-12/IL-23 p40 inhibitor, in pts with moderate-to-severe CD refractory to anti-tumor necrosis factor (TNF)a therapy, RZB met both primary endpoints (week [wk] 24 clinical remission in 50% of the pt population [RZB non-inferior to UST], and wk 48 endoscopic remission [superiority of RZB to UST].¹ Here, the efficacy of RZB versus (vs) UST with respect to changes from baseline (BL) in C-reactive protein (CRP) and fecal calprotectin FCP, as well as a composite endpoint of FCP or CRP normalization and clinical remission (biologic remission), were assessed in SEQUENCE.

SEQUENCE (NCT04524611) was an open-label, multicenter, randomized, efficacy assessment-blinded study. Pts in the primary efficacy analysis set were randomized 1:1 to receive RZB (600mg intravenous [IV] induction at BL, wk4, and wk8 followed by 360mg subcutaneous [SC] maintenance dosing every 8 wks [Q8w] starting at wk12) or UST (single weight-based IV induction dose followed by 90mg SC maintenance dosing, treatment Q8w starting at wk8) up to wk48. Randomization was stratified by BL steroid use and the number of failed anti-TNFs. Post-hoc analyses assessed the change from BL in FCP and high sensitivity (hs)-CRP at wks 8, 24, and 48 using a mixed-effect model with repeated measures. Biologic remission (clinical remission [CDAI <150] and FCP ≤250mg/kg or hs-CRP ≤5mg/L), a prespecified, non-ranked efficacy endpoint at wks 24 and 48 (post-hoc analysis at wk8), was also assessed at the same timepoints using non-responder imputation while incorporating multiple imputation to handle missing data due to COVID-19 and geopolitical conflicts (see Figure footnote). These endpoints were evaluated in the full pt population. Treatment differences were adjusted for the randomization stratification factors. All P values are nominal.

As early as wk8, with RZB vs UST, a greater reduction from BL in FCP (wk8: -1014.0 [CI -1379.4 to -648.5] vs -650.2 [CI -997.8 to -302.7]) and hs-CRP (wk8: -10.6 [CI -13.0 to -8.2] vs -5.5 [CI -7.8 to -3.1], P< 0.01) were observed. At wk8, 24 and 48, a greater proportion of pts with RZB versus (vs) UST achieved biologic remission (wk8: 26.3% vs 21.9%; wk24: 42.8% vs 24.9%, P< 0.0001; wk48: 46.3% vs 27.5%, P< 0.0001) (Figure). The safety profiles of RZB and UST were consistent with published results.¹

A greater proportion of pts with CD who failed anti-TNFa therapy achieved biologic remission with RZB vs UST. Average reductions in inflammatory biomarkers were greater with RZB than UST and were demonstrated as early as wk8.

¹doi.org/10.1002/ueg2.12474