S1142 Impact of Guselkumab Therapy on Histologic and Combined Histologic and Endoscopic Outcomes in Patients With Moderately to Severely Active Ulcerative Colitis: Week 12 Results From the Phase 3 QUASAR Induction Study

Introduction: The Phase 3 QUASAR induction study evaluated efficacy and safety of guselkumab (GUS), an IL-23p19 subunit antagonist, in patients (pts) with moderately to severely active UC. Here we present results for effects of GUS induction on histologic and combined histologic and endoscopic outcomes at Week (Wk) 12. Methods: Pts with modified Mayo score of 5-9 and a centrally reviewed Mayo endoscopy subscore (MES)≥2 at induction baseline (BL) were randomized 3:2 to receive either GUS 200mg IV or placebo (PBO) IV at Wks0, 4, and 8. Colonic biopsies collected during endoscopy at BL and Wk12 were used to evaluate treatment effect on histology using three methods: Geboes score (GS), Robarts Histopathology Index (RHI), and Nancy Histological Index (NHI). Histologic improvement (GS≤3.1), histologic remission (GS≤2 B.0), combined histologic improvement and endoscopic improvement (GS≤3.1 and MES of 0 or 1 with no friability; histo-endoscopic mucosal improvement; HEMI), and combined histologic remission and endoscopic normalization (GS≤2 B.0 and MES of 0) were evaluated at Wk12. HEMI at Wk12 was a major secondary endpoint. All other analyses were not multiplicity controlled (nominal P-values). Results: A total of 701 pts were assessed (mean UC disease duration, 7.52yrs; mean modified Mayo score, 6.9; MES of 3, 67.9%). BL demographics and disease characteristics were similar across treatment groups. Histologic activity at BL was similar across the GUS and PBO cohorts: mean total GS (11.8 vs 11.9, respectively), mean RHI (16.6 vs 16.6), and mean NHI (2.7 vs 2.8). The proportion of GUS- and PBO-treated pts with histologic improvement at Wk12 was 44.9% and 21.4%, respectively (adjusted Δ: 23.7%; P< 0.001; Table 1). Histologic remission at Wk12 was achieved by 39.9% and 18.6% of GUS- and PBO-treated pts, respectively (adjusted Δ: 21.5%; P< 0.001). Identical results were seen across 2 additional definitions of histologic remission (ie, RHI and NHI). The proportion of GUS-treated pts achieving HEMI at Wk12 was significantly greater than PBO-treated pts (23.5% vs 7.5%, respectively; adjusted Δ: 16.2%; P< 0.001). The proportion of GUS- and PBO-treated pts with histologic remission and endoscopic normalization at Wk12 was 13.5% and 3.9%, respectively (adjusted Δ: 9.8%; P< 0.001). Conclusion: Pts with moderately to severely active UC treated with GUS 200mg IV induction experienced clinically meaningful improvements in histologic and combined histologic and endoscopic outcomes at Wk12. Table 1. - Summary of Histologic and Combined Histologic and Endoscopic Outcomes at Week 12 Placebo IV Guselkumab200 mg IV Adjusted treatment difference (95% CI) P-value Full analysis set, N 280 421 - Histologic improvement, n (%)(Neutrophil infiltration in < 5% of crypts, no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system [ie, Geboes histologic score ≤3.1]) 60 (21.4) 189 (44.9) 23.7 (17.0, 30.3)*** Histologic remission, n (%)(Absence of neutrophils from the mucosa [both lamina propria and epithelium], no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system [ie, Geboes histologic score ≤2 B.0])a 52 (18.6) 168 (39.9) 21.5 (15.1, 27.9)*** Histologic remission by alternative definition, n (%)(Nancy Histological Index ≤ 1) 52 (18.6) 168 (39.9) 21.5 (15.1, 27.9)*** Histo-endoscopic mucosal improvement, n (%)(Achieving a combination of histologic improvement [ie, Geboes histologic score ≤3.1] and endoscopic improvement [Mayo endoscopy subscore of 0 or 1 with no friability]) 21 (7.5) 99 (23.5) 16.2 (11.1, 21.2) P< 0.001 Histologic remission and endoscopic normalization, n (%)(Absence of neutrophils from the mucosa [both lamina propria and epithelium], no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system [ie, Geboes histologic score ≤2 B.0] and Mayo endoscopy subscore of 0) 11 (3.9) 57 (13.5) 9.8 (5.8, 13.7)*** ***Nominal P< 0.001.aThis definition is equivalent to histologic remission by alternative definition using the Robarts Histopathology Index (RHI ≤ 3, with subscores of 0 for lamina propria neutrophils and neutrophils in the epithelium and without ulcers or erosion).Note: Patients who had a prohibited change in UC medication, an ostomy or colectomy, or discontinued study agent due to lack of therapeutic effect or due to an AE of worsening of UC, or due to other reasons except for COVID-19 related reasons (excluding COVID-19 infection) or regional crisis in Russia and Ukraine prior to Week 12 were considered not to have achieved the endpoint. Patients who had an unevaluable biopsy (i.e., a biopsy that was collected, but could not be assessed due to sample preparation or technical errors) or were missing the endoscopy subscore (if applicable) or any of the histology components pertaining to this endpoint (i.e., assessment of neutrophils in epithelium, crypt destruction, or erosions or ulcerations or granulations) at Week 12 were considered not to have achieved the endpoint. The adjusted treatment difference and confidence intervals were based on the Wald statistic with Cochran-Mantel-Haenszel weight. The P-values were based on the Cochran-Mantel-Haenszel (CMH) chi-square test, stratified by ADT-Failure status (Yes/No) and concomitant use of corticosteroids at baseline (Yes/No).

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