S1447 Histologic and Combined Histologic and Endoscopic Outcomes After Guselkumab Maintenance Therapy in Patients With Moderately to Severely Active Ulcerative Colitis: Week 44 Results From the Phase 3 QUASAR Maintenance Study

Introduction: The phase 3 QUASAR maintenance study (NCT04033445) evaluated the efficacy and safety of guselkumab (GUS), a dual-acting IL-23p19 subunit inhibitor that potently neutralizes IL-23, in patients (pts) who achieved clinical response to 12 weeks of intravenous (IV) GUS. Here we present results for effects of GUS maintenance on histologic and combined histologic and endoscopic outcomes at Week (Wk) 44. Methods: At maintenance baseline (BL), clinical responders following 12 weeks of GUS IV induction from the QUASAR Phase 2b and 3 induction studies were randomized 1:1:1 to GUS 200 mg subcutaneous (SC) every 4 weeks, GUS 100 mg SC every 8 weeks, or GUS withdrawal (PBO SC). Colonic biopsies were collected during endoscopy at maintenance BL and Wk 44 to evaluate treatment effect on histology measured using Geboes, Robarts, and Nancy Histological Index. Histologic improvement, histologic remission, the combination of histologic improvement and endoscopic improvement (histo-endoscopic mucosal improvement; HEMI), the combination of histologic remission and endoscopic improvement, and the combination of histologic remission and endoscopic remission (histo-endoscopic mucosal remission) were evaluated at Wk 44 (see Table 1 for definitions). Results: Of the 568 pts randomized (at induction BL: mean age, 40.7yrs; mean UC disease duration, 7.8yrs; mean modified Mayo score, 6.9 [63.9% with severe disease]; Mayo endoscopy subscore of 3, 66.4%), 190 were receiving GUS 200 mg every 4 weeks, 188 GUS 100 mg every 8 weeks, and 190 PBO. BL characteristics were similar across treatment groups. Histologic activity at maintenance BL was similar for the GUS 200 mg every 4 weeks, GUS 100 mg every 8 weeks, and PBO treatment groups (mean continuous Geboes total score: 6.7, 6.8, and 6.9, respectively). Improvements in histologic activity at Wk 44 were observed in pts treated with GUS 200 mg every 4 weeks and GUS 100 mg every 8 weeks, while pts assigned to PBO worsened. At Wk 44, greater proportions of pts treated with GUS 200 mg every 4 weeks and GUS 100 mg every 8 weeks achieved the assessed endpoints compared to PBO (Table 1). Across biologic/JAK inhibitor therapy history subpopulations, greater proportions of GUS-treated pts achieved the assessed endpoints compared to PBO. Conclusion: In this phase 3 maintenance study, pts with UC treated with GUS 200 mg SC every 4 weeks or GUS 100 mg SC every 8 weeks experienced clinically meaningful improvements in histologic and combined histologic and endoscopic outcomes at Wk 44 compared to PBO-treated pts. Table 1. - Summary of Histologic and Combined Histologic and Endoscopic Outcomes at Week 44 GUS Withdrawal (Placebo) GUS 100 mg SC every 8 weeks GUS 200 mg SC every 4 weeks Primary analysis population, N 190 188 190 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]) 58 (30.5) 122 (64.9) 122 (64.2) Adjusted treatment difference (95% CI)Nominal P-value - 33.6 (24.3, 42.9) P < 0.001 32.6 (23.3, 41.9) P < 0.001 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 51 (26.8) 111 (59.0) 115 (60.5) Adjusted treatment difference (95% CI)Nominal P-value - 31.2 (21.9, 40.5) P < 0.001 32.6 (23.5, 41.8) P < 0.001 Histo-endoscopic mucosal improvement (HEMI), n (%)(Achieving a combination of histologic improvement and endoscopic improvement [Mayo endoscopy subscore of 0 or 1 with no friability]) 32 (16.8) 82 (43.6) 91 (47.9) Adjusted treatment difference (95% CI)Multiplicity-controlled P-value - 25.7 (17.1, 34.3) P < 0.001 29.6 (21.1, 38.0) P < 0.001 Histologic remission and endoscopic improvement, n (%)(Geboes histologic score ≤2 B.0 and endoscopic improvement) 30 (15.8) 78 (41.5) 89 (46.8) Adjusted treatment difference (95% CI)Nominal P-value - 24.7 (16.2, 33.2) P < 0.001 29.6 (21.3, 38.0) P < 0.001 Histo-endoscopic mucosal remission, n (%)(Geboes histologic score ≤2 B.0 and Mayo endoscopy subscore of 0) 27 (14.2) 59 (31.4) 62 (32.6) Adjusted treatment difference (95% CI)Nominal P-value - 16.2 (8.2, 24.3) P < 0.001 16.9 (9.2, 24.7) P < 0.001 a Results for histologic remission by alternative definitions using Robarts Histopathology Index (RHI ≤ 3, with subscores of 0 for lamina propria neutrophils and neutrophils in the epithelium and without ulcers or erosion) and Nancy Histological Index (NHI ≤ 1) were identical.Note: Patients who had a prohibited change in UC medication, an ostomy or colectomy, a dose adjustment (including sham dose adjustment), 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 44 were considered not to have achieved the endpoint. Patients who had an unevaluable biopsy (ie, 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 an endpoint at Week 44 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 (CMH) weight. The P-values were based on the CMH chi-square test, stratified by clinical remission status at maintenance baseline (Yes/No), and induction treatment (guselkumab 400 mg IV, guselkumab 200 mg IV, placebo IV crossover to guselkumab 200 mg IV).

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