Early Symptomatic Improvement With Guselkumab Induction Treatment in Moderately to Severely Active Ulcerative Colitis: Results From the Phase 3 QUASAR Induction Study

Introduction: The Phase 3 QUASAR Induction Study (NCT04033445) was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study of guselkumab (GUS), an interleukin-23 p19 subunit antagonist, in patients (pts) with moderately to severely active ulcerative colitis (UC). Here the early onset of symptom improvement was evaluated. Methods: Pts were randomized in a 3:2 ratio to receive IV GUS 200mg or placebo (PBO) at Weeks (Wks) 0, 4, and 8. The primary analysis population included treated pts with a baseline modified Mayo score of 5 to 9, and an endoscopy subscore ≥ 2 (centrally read). Through Wk12, pts recorded stool production and episodes of rectal bleeding in a diary. Symptomatic remission at Wks 2, 4, and 12 were major secondary endpoints. All other analyses were not multiplicity controlled (nominal P-values). Results: The primary analysis population included 701 randomized and treated pts (mean UC duration, 7.5yrs, Mayo endoscopy subscore=3 [severe disease], 67.9%, and mean modified Mayo score, 6.9, at baseline). At baseline, 49.1% had prior inadequate response/intolerance to advanced therapies (ADT-IR) for UC; nearly half of these (47.4%) had ≥2 ADT-IR classes. At baseline, for the GUS and PBO groups, respectively, mean absolute number of stools per day were 7.10 and 6.96; stool frequency subscores of 0 or 1 were observed in 10.0% and 9.6%; and mean rectal bleeding subscores were 1.7 and 1.8. As early as Wk1 and increasing through Wk12, greater symptomatic improvement was seen in pts treated with GUS compared with PBO (Figure 1). At Wks 2, 4, 8, and 12, symptomatic remission was achieved by GUS- vs PBO-treated pts in 12.1% vs 9.3%, 22.6% vs 12.9%, 39.7% vs 20.7%, and 49.9% vs 20.7% (all P< 0.001, except Wk2, P=0.210), respectively. For GUS vs PBO, percentages of pts with stool frequency subscore of 0 or 1 at Wks 2, 4, 8, and 12 were 26.1% vs 18.2%, 41.3% vs 25.4%, 53.4% vs 29.6%, and 60.1% vs 31.8% (all P< 0.001, except Wk2, P< 0.05), respectively; percentages of pts with rectal bleeding subscores of 0 at Wks 2, 4, 8, and 12 were 24.2% vs 19.3%, 36.8% vs 22.9%, 55.8% vs 33.2%, and 64.6% vs 28.6% (all P< 0.001, except Wk2, P=0.110), respectively. Treatment differences for GUS vs PBO were evident across Wk12 symptomatic outcomes (Table 1). Conclusion: GUS 200mg IV induction was effective in improving symptoms as early as 1 week after the first dose in pts with moderately to severely active UC. Symptomatic improvements increased through Wk12.Figure 1.: Symptomatic response through Wk12. Table 1. - Symptomatic outcomes at Wk12 Placebo IV Guselkumab 200 mg IV Treatment Difference d (95% CI) Primary analysis population, N 280 421 - Symptomatic response,ab proportion of patients (95% CI) 35.0% (29.4%, 40.6%) 71.7% (67.4%, 76.0%) 37.0% (30.1%, 43.9%)*** Symptomatic remission,ac proportion of patients (95% CI) 20.7% (16.0%, 25.5%) 49.9% (45.1%, 54.7%) 29.4% (22.8%, 36.0%), P< 0.001 Stool frequency subscore of 0 or 1 a proportion of patients (95% CI) 31.8% (26.3%, 37.2%) 60.1% (55.4%, 64.8%) 28.5% (21.5%, 35.6%)*** Rectal bleeding subscore of 0 a proportion of patients (95% CI) 28.6% (23.3%, 33.9%) 64.6% (60.0%, 69.2%) 36.2% (29.3%, 43.2%)*** Absolute number of stools per day,a N=274 N=420 mean change from baseline (95% CI) -1.4 (-1.7, -1.0) -3.2 (-3.5, -2.8) -1.8 (-2.20, -1.37)*** Rectal bleeding subscore,a N=274 N=420 mean change from baseline (95% CI) -0.6 (-0.7, -0.5) -1.2 (-1.3, -1.1) -0.7 (-0.8, -0.5)*** ***Nominal P< 0.001.aPatients who had a prohibited change in UC medication, an ostomy or colectomy, or discontinued study agent due to lack of efficacy or an adverse event 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 for binary endpoints and had baseline observation carried forward for continuous endpoints. Patients who were missing 1 or more components pertaining to a specified endpoint were considered not to have achieved the endpoint for binary endpoints. The P-values for binary endpoints were based on the Cochran-Mantel-Haenszel (CMH) chi-square test. The P-values for continuous endpoints were based on a Mixed-Effect Model Repeated Measures.bSymptomatic response was defined a decrease from induction baseline in the symptomatic Mayo score (sum of the stool frequency and the rectal bleeding subscores) by ≥ 30% and ≥ 1 point, with either a ≥ 1 point decrease from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1.cSymptomatic remission was defined as a stool frequency subscore of 0 or 1 and not increased from induction baseline, and a rectal bleeding subscore of 0.dTreatment differences in proportions were adjusted for strata (ADT-IR status and concomitant use of corticosteroids at baseline) based on Cochran-Mantel-Haenszel weight.