The Effect of Guselkumab Induction Therapy in Patients With Moderately to Severely Active Ulcerative Colitis: QUASAR Phase 2b Induction Results at Week 12 by Prior Inadequate Response or Intolerance to Advanced Therapy

ABSTRACT

Introduction: QUASAR (NCT04033445) is a phase 2b randomized, double-blind, placebo-controlled study that evaluates guselkumab (GUS), an interleukin-23 p19 subunit antagonist, as induction treatment in patients with moderately to severely active ulcerative colitis (UC) who had an inadequate response or intolerance to conventional (ie, thiopurines or corticosteroids) or advanced therapy (ADT;ie, tumor necrosis factor alpha antagonists, vedolizumab, or tofacitinib). Conclusion: Treatment with GUS resulted in greater improvements compared with placebo across key clinical and endoscopic/histologic outcome measures at Week 12 in patients with moderately to severely active UC with or without a history of inadequate response/intolerance to ADT. Efficacy at Week 12 by prior response/intolerance to ADT Placebo IV (N=105) GUS 200 mg IV (N=101) GUS 400 mg IV (N=107) GUS Combined(N=208) Patients with a history of inadequate response/intolerance to ADT 51 46 51 97  Clinical response a1,b,c,d,e (95% CI) 25.5% (14.3, 39.6) 54.3%* (39.0, 69.1) 47.1%* (32.9, 61.5) 50.5%* (40.2, 60.8)  Clinical remission a2,b,c,d,e (95% CI) 7.8% (2.2, 18.9) 17.4% (7.8, 31.4) 17.6% (8.4, 30.9) 17.5% (10.6, 26.6)  Symptomatic remission a3,b,c,d,e (95% CI) 17.6% (8.4, 30.9) 39.1%* (25.1, 54.6) 37.3%* (24.1, 51.9) 38.1%* (28.5, 48.6)  Endoscopic improvement a4,b,c,d,e (95% CI) 9.8% (3.3, 21.4) 23.9% (12.6, 38.8) 21.6% (11.3, 35.3) 22.7% (14.8, 32.3)  Histo-endoscopic mucosal improvement a5,b,c,d,e (95% CI) 5.9% (1.2, 16.2) 13.0% (4.9, 26.3) 19.6%* (9.8, 33.1) 16.5% (9.7, 25.4)  Endoscopic normalization a6,b,c,d,e (95% CI) 5.9% (1.2, 16.2) 10.9% (3.6, 23.6) 5.9% (1.2, 16.2) 8.2% (3.6, 15.6) Patents with no history of inadequate response/intolerance to ADT 54 55 56 111  Clinical response a1,b,c,d,e (95% CI) 29.6% (18.0, 43.6) 67.3%** (53.3, 79.3) 73.2%** (59.7, 84.2) 70.3%** (60.9, 78.6)  Clinical remission a2,b,c,d,e (95% CI) 11.1% (4.2, 22.6) 32.7%* (20.7, 46.7) 32.1%* (20.3, 46.0) 32.4%* (23.9, 42.0)  Symptomatic remission a3,b,c,d,e (95% CI) 22.2% (12.0, 35.6) 58.2%** (44.1, 71.3) 57.1%** (43.2, 70.3) 57.7%** (47.9, 67.0)  Endoscopic improvement a4,b,c,d,e (95% CI) 14.8% (6.6, 27.1) 36.4%* (23.8, 50.4) 39.3%* (26.5, 53.2) 37.8%* (28.8, 47.5)  Histo-endoscopic mucosal improvement a5,b,c,d,e (95% CI) 11.1% (4.2, 22.6) 27.3%* (16.1, 41.0) 33.9%* (21.8, 47.8) 30.6%* (22.2, 40.1)  Endoscopic normalization a6,b,c,d,e (95% CI) 7.4% (2.1, 17.9) 23.6%* (13.2, 37.0) 21.4%* (11.6, 34.4) 22.5%* (15.1, 31.4) * Nominal p-value < 0.05. ** Nominal p-value < 0.001. a1 Clinical response is defined as decrease from induction baseline in the modified Mayo score by ≥30% and ≥2 points, with either a ≥1-point decrease from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1. a2 Clinical remission is defined as stool frequency subscore of 0 or 1 with no increase from induction baseline, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1 with no friability present on the endoscopy. a3 Symptomatic remission is defined as a stool frequency subscore of 0 or 1 with no increase from induction baseline and a rectal bleeding subscore of 0. a4 Endoscopic improvement is defined as an endoscopy subscore of 0 or 1 with no friability present on the endoscopy. a5 Histo-endoscopic mucosal improvement is defined as achieving a combination of histologic improvement (neutrophil infiltration in < 5% of crypts, no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system) and endoscopic improvement, a6 Endoscopic normalization is defined as an endoscopy subscore of 0. b Patients 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 prior to the Week 12 visit were considered not to have achieved the endpoint. c Data after discontinuation of study agent due to COVID-19 related reasons (excluding COVID-19 infection) were considered to be missing. d Patients who were issing one or more components pertaining to a specified endpoint at Week 12 were considered not to have achieved the endpoint. e The p-values were based on the Cochran-Mantel-Haenszel (CMH) chi-square test.