S1059 the Efficacy of Induction Treatment with Guselkumab in Patients with Moderately to Severely Active Ulcerative Colitis: Phase 3 QUASAR Induction Study Results at Week 12 by Prior Advanced Therapy History

Introduction: The Phase 3 QUASAR induction study (NCT04033445) was a randomized, double-blind, placebo-controlled study that evaluated guselkumab (GUS), an interleukin-23 p19 subunit antagonist, in patients (pts) with moderately to severely active ulcerative colitis (UC) who had an inadequate response, loss of response, or intolerance to corticosteroids, immunosuppressants and/or advanced therapy (ADT, i.e., tumor necrosis factor antagonists, integrin receptor antagonists [vedolizumab], and/or Janus kinase [JAK] inhibitors [tofacitinib]). Here we report induction efficacy results for GUS compared with placebo (PBO) by history of inadequate response, loss of response, or intolerance to ADT (ADT-IR). Methods: Pts were randomized 3:2 to receive IV GUS 200mg or PBO at Weeks (Wks) 0, 4, and 8. The primary analysis population included pts with a baseline modified Mayo score of 5 to 9 and a centrally reviewed endoscopy subscore ≥2. Primary endpoint was clinical remission at Wk12. Symptomatic remission, clinical response, endoscopic improvement, histo-endoscopic mucosal improvement (HEMI), and endoscopic normalization were assessed at Wk12. Results: Of the 701 pts in the primary analysis population, 357 (50.9%) had no history of ADT-IR (of which 95.0% were ADT-naïve) ; 344 (49.1%) had a history of ADT-IR. Among the ADT-IR pts, the proportions with a history of inadequate response/loss of response/intolerance to TNF antagonists, vedolizumab, tofacitinib and multiple ADT classes were 87.5%, 54.1%, 18.0% and 47.4%, respectively. At baseline, pts with a history of ADT-IR had longer disease duration (mean 8.9 vs 6.2 yrs), more severe endoscopic disease (endoscopy subscore of 3, 78.5% vs 57.7%), higher CRP (median 5.3 mg/L vs 3.4 mg/L and proportion of pts >3mg/L 64.1% vs 53.7%) and higher fecal calprotectin (median 1647 mg/kg vs 1589 mg/kg and proportion of pts >250 mg/kg 92.3% vs 86.9%) compared with pts without a history of ADT-IR. Greater proportions of patients treated with GUS vs PBO achieved primary and key secondary endpoints at Wk12 in both subgroups of pts with and without a history of ADT-IR (Table 1). Treatment differences for GUS vs PBO were generally greater among pts without a history of ADT-IR compared with those with such a history. Conclusion: Induction treatment with GUS 200mg IV vs PBO resulted in greater improvements across key clinical, symptomatic, and endoscopic/histologic outcomes at Wk12 among moderately to severely active UC pts with and without a history of ADT-IR. Table 1. - Primary and key secondary endpoints by history of inadequate response/loss of response/intolerance to advanced therapy (ADT-IR) No history of ADT-IR History of ADT-IR Placebo IV GUS 200mg IV Adjusted treatment difference (95% CI)c Placebo IV GUS 200mg IV Adjusted treatment difference (95% CI)c Primary analysis population, N 144 213 - 136 208 - Clinical remission at Wk12a1b (primary endpoint), N (%) 17 (11.8%) 69 (32.4%) 20.6% (12.4%, 28.8%)*** 5 (3.7%) 26 (12.5%) 8.8% (3.4%, 14.3%)** Symptomatic remission at Wk 12,a2b N (%) 39 (27.1%) 130 (61.0%) 33.9% (24.2%, 43.7%)*** 19 (14.0%) 80 (38.5%) 24.5% (15.7%, 33.3%)*** Clinical response at Wk 12,a3 b N (%) 51 (35.4%) 152 (71.4%) 36.0% (26.1%,45.8%)*** 27 (19.9%) 107 (51.4%) 31.6% (22.0%, 41.1%)*** Endoscopic improvement at Wk 12,a4b N (%) 24 (16.7%) 82 (38.5%) 21.8% (12.9%,30.8%)*** 7 (5.1%) 31 (14.9%) 9.8% (3.7%, 15.8%)** Histo-endoscopic mucosal improvement at Wk 12,a5b N (%) 15 (10.4%) 71 (33.3%) 22.9% (14.9%, 31.0%)*** 6 (4.4%) 28 (13.5%) 9.1% (3.3%, 14.8%)** Endoscopic normalization at Wk 12,a6b N (%) 11 (7.6%) 45 (21.1%) 13.5% (6.5%, 20.4%)*** 3 (2.2%) 18 (8.7%) 6.4% (1.9%, 11.0%)* *P-value < 0.05. **P-value < 0.01. ***P-value < 0.001. All P-values are nominal. The P-values were based on the Cochran-Mantel-Haenszel (CMH) chi-square test.a1Clinical 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.a2Symptomatic 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.a3Clinical 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. Modified Mayo score is a 3-component (stool frequency, rectal bleeding, and endoscopy subscores) Mayo score without the physician’s global assessment.a4Endoscopic improvement is defined as an endoscopy subscore of 0 or 1 with no friability present on the endoscopy.a5Histo-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.a6Endoscopic normalization is defined as an endoscopy subscore of 0.bPatients 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 other reasons except for COVID-19 related reasons (excluding COVID-19 infection) or regional crisis in Russia and Ukraine prior to the Week 12 visit were considered not to have achieved the endpoint. Patients who were missing one or more components pertaining to a specified endpoint at Week 12 were considered not to have achieved the endpoint.cThe adjusted treatment difference and confidence intervals were based on the Wald statistic with Cochran-Mantel-Haenszel weight.