S1240 The Efficacy of Maintenance Treatment with Guselkumab in Patients With Moderately to Severely Active Ulcerative Colitis: Phase 3 QUASAR Maintenance Study Results at Week 44 by Biologic/Janus Kinase History

Introduction: The Phase 3 QUASAR Maintenance Study evaluated the efficacy of maintenance treatment with subcutaneous (SC) guselkumab (GUS), a dual-acting IL-23p19 subunit inhibitor, in patients (pts) with ulcerative colitis (UC) who achieved clinical response following intravenous GUS induction treatment. Here, we report Week (Wk) 44 efficacy and safety results for GUS treatment compared with withdrawal (placebo) by history of treatment with biologics/Janus kinase inhibitors (BIO/JAK). Methods: At maintenance baseline, clinical responders to 12 wks of GUS IV induction from QUASAR Phase 2b and Phase 3 induction studies (NCT04033445) were randomized 1:1:1 to GUS 200mg SC every 4 weeks, GUS 100mg SC every 8 weeks, or placebo (GUS withdrawal). The primary analysis population included randomized and treated pts in the Maintenance Study with a modified Mayo score of 5-9 at induction baseline. Key clinical, histologic, and endoscopic efficacy endpoints and safety events were evaluated through Wk44. Results: Of the 568 pts included, 240 (42.3%) had a history of inadequate response or intolerance to BIO/JAK (BIO/JAK-IR) and 309 (54.4%) were BIO/JAK naïve, At induction baseline, BIO/JAK-IR pts had longer disease duration (mean 9.94 vs 6.25 years) and more severe endoscopic disease (Mayo endoscopic subscore[MES]=3, 79.6% vs 56.7%) compared with pts with no BIO/JAK history. Among both the BIO/JAK-IR and naïve subpopulations, higher proportions of GUS-treated pts achieved the key efficacy endpoints at Wk44 compared with withdrawal pts (Table 1). The proportions of pts who met the key endpoints at Wk44 were generally higher in the BIO/JAK naïve subpopulation compared with the BIO/JAK-IR subpopulation across treatment groups, however, treatment differences were generally greater in BIO/JAK-IR pts. Among the anti-TNF-IR, vedolizumab-IR, or tofacitinib-IR pts, higher proportions of GUS-treated pts achieved the key endpoints at Wk44 compared with withdrawal pts (Figure 1). Through Wk44, adverse events for the BIO/JAK-IR and BIO/JAK naïve subpopulations were consistent with the overall population, and no new safety concerns were identified. Conclusion: Maintenance treatment with both GUS dosing regimens resulted in greater improvements compared with placebo withdrawal across key clinical, endoscopic, and histologic endpoints at Wk44 regardless of prior history with biologics/JAK inhibitors. Safety results for both GUS maintenance dose regimens were comparable across subpopulations by treatment history and consistent with the known safety profile of GUS.Figure 1.: Key endpoints at Maintenance Week 44 by history of anti-TNF, vedolizumab, or tofacitinib therapy: Primary analysis population. *Nominal P <0.05. **Nominal P <0.01. ***Nominal P <0.001. Denominator is the number of pts who had inadequate response or intolerance to anti-TNFs, vedolizumab, or tofacitinib, regardless of other advanced therapies including adalimumab, golimumab, infliximab, tofacitinib, vedolizumab, and their biosimilars. Pts who had a prohibited change in UC medication, an ostomy or colectomy, a dose adjustment (including a sham dose adjustment), 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 Wk 44 visit were considered not to have achieved the endpoint. Pts who were missing 1 or more components pertaining to a specified endpoint at Wk 44 were considered not to have achieved the endpoint. COVID-19, coronavirus disease 2019; Pts, patients; TNF, tumor necrosis factor; Wk, week. Table 1. - Key endpoints at Maintenance Week 44 by history of biologic/JAK inhibitor therapy: Primary analysis population BIO/JAK-IR Patients BIO/JAK Naive Patients GUS Withdrawal (Placebo)(N=75) GUS 100mg SC every 8 weeks(N=77) GUS 200 mg SC every 4 weeks(N=88) GUS Withdrawal (Placebo)(N=108) GUS 100 mg SC every 8 weeks(N=105) GUS 200mg SC every 4 weeks(N=96) Clinical remission, n (%)a1b Adjusted treatment difference (95%CI) 6 (8.0%) 31 (40.3%) 30.4% (18.7%, 42.1%) P < 0.001 35 (39.8%) 32.4% (21.1%, 43.7%) P < 0.001 28 (25.9%) 53 (50.5%) 24.3% (12.0%, 36.5%) P < 0.001 56 (58.3%) 28.8% (16.5%, 41.1%) P < 0.001 Endoscopic improvement, n (%)a2b Adjusted treatment difference (95%CI) 6 (8.0%) 35 (45.5%) 35.8% (23.8%, 47.8%) P < 0.001 37 (42.0%) 34.6% (23.1%, 46.0%) P < 0.001 28 (25.9%) 56 (53.3%) 27.2% (15.0%, 39.5%) P < 0.001 57 (59.4%) 30.0% (17.6%, 42.4%) P < 0.001 Histo-endoscopic mucosal improvement, n (%)a3b Adjusted treatment difference (95%CI) 6 (8.0%) 29 (37.7%) 27.7% (16.0%, 39.5%) P < 0.001 34 (38.6%) 31.2% (19.8%, 42.5%) P < 0.001 25 (23.1%) 52 (49.5%) 26.1% (14.0%, 38.2%) P < 0.001 54 (56.3%) 29.5% (17.3%, 41.7%) P < 0.001 Endoscopic remission (MES=0), n (%)a4b Adjusted treatment difference (95%CI) 6 (8.0%) 24 (31.2%) 21.4% (10.0%, 32.7%) P < 0.001 21 (23.9%) 16.3% (6.4%, 26.1%) P =0.005 22 (20.4%) 40 (38.1%) 17.3% (5.6%, 29.1%) P =0.005 40 (41.7%) 17.5% (6.0%, 29.0%) P =0.004 Biologic/JAK inhibitor experienced without documented inadequate response or intolerance to biologics/JAK inhibitors: placebo, n=7; GUS 100 mg, n=6; GUS 200 mg, n=6. All P-values were nominal. P-values were based on the CMH test, stratified by clinical remission status at maintenance baseline and induction treatment, except for the maintenance of clinical remission, which was based on the Fisher’s exact test . Adjusted treatment difference was based on the Wald statistic with CMH weight.a1Clinical remission: A Mayo stool frequency subscore of 0 or 1 and not increased from induction baseline, a Mayo rectal bleeding subscore of 0, and a Mayo endoscopic subscore of 0 or 1 with no friability.a2Endoscopic improvement: An endoscopy subscore of 0 or 1 with no friability present on the endoscopy.a3Histo-endoscopic mucosal improvement: Achieving a combination of histologic improvement (neutrophil infiltration in < 5% of crypts, no crypt destruction, and no erosions, ulcerations or granulation tissue per Geboes grading system) and endoscopic improvement.a4Endoscopic remission (normalization): An endoscopic subscore of 0.bPts who had a prohibited change in UC medication, an ostomy or colectomy, a dose adjustment (including a sham dose adjustment), 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 Wk 44 visit were considered not to have achieved the endpoint. Pts who were missing 1 or more components pertaining to a specified endpoint at Wk 44 were considered not to have achieved the endpoint.

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