S716 Induction Combination Therapy With Guselkumab and Golimumab Followed by Guselkumab Monotherapy Maintenance: Results of the Phase 2a, Randomized, Double-Blind, Proof-of-Concept VEGA Study

Introduction: Week (wk) 12 data from the VEGA study demonstrated that dual blockade of interleukin (IL)-23 and TNFα more effectively induced clinical response, clinical remission, endoscopic improvement, and composite histologic-endoscopic outcomes than either monotherapy alone. The efficacy and safety of combination induction therapy with guselkumab (GUS) + golimumab (GOL) followed by GUS monotherapy for maintenance (combination GUS) vs GUS or GOL alone were evaluated through wk38 in adults with moderately-to-severely active UC. Methods: 214 patients (pts) naïve to TNFα antagonists and refractory or intolerant to conventional therapy were randomized to receive GUS 200mg intravenous (IV) at wks0, 4, and 8 100mg subcutaneous (SC) every 8 wks (q8w) (n=71); GOL 200mg subcutaneous (SC) at wk0 then 100mg SC at wk2 and q4w thereafter (n=72); or combination therapy with GUS 200mg IV+GOL 200mg SC at wk0, GOL 100mg SC at wks2, 6, and 10, and GUS 200mg IV at wks4 and 8 followed by GUS 100 mg SC q8w (n=71). After wk12, pts randomized to monotherapy continued treatment through the final efficacy assessment at wk38, while pts randomized to the combination group transitioned to maintenance GUS. Clinical, endoscopic, histologic, and composite histologic-endoscopic endpoints were assessed. Safety was assessed through the final safety visit (up to wk50 or 16 wks after the final dose of study intervention). Results: Overall, 13.1% of pts discontinued treatment prior to wk34 (final dose of study intervention). Clinical remission rates (based on the full Mayo score) at wk38 in the combination GUS group (43.7%) were greater than the GUS and GOL monotherapy groups (31.0% and 22.2%, respectively, Table). Rates of clinical remission by modified Mayo (mMayo) score components, endoscopic improvement, endoscopic normalization, histologic remission, and composite histologic-endoscopic endpoints at wk38 were also greater in the combination GUS group than the GUS or GOL monotherapy groups. GUS monotherapy resulted in greater rates of clinical, endoscopic, and histologic outcomes than GOL monotherapy at wk38. Adverse event (AE), serious AE, infection, and serious infection rates were comparable among treatment groups through the final safety visit. Conclusion: Pts who received combination GUS treatment maintained greater rates of clinical remission, endoscopic improvement, endoscopic normalization, and both histologic remission and endoscopic improvement at wk38 than those who received GUS or GOL monotherapy. Table 1. - Efficacy at wk 38; intent-to-treat population Outcome, n (%) GOL (N=72) GUS (N=71) Combination → GUS (N=71) Δ (80% CI) a P-value b Combination → GUS vs. GOL Δ (80% CI) a P-value b Combination → GUS vs. GUS Clinical remission c,d 16 (22.2) 22 (31.0) 31 (43.7) 21.5 (11.9, 31.2)0.006 12.7 (2.7, 22.7)0.109 Clinical remission (based on mMayo) c,e 15 (20.8) 22 (31.0) 34 (47.9) 27.1 (17.7, 36.6)< 0.001 16.9 (7.0, 26.8)0.033 Symptomatic remission c,f 43 (59.7) 49 (69.0) 49 (69.0) 9.4 (-0.6, 19.4)0.238 0.0 (-9.7, 9.7)1.000 Endoscopic improvementc.g 16 (22.2) 23 (32.4) 35 (49.3) 27.2 (17.6, 36.7)< 0.001 16.9 (7.0, 26.8)0.033 Endoscopic normalization c,h 5 (6.9) 11 (15.5) 18 (25.4) 18.5 (11.1, 25.9)0.002 9.9 (1.6, 18.2)0.134 Histologic remission c,i 18 (25.0) 29 (40.8) 36 (50.7) 25.8 (16.1, 35.5)0.001 9.9 (-0.4, 20.1)0.224 Both histologic remission and endoscopic improvement c,g,i 10 (13.9) 15 (21.1) 30 (42.3) 28.5 (19.6, 37.4)< 0.001 21.1 (11.8, 30.5)0.005 Both histologic remission and endoscopic normalization c,h,i 4 (5.6) 9 (12.7) 17 (23.9) 18.5 (11.3, 25.6)0.002 11.3 (3.3, 19.2)0.074 aThe adjusted treatment difference between the combination therapy vs. the monotherapy groups and the confidence interval were based on the Wald statistic with the Cochran-Mantel-Haenszel (CMH) weight.bThe p-value was based on the 2-sided CMH chi-square test, stratified by corticosteroid use at baseline (Yes, No). All P-values are nominal.cPts who had an ostomy or colectomy, had a protocol-prohibited change in concomitant UC medications, or discontinued study intervention due to lack of a therapeutic effect or an adverse event of worsening UC, or discontinued study agent early due to COVID-19 related reasons (excluding COVID-19 infection) prior to the wk 38 visit were considered to not have achieved the binary endpoints. Pts with missing data at wk 38 were considered to not have achieved the binary endpoints.dClinical remission is defined as Mayo score ≤2, with no individual subscore >1.eClinical remission (based on the mMayo) is defined as a stool frequency subscore of 0 or 1, where the stool frequency subscore has not increased from baseline, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1 with no friability present on endoscopy.fSymptomatic remission is defined as Mayo stool frequency subscore of 0 or 1, where the stool frequency subscore has not increased from baseline, and a rectal bleeding subscore of 0.gEndoscopic improvement is defined as an endoscopy subscore of 0 or 1 with no friability present on the endoscopy.hEndoscopic normalization is defined as an endoscopy subscore of 0.iHistologic remission is defined as 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.

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