Vedolizumab Maintenance Therapy for Ulcerative Colitis: Results of GEMINI I, a Randomized, Placebo-Controlled, Double-Blind, Multicenter Phase 3 Trial (2012)

Purpose: To assess the efficacy and safety of vedolizumab (VDZ), an investigational gut-selective monoclonal antibody targeting the α4β7 integrin, for maintaining clinical response and remission for 52 weeks in patients with moderate to severely active ulcerative colitis (UC) in whom at least 1 prior therapy had failed. Methods: Eligible adult patients had a Mayo score of ≥6 and endoscopic subscore of ≥2 despite corticosteroids (CSs), purine antimetabolites, and/or TNFα antagonists. After 2 induction doses of VDZ (weeks 0 and 2), patients with clinical response (reduction in Mayo score of ≥3 points and ≥30% from baseline, plus decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤1) at week 6 were randomized 1:1:1 to VDZ 300 mg IV every 4 weeks, VDZ 300 mg IV every 8 weeks, or placebo for 46 weeks. The primary outcome was clinical remission (Mayo score of ≤2 points and no individual subscore >1) at week 52. Secondary outcomes were durability of clinical response and durability of clinical remission (ie, endpoint met at both weeks 6 and 52), mucosal healing (Mayo endoscopic subscore of ≤1 point), and CS-free remission at 52 weeks. Results: Of 895 patients enrolled (mean age 40.3 yrs, mean disease duration 6.9 yrs, mean baseline Mayo score 8.6), 373 met response criteria at 6 weeks (ITT population) and were randomized to receive VDZ q4 wks (n=125), VDZ q8 wks (n=122), or placebo (n=126). A significantly greater proportion of VDZ-treated patients than placebo-treated patients achieved clinical remission, mucosal healing, and CS-free remission at 52 weeks and durable response and remission (Table 1). 32% of the ITT population had prior anti-TNFα failure. Clinical remission and durable clinical response rates were greater in VDZ than placebo patients regardless of prior anti-TNF treatment status (Table 2). In the safety population (N=895) for weeks 0-52, rates of adverse events (AEs), serious AEs, and serious infections were similar between the VDZ and placebo groups. No increase in rates of opportunistic or enteric infections was observed in the VDZ group. One death occurred—a 66-yr-old man who received 1 induction dose of VDZ died 14 days later from acute coronary syndrome.Table 1: Clinical remission, durable clinical response, mucosal healing, durable remission, and corticosteroid-free remission, ITT population ( n =373)Table: [1522] Table 2. Clinical remission and durable clinical response at 52 weeks in patients with prior anti-TNF failure or without anti-TNF exposure, ITT populationaConclusion: Maintenance therapy with VDZ every 4 or 8 weeks was significantly more effective than placebo in achieving clinical remission, durable clinical response and remission, mucosal healing, and corticosteroid-free remission in UC patients with a high rate of prior anti-TNF failure. No increase in rates of infectious complications was observed with VDZ. We speculate that this finding may reflect the gut-selective anti-inflammatory effect of this monoclonal antibody. Disclosure: This study was suported by Millennium Pharmaceuticals, Inc. Dr. Feagan - Grant/Research Support, Merck, Otsuka, Milllennium, Tillotts, Abbott, Protein Design Labs, Boehringer Engelheim, Novartis, Centocor, Berlex, Synta, Elan/Biogen, UCB Pharma, BMS, Proctor and Gamble, Osiris, Genentech, CombinatoRx, ActoGeniX, Wyeth, Consultant, Synta, Millennium, Merck, Centocor, Elan/Biogen, Janssen-Ortho, Protein Design Labs, ISIS, Teva Pharmaceuticals, Santarus, Bristol-Myers Squibb, Celgene, Combinatorx, UCB Pharma, Napo Pharma, Abbott, Proctor and Gamble, Osiris, Berlex, Astra Zeneca, GeneLogic Inc. Cerimon Pharm., Tioga Pharm, Serono, Genentech, Tillotts, Unity Pharmaceuticals, Albireo Pharma, Given Imaging Inc., Salix Pharm., Ore Pharm. (previously GeneLogic), Novonordisk, GSK, Actogenix, Prometheus Therapeutics and Diagnostics, Athersys, Alba Therapeutics, Axcan, Funxional Therapeutics, Gilead, Nektar, Pfizer, Shire, Wyeth, Zealand Pharm, Zyngenia, gICare Pharma Inc., Speakers Bureau, UCB, Abbott, J&J/Janssen, Advisory Boards, Astra Zeneca, Elan/Biogen, Celltech, Merck, Celgene, Novartis, Given Imaging Inc., UCB Pharma, Salix Pharmaceuticals, Abbott Laboratories, Centocor Inc. Pfizer, Axcan, Tillotts Pharma AG, Prometheus Laboratories; Dr. Rutgeerts - Consultant/Lectures/Research Support, Centocor, Merck, UCB, Abbott, Genentech/Roche, Pfizer, Hoffmann-LaRoche, Bristol Myers Squibb, Tillotts, GSK, chemo-Centryx, Neovacs, Millennium Pharmaceuticals and Takeda Pharmaceuticals; Dr. Sands - Consultant and Grant/Research Support, Takeda Pharmaceuticals; Dr. Sandborn - Consultant and Grant/Research Support, Millennium Pharmaceuticals and Takeda Pharmaceuticals; Dr. Colombel - Consultant, Takeda Pharmaceuticals; Dr. Hanauer - Consultant and Advisory Boards, Takeda Pharmaceuticals; Dr. van Assche - Consultant, Millennium Pharmaceuticals and Takeda Pharmaceuticals; Dr Danese - Consultant, Schering Plough, Astra-Zeneca, Abbott Laboratories, Novo Nordisk, Cellerix, Salix, Ferring, Merck Sharp & Dohme, MillenniumPharmaceuticals and Takeda Pharmaceuticals, Lecture Fees/Speakers Bureau, UCB Pharma, Ferring, Vifor and Merck Sharp & Dohme; Drs. Fox, Milch, Sankoh, Wyant, and Xu - Employees, Millennium Pharmaceuticals; Dr. Parikh - Employee, Takeda Pharmaceuticals International; Drs. Axler and Kim - no relationships to disclose.