OP08 Mucosal healing with vedolizumab in inflammatory bowel disease patients with chronic pouchitis: Evidence from EARNEST, a randomized, double-blind, placebo-controlled trial

Abstract

Background Mucosal healing (MH) is an important treatment goal for inflammatory bowel disease (IBD). Vedolizumab (VDZ), a gut-selective anti-lymphocyte trafficking agent, has shown potential to achieve MH.1,2 EARNEST, a randomized double-blind placebo-controlled trial of VDZ in chronic pouchitis,3 offers a robust dataset systematically collected from the inflamed pouch mucosa to further explore the impact of VDZ treatment on MH. Methods EARNEST evaluated intravenous VDZ (300 mg) vs placebo (PBO) administered at weeks 0, 2, 6, 14, 22, and 30, in adult patients (pts) with active chronic pouchitis despite antibiotic therapy after proctocolectomy and ileal pouch-anal anastomosis for ulcerative colitis. Endoscopic imaging was captured and centrally read at baseline, Week (W) 14, and W34. Total ulceration and SES-CD (modified to apply to a single segment) were evaluated. Microscopic inflammation was also evaluated using the Pouchitis Disease Activity Index (PDAI) histological component. Pre-specified exploratory endpoints included changes in total ulceration and SES-CD remission (score ≤2); MH was defined post-hoc as SES-CD=0 plus PDAI histology score ≤1 (none/mild polymorphic nuclear leukocyte infiltration and no ulceration). Fecal calprotectin (FCP) levels were explored by MH status. PDAI remission (score <7 and ≥3 point-reduction from baseline) and Inflammatory Bowel Disease Questionnaire (IBDQ) remission (score ≥170) were assessed in pts with/without MH at W14. Results In total, 98 pts had endoscopic evaluations (VDZ n=48; PBO n=50). Ulcers/erosions were higher in VDZ pts at baseline with a greater reduction at W14 and W34 with VDZ vs PBO (Table 1). More pts treated with VDZ vs PBO achieved reduction in ulcerated surface area, complete absence of ulceration/erosions and SES-CD remission. At W14, 7/42 (16.7%) pts had MH on VDZ vs 1/40 (2.5%) on PBO. All 7 VDZ pts with MH at W14 were in PDAI remission at W14 and W34; 6/7 (85.7%) pts achieved IBDQ remission at W14 and 5/7 (71.4%) achieved IBDQ remission at both W14 and W34. Of the 35 VDZ-treated pts without MH at W14, 11/35 (31.4%) achieved PDAI remission at W14, 11/35 (31.4%) at W34, and 9/35 (25.7%) at both W14 and W34; 13/35 (37.1%) achieved IBDQ remission at W14, 17/35 (48.6%) at W34, and 12/35 (34.3%) at both W14 and W34. MH was associated with FCP ≤250 µg/g while ~40-60% of pts without MH had FCP >250 µg/g (Table 2). Conclusion VDZ was associated with better control of markers of inflammation vs PBO, based upon improvements in endoscopic/histologic outcomes in the pouch mucosa, as well as improved outcomes reported by pts. These effects of VDZ in the pouch mucosa are consistent with those observed in the wider patient population with IBD.

Systematic review and meta‐analysis of randomised controlled trials: Medical therapies for the treatment and prevention of pouchitis

“…In the EARNEST trial, vedolizumab led to a higher proportion of patients with reduction in ulcers/erosions in the pouch, ulcerated surface area and endoscopic mucosal healing as measured by the SES‐CD score and histological remission. Furthermore, achieving mucosal healing at week 14 was associated with a higher likelihood of clinical remission and improved quality of life at week 34 6 …”

“…In 2022, the results of the EARNEST trial were presented. 6,7 This was a phase 4, randomised placebocontrolled trial of vedolizumab in patients with active chronic pouchitis and demonstrated the benefit of vedolizumab across a range of endpoints (clinical, endoscopic and histological). Despite the relatively small sample size, reflective of the orphan nature of this indication, the EARNEST trial led to the approval of vedolizumab for chronic pouchitis by the European Medicines Agency.…”

“…Furthermore, achieving mucosal healing at week 14 was associated with a higher likelihood of clinical remission and improved quality of life at week 34. 6 The strengths of this systematic review include the comprehensive search for all RCTs of medical therapy for the treatment and prevention of pouchitis, which provides a contemporary summary of medical therapy that has been assessed in pouchitis. Another strength is that we assessed study quality using the Cochrane risk of bias tool and we assessed the certainty of the evidence using the GRADE criteria.…”

“…Uncontrolled studies have suggested tumour necrosis factor (TNF) antagonists and ustekinumab may be effective for the treatment of antibiotic‐refractory pouchitis 5 . Recently, vedolizumab a monoclonal antibody blocking the interaction of α 4 β 7 integrin with mucosal addressin cell adhesion molecule‐1, inhibiting migration of gastrointestinal‐homing T lymphocytes across the gut vascular endothelium, was approved by the European Medicines Agency for treatment of chronic pouchitis based on the results of the phase 4 EARNEST trial 6,7 …”

“…5 Recently, vedolizumab a monoclonal antibody blocking the interaction of α 4 β 7 integrin with mucosal addressin cell adhesion molecule-1, inhibiting migration of gastrointestinal-homing T lymphocytes across the gut vascular endothelium, was approved by the European Medicines Agency for treatment of chronic pouchitis based on the results of the phase 4 EARNEST trial. 6,7 The primary objective of this systematic review was to assess the efficacy and safety of various medical therapies including, antibiotics, probiotics, biologics, small molecules, microbiome and faecal microbiota transplantation (FMT) for the treatment and prevention of pouchitis in patients with IPAA following colectomy for UC.…”