91 Sustained Therapeutic Benefit of Vedolizumab Throughout 1 Year in Crohn's Disease in Gemini II, a Randomized, Placebo-Controlled, Double-Blind, Multicenter Study

Abstract

Introduction: Laquinimod (LAQ) is a novel oral immunomodulator in development for the treatment of Crohn's disease (CD). LAQ has an immune modulatory effect on antigen presenting cells (mainly M2 monocytes), directing T cells towards an antiinflammatory phenotype& resulting in down regulation of proinflammatory cytokines. This study evaluated the safety & efficacy of LAQ in patients with active moderate-severe CD and also assessed the impact of the drug on fecal calprotectin as an objective biomarker of intestinal inflammation. Methods: Phase IIa, multicenter, sequential-cohorts RCT with LAQ doses of 0.5, 1, 1.5, or 2 mg/day or placebo (45 patients per cohort randomized 2:1) for 8 weeks with 4-weeks follow-up. CD patients with a CD Activity Index (CDAI) of 220-450 & serum CRP .5mg/ L or mucosal ulcerations evident on endoscopy were included. Stable concomitant therapies (corticosteroids, immunosuppressive drugs [AZT, 6MP, MTX], 5-ASA, antibiotics) & prior anti-TNF use were allowed. Elevated fecal calprotectin was not required. Comprehensive safety monitoring and assessments were performed. Efficacy analyses included the proportions of patients in remission (CDAI ,150 & no treatment failure [TF]), those with a response 100 (i.e. 100 point CDAI reduction & no TF) and those who had a reduction in fecal calprotectin defined as a decrease from ≥250 μg/g to below 250 μg/g & ≥50% reduction. This study was exploratory & no hypothesis testing was planned. Results: Overall 117 patients received LAQ & 63 pts received placebo. AEs occurred in 86-97% of LAQ groups vs. 83% in pooled placebo group; most common AEs were headache, abdominal pain, nausea & vomiting, and musculoskeletal pain. For pooled LAQ and placebo groups, mean (SD) baseline CDAI were 298(58) & 311(75), and median (IQR) fecal calprotectin levels were 389(749) & 475(802) μg/g, respectively. At week 8, effects on remission and response were observed with the 0.5 mg LAQ dose; 1mg dose showed lower magnitude effects and higher LAQ doses showed similar effects to placebo (Table). All doses reduced fecal calprotectin. Conclusions: This study indicates that treatment with LAQ is well tolerated and the 0.5 and 1 mg doses may have clinically relevant effects on remission & response. All doses (LAQ 0.5-2 mg) were found to reduce objective measures of intestinal inflammation in active CD.