Heinfried H Radeke1,2, Jürgen Stein1, Gert Van Assche3, Gerhard Rogler4, Peter L Lakatos5, Florian Muellershausen6, Pierre Moulin6, Philip Jarvis6, Laurence Colin6, Peter Gergely6, Wolfgang Kruis7. 1. Interdisciplinary Crohn Colitis Centre Rhein-Main, Frankfurt am Main, Germany. 2. Hospital of the Goethe University Frankfurt/Main, Frankfurt am Main, Germany. 3. Translational Research in Gastrointestinal Disorders, School of Medicine, University of Leuven, Leuven, Belgium. 4. Clinic of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. 5. IBD Centre, Department of Medicine, McGill University, Montreal, Québec, Canada. 6. Novartis Basel, Basel, Switzerland. 7. Evangelisches Krankenhaus, Cologne, Germany.
Abstract
BACKGROUND AND AIMS: KRP203 is a potent oral agonist of the sphingosine-1-phosphate receptor subtype 1 that induces the sequestration of peripheral lymphocytes, thereby potentially reducing the number of activated lymphocytes circulating to the gastrointestinal tract. METHODS: We conducted a multicentre, double-blind, placebo-controlled, parallel-group, proof-of-concept study to evaluate the efficacy, safety, and tolerability of KRP203 in patients with moderately active 5-aminosalicylate-refractory ulcerative colitis (UC). Patients were randomly assigned to receive 1.2 mg KRP203 or placebo daily for 8 weeks. Primary efficacy variable was clinical remission, defined as partial Mayo Score 0-1 and modified Baron Score 0-1 with rectal bleeding subscore 0. RESULTS: KRP203 was safe and well tolerated overall. The most common adverse events (AEs) were gastrointestinal disorders and headache. Importantly, no KRP203-related cardiac AEs were reported. Total peripheral lymphocytes and selectively affected lymphocyte subtypes decreased, causing marked decreases in naive and central memory CD4+ and CD8+ T cells, and also in B cells. Clinical remission occurred in 2/14 (14%) patients under KRP203, compared with 0/8 (0%) under placebo. CONCLUSIONS: Overall, KRP203 was safe and well tolerated by patients with UC. Importantly, no cardiac AEs were reported. Although KRP203 did not meet the minimum clinically relevant threshold for efficacy, the results may suggest that KRP203 treatment is superior to placebo. However, in this small study population, the difference was insignificant. Based on these data, studies with an improved design and a larger population should be considered.
BACKGROUND AND AIMS: KRP203 is a potent oral agonist of the sphingosine-1-phosphate receptor subtype 1 that induces the sequestration of peripheral lymphocytes, thereby potentially reducing the number of activated lymphocytes circulating to the gastrointestinal tract. METHODS: We conducted a multicentre, double-blind, placebo-controlled, parallel-group, proof-of-concept study to evaluate the efficacy, safety, and tolerability of KRP203 in patients with moderately active 5-aminosalicylate-refractory ulcerative colitis (UC). Patients were randomly assigned to receive 1.2 mg KRP203 or placebo daily for 8 weeks. Primary efficacy variable was clinical remission, defined as partial Mayo Score 0-1 and modified Baron Score 0-1 with rectal bleeding subscore 0. RESULTS: KRP203 was safe and well tolerated overall. The most common adverse events (AEs) were gastrointestinal disorders and headache. Importantly, no KRP203-related cardiac AEs were reported. Total peripheral lymphocytes and selectively affected lymphocyte subtypes decreased, causing marked decreases in naive and central memory CD4+ and CD8+ T cells, and also in B cells. Clinical remission occurred in 2/14 (14%) patients under KRP203, compared with 0/8 (0%) under placebo. CONCLUSIONS: Overall, KRP203 was safe and well tolerated by patients with UC. Importantly, no cardiac AEs were reported. Although KRP203 did not meet the minimum clinically relevant threshold for efficacy, the results may suggest that KRP203 treatment is superior to placebo. However, in this small study population, the difference was insignificant. Based on these data, studies with an improved design and a larger population should be considered.
Authors: G Van Assche; W J Sandborn; B G Feagan; B A Salzberg; D Silvers; P S Monroe; W M Pandak; F H Anderson; J F Valentine; G E Wild; D J Geenen; R Sprague; S R Targan; P Rutgeerts; V Vexler; D Young; R S Shames Journal: Gut Date: 2006-04-07 Impact factor: 23.059
Authors: William J Sandborn; Brian G Feagan; Douglas C Wolf; Geert D'Haens; Severine Vermeire; Stephen B Hanauer; Subrata Ghosh; Heather Smith; Matthew Cravets; Paul A Frohna; Richard Aranda; Sheila Gujrathi; Allan Olson Journal: N Engl J Med Date: 2016-05-05 Impact factor: 91.245