PMID- 33313070 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220418 IS - 2296-9365 (Electronic) IS - 2296-9403 (Print) IS - 2296-9365 (Linking) VI - 5 IP - 4 DP - 2020 Nov TI - A Multicentre, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy, Safety, and Tolerability of the S1P Receptor Agonist KRP203 in Patients with Moderately Active Refractory Ulcerative Colitis. PG - 180-190 LID - 10.1159/000509393 [doi] AB - 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. CI - Copyright (c) 2020 by S. Karger AG, Basel. FAU - Radeke, Heinfried H AU - Radeke HH AD - Interdisciplinary Crohn Colitis Centre Rhein-Main, Frankfurt am Main, Germany. AD - Hospital of the Goethe University Frankfurt/Main, Frankfurt am Main, Germany. FAU - Stein, Jurgen AU - Stein J AD - Interdisciplinary Crohn Colitis Centre Rhein-Main, Frankfurt am Main, Germany. FAU - Van Assche, Gert AU - Van Assche G AD - Translational Research in Gastrointestinal Disorders, School of Medicine, University of Leuven, Leuven, Belgium. FAU - Rogler, Gerhard AU - Rogler G AD - Clinic of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. FAU - Lakatos, Peter L AU - Lakatos PL AD - IBD Centre, Department of Medicine, McGill University, Montreal, Quebec, Canada. FAU - Muellershausen, Florian AU - Muellershausen F AD - Novartis Basel, Basel, Switzerland. FAU - Moulin, Pierre AU - Moulin P AD - Novartis Basel, Basel, Switzerland. FAU - Jarvis, Philip AU - Jarvis P AD - Novartis Basel, Basel, Switzerland. FAU - Colin, Laurence AU - Colin L AD - Novartis Basel, Basel, Switzerland. FAU - Gergely, Peter AU - Gergely P AD - Novartis Basel, Basel, Switzerland. FAU - Kruis, Wolfgang AU - Kruis W AD - Evangelisches Krankenhaus, Cologne, Germany. LA - eng PT - Journal Article DEP - 20200821 PL - Switzerland TA - Inflamm Intest Dis JT - Inflammatory intestinal diseases JID - 101677990 PMC - PMC7706482 OTO - NOTNLM OT - Clinical trials OT - Sphingosine-1-phosphate OT - Ulcerative colitis COIS- H.H.R. has received expenses from Novartis for attendance of the investigator meeting for this study and has no other conflicts of interest. W.K. has received consultancy fees from Falk, Ferring, Genetic Analysis, Istitut Allergosan, Nikkiso, and Otsuka, and lecturing fees from Abbvie, Ardeypharm, and Tillotts. J.S. has received consultancy fees from Abbvie, Fresenius-Kabi, Immundiagnostik, MSD, Pharmacosmos, Takeda, GI Dynamics, and Vifor; lecturing fees from Abbvie, Falk Foundation, Ferring, Immundiagnostik, MSD, Pharmacosmos, Takeda, Thermofischer, GI Dynamics, and Vifor; and payment for manuscript preparation from Abbvie, Falk Foundation, GI Dynamics, and MSD. P.L.L. has no conflicts of interest to declare. P.J. and P.G. are employees of Novartis. L.C. is an employee and stockholder of Novartis. P.M. is an employee and stockholder of Novartis Institutes of Biomedical Research. F.M. is an employee and stockholder of Novartis Bioventures Ltd. G.R. has consulted to Abbot, Abbvie, Augurix, Boehringer, Calypso, FALK, Ferring, Fisher, Genentech, Essex/MSD, Novartis, Pfizer, Phadia, Roche, UCB, Takeda, Tillots, Vifor, Vital Solutions, and Zeller; received speaker's honoraria from Astra Zeneca, Abbott, Abbvie, FALK, MSD, Phadia, Tillots, UCB, and Vifor; and received educational and research grants from Abbot, Abbvie, Ardeypharm, Augurix, Calypso, Essex/MSD, FALK, Flamentera, Novartis, Roche, Takeda, Tillots, UCB, and Zeller. G.A. has received expenses from Novartis for meetings in connection with this study; consultancy fees from Janssen, Takeda, and Abbvie; and lecturing fees from Abbvie and Pfizer. EDAT- 2020/12/15 06:00 MHDA- 2020/12/15 06:01 PMCR- 2020/08/21 CRDT- 2020/12/14 10:59 PHST- 2020/01/15 00:00 [received] PHST- 2020/06/15 00:00 [accepted] PHST- 2020/12/14 10:59 [entrez] PHST- 2020/12/15 06:00 [pubmed] PHST- 2020/12/15 06:01 [medline] PHST- 2020/08/21 00:00 [pmc-release] AID - iid-0005-0180 [pii] AID - 10.1159/000509393 [doi] PST - ppublish SO - Inflamm Intest Dis. 2020 Nov;5(4):180-190. doi: 10.1159/000509393. Epub 2020 Aug 21.