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* = Presenting author

P372 A multicentre, double-blind, placebo-controlled, parallel group, proof of concept study to evaluate the efficacy, safety and tolerability of the S1P receptor modulator KRP203 in subjects with moderately active refractory ulcerative colitis*

H. H. Radeke*1, 2, J. Stein1, 3, W. Kruis4

1Interdisciplinary Crohn Colitis Centre Rhein-Main, Frankfurt/Main, Germany, 2Pharmazentrum Frankfurt, Hospital of the Goethe University Frankfurt, Frankfurt/Main, Germany, 3DGD Clinics Sachsenhausen, Frankfurt/Main, Germany, 4LKP, Evangelisches Krankenhaus Kalk, Cologne, Germany

Background

Since fingolimod (FTY720) was successfully introduced for the treatment of multiple sclerosis, a range of sphingosine-1-phosphate (S1P) receptor targeting compounds has been developed. We present a clinical phase II study with the partial S1P receptor agonist KRP203. Similar to FTY720, this prodrug is phosphorylated in vivo, where out of the 5 S1P receptors, KRP phosphate targets S1P1, S1P4, and S1P5. Unlike FTY phosphate, however, it shows only partial agonism on the S1P3 receptor. Preclinical results suggest that KRP203 may represent a novel treatment modality for patients with active ulcerative colitis (UC). Aim of the study was to prove the concept that KRP203 reduces lymphocyte recruitment to the inflamed intestine in UC, and to evaluate its efficacy, safety and tolerability.

Methods

This was a multicentre, double-blind, placebo-controlled, parallel group, proof of concept study in patients with moderately active refractory UC. It was planned to randomise 72 patients into the study and to perform an interim efficacy analysis after 30 patients had completed 8 weeks’ treatment with 1.2 mg KRP203 or placebo (2:1) whilst recruitment continued.

Results

Of the 30 patients randomised, 27 patients were included in the data analysis (17 KRP203 / 10 placebo). There was a high rate of early discontinuation (47% [n = 8] KRP203 / 50% [n = 5] placebo), most commonly because of unsatisfactory therapeutic effect (29% [n = 5] KRP203 and 40% [n = 4] placebo). Further, 14 KRP203 and 8 placebo patients qualified for the primary efficacy analysis. KRP203 and KRP203-P concentration within periods already studied in phase I trials was similar for UC patients and healthy volunteers. Remission was observed in 2 of 14 patients (14%) in the KRP203 group, and 0 of 8 (0%) in the placebo group. The results may suggest that KRP203 treatment is superior to placebo, but inferior to the minimal clinically relevant threshold of 20% (H1). A marked reduction in peripheral blood lymphocyte numbers was noted in all KRP203-treated patients, which, however, did not correlate with major clinical benefit. KRP203 was safe and well tolerated, with no reported cardiac AEs in the KRP203 group.

Conclusion

The present study was the first placebo-controlled, parallel group, multicentre study to evaluate the safety and efficacy of KRP203 in patients with treatment refractory UC. KRP203 was overall safe and well tolerated, and importantly, there were no reported cardiac adverse events. Even though KRP203 was inferior to the minimal clinically relevant threshold, the results may suggest that KRP203 treatment is superior to placebo. Based on these data, studies with an improved design and including more patients should be initiated.

*Trial sponsored by Novartis, Basel (Switzerland).