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Lexicon announces IBS trial results

Lexicon Pharmaceuticals’ TPH inhibitor LX1031 has been shown in a phase II trial to be well tolerated and provide clinical benefit to patients with irritable bowel syndrome

The biopharmaceutical company Lexicon Pharmaceuticals has announced the results of its phase II clinical trial of the tryptophan hydroxylase (TPH) inhibitor LX1031 for patients with non-constipating irritable bowel syndrome (IBS). Developed using Lexicon's proprietary gene knockout technology, LX1031 is an oral, locally acting, small molecule, designed to inhibit TPH in the gastrointestinal (GI) tract, thereby reducing the mucosal production of serotonin (5-HT).

In the 28-day, multicentre, randomised, double-blind, placebo-controlled phase II study, 155 patients with non-constipating IBS received four doses daily of LX1031 at two dose levels (250mg and 1000mg). Urinary levels of 5-hydroxyindoleacetic acid (5-HIAA), a biomarker of pharmacodynamic activity, were measured 24 hours after administration and then at weeks 4 and 6.

Compared with those treated with placebo, patients treated with the 1000mg dose of LX1031 showed a significant improvement in relief of IBS pain and discomfort (the study's primary efficacy endpoint) at week 1 (25.5 per cent). This was followed by non-significant improvements at weeks 2 (17.9 per cent), 3 (16.3 per cent) and 4 (11.6 per cent). Compared with placebo, LX1031 also significantly improved stool consistency.

The improvement in pain levels was correlated with a reduction in 5-HIAA: this suggests not only that the efficacy of LX1031 is related to the extent of 5-HT biosynthesis inhibition, but also that urinary levels of 5-HIAA could be used as biomarker to identify patients most likely to respond to inhibitors of 5-HT synthesis.

LX1031 was safe and well-tolerated at 250mg and 1000mg.

These trial results have been published in the August 2011 issue of Gastroenterology, which also features an expert editorial discussing the study, its implications and the potential utility of this mechanism of action in GI disease.

Additionally, Lexicon has also recently completed a phase I study of follow-on compound LX1033, which is significantly more potent than its predecessor, achieving similar results with lower and less frequent doses. Lexicon now intends to advance LX1033 into a phase II trial as its lead candidate in IBS. The company is also developing clinical programmes for the treatment of diabetes, carcinoid syndrome and rheumatoid arthritis.

11th August 2011


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