Indication
Irritable Bowel Syndrome (IBS)

Stage of Development
Phase 2a completed



Clinical Data
Lexicon completed a Phase 2 clinical trial of LX1031 in patients with non-constipating IBS in November 2009.  Top-line results showed that treatment with one gram of LX1031 four times daily produced a statistically significant improvement in global assessment of relief of IBS pain and discomfort over the four-week dosing period as compared to placebo (p=0.0465).  Improvements in global assessment parameters also corresponded with statistically significant improvements in stool consistency.  Notably, increased clinical response correlated with a greater reduction in serotonin synthesis as reflected by measures of urinary 5-HIAA, a breakdown product of serotonin. 

The Phase 2 clinical trial, which began at the end of December 2008, was a four-week, randomized, double-blind, placebo-controlled study to evaluate the safety and tolerability of LX1031 and its effects on symptoms associated with IBS.  The study included 155 patients with either diarrhea-predominant IBS or mixed IBS.  Two dose levels were evaluated:  a 250 mg dose and a 1,000 mg dose, each administered four times daily (QID).  LX1031 was well tolerated, with no statistically significant differences in adverse events observed between placebo and either treatment group.  Efficacy endpoints evaluated included a global assessment of adequate relief, as well as measures of specific symptoms associated with IBS.  Based on the positive data obtained, Lexicon intends to pursue the development of LX1031 as a novel treatment for patients with IBS.  To view the video presentation from the GASTRO 2009 conference, click here.

Previously, Lexicon successfully completed Phase 1 clinical trials of LX1031.  In all trials completed to date, all dose levels and dosing regimes were well tolerated with infrequent adverse events observed.  For additional information about the Phase 1 clinical results, please view our video presentation.   

Overview
LX1031 is an orally-delivered small molecule designed to regulate gastrointestinal (GI) function by reducing the amount of serotonin available for receptor activation in the GI tract without affecting serotonin levels in the brain.  Serotonin is a key regulator of GI function, and is associated with the most common symptoms of IBS:  problems with bowel motility and GI discomfort.

Key Target
The target for LX1031 is tryptophan hydroxylase (TPH), the rate-limiting enzyme for serotonin production found in enterochromaffin (EC) cells of the GI tract.  From research conducted in the Genome5000^TM program, Lexicon scientists found that mice lacking the non-neuronal form of this enzyme, TPH1, have virtually no serotonin in the GI tract, but do maintain normal levels of serotonin in the brain.

Tryptophan hydroxylase (TPH), located in enterochromaffin (EC) cells of the GI tract, is a key enzyme in the production of serotonin. LX1031 reduces serotonin production locally in the GI tract by inhibiting TPH activity.

Preclinical Data
In preclinical studies, LX1031 caused a dose-dependent reduction in the amount of serotonin in the GI tract of multiple species without affecting brain serotonin levels.

Serotonin (brown staining) is made within the EC cells of the intestine (left). A Lexicon proof-of-concept compound reduces serotonin production in mouse EC cells (right).

Related Publications

Brown PM, Jackson JI, Frazier KS, Turner CA, Shi ZC, Liu Q (2009). LX1031: Inhibition of Serotonin Synthesis as a New Target in the Management of Irritable Bowel Syndrome (IBS). 2009 Digestive Disease Week (DDW)  Poster 

Brian Zambrowicz, Ph.D. (2009). LX1031: A New Approach for Managing Irritable Bowel Syndrome (IBS). 2009 Digestive Disease Week (DDW)  Presentation (1 MB)

Brown PM, Jackson JI, Frazier KS, Turner CA, Shi ZC, Liu Q (2007). From Mouse Knockout to Investigational Drug: LX1031, A Novel Potential Treatment for Irritable Bowel Syndrome. 2007 Annual Scientific Meeting of the American College of Gastroenterology.   Poster (8.73 MB)

Gershon MD and Tack J (2007). The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 132:397-414. 

Gershon MD (2005). Nerves, reflexes, and the enteric nervous system: pathogenesis of the irritable bowel syndrome. J Clin Gastroenterol 39:S184-193.

De Ponti F (2004). Pharmacology of serotonin: what a clinician should know. Gut 53:1520-1535.

Gershon MD (2003). Serotonin and its implication for the management of irritable bowel syndrome. Rev Gastroenterol Disord 3 Suppl 2:S25-34.

Gingrich JA, Ansorge MS, Merker R, Weisstaub N and Zhou M (2003). New lessons from knockout mice: The role of serotonin during development and its possible contribution to the origins of neuropsychiatric disorders. CNS Spectr 8(8);572-7.

Veenstra-VanderWeele J., Cook EH. (2003). Knockout Mouse Points to Second Form of Tryptophan Hydroxylase. Mol Interv. 3(2):72-5, 50.

Walther DJ, Peter JU, Bashammakh S, Hortnagl H, Voits M, Fink H and Bader M (2003). Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 299:76.