Indication
Irritable Bowel Syndrome (IBS)

Stage of Development
Completed Phase 1



Clinical Data
Lexicon has 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.  Based on the successful outcome of the Phase 1 clinical trials, Lexicon expects to initiate a Phase 2 proof-of-concept clinical trial in IBS patients by the end of 2008.  The clinical trial is planned as a four-week, randomized, double-blind, placebo-controlled study designed to evaluate the safety, tolerability, and effects of LX1031 on symptoms associated with IBS.  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 (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

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

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

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

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

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

Veenstra-VanderWeele J., Cook EH., Knockout Mouse Points to Second Form of Tryptophan Hydroxylase. Mol Interv. 2003 Mar;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.