LX1031
Status
Phase 1b complete
Indications
Irritable Bowel Syndrome (IBS)
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 and without disrupting central nervous system functions. Serotonin is a key regulator of GI function, and is associated with the most common symptoms of IBS: bowel motility, nausea and GI discomfort.
Principal 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 project, 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.
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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 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 with no observed adverse effects across a broad range of medically relevant parameters.
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Serotonin (brown staining) is made within the EC cells of the intestine (left). A Lexicon proof-of-concept compound reduces serotonin production in EC cells (right). |
Clinical Status
In Phase 1 clinical trials, LX1031 was administered to 79 healthy volunteers. All dose levels and dosing regimes were well tolerated with infrequent adverse events at all dose levels tested. Lexicon is conducting an additional Phase 1 dose escalation study with LX1031 to explore additional dosage parameters.
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
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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.
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