New Mechanisms of Action

LX1033

Indication*
Irritable Bowel Syndrome (IBS)

Overview
LX1033 is an orally-delivered inhibitor of tryptophan hydroxylase (TPH), the rate-limiting enzyme necessary for the biosynthesis of serotonin.  LX1033 was designed to be more potent than our first-generation serotonin synthesis inhibitor, LX1031, while also acting locally within the gastrointestinal (GI) tract to reduce the amount of serotonin in the intestine without affecting serotonin levels in the brain.  Serotonin is a key regulator of GI function and is associated with symptoms of IBS-d including diarrhea and abdominal pain. Reduction of serotonin synthesis can be measured in patients by testing levels of a biomarker, 5-HIAA, a breakdown product of serotonin.  Local reduction of serotonin synthesis in the GI tract may offer a new approach to the management of IBS-d and the biomarker can provide a useful tool in the medical management of this condition.

           

Tryptophan hydroxylase (TPH), located in enterochromaffin (EC) cells of the GI tract, is the rate-limiting enzyme necessary for the production of serotonin. LX1033 reduces peripheral serotonin production by inhibiting TPH activity locally in the GI tract. LX1033 does not cross the blood-brain barrier and therefore does not affect serotonin levels in the brain.  

Clinical Data
In a Phase 1 clinical trials, LX1033 was well tolerated at all doses and produced a statistically significant reduction in serotonin synthesis as measured by the reduction in levels of 5-hydroxyindoleacetic acid (5-HIAA), a biomarker for serotonin synthesis. Importantly, a greater reduction in serotonin synthesis was achieved with lower and less frequent dosing than was observed with LX1031, which had previously demonstrated clinical benefit to IBS patients in a Phase 2a clinical trial.

Status
Lexicon has completed a Phase 2 clinical trial of LX1033 in 373 patients with IBS-d.  For more detailed information regarding the top-line Phase 1 results, please see our press release here.

About Irritable Bowel Syndrome
IBS is a common disorder characterized by abdominal pain, cramping, and changes in bowel function.  It is classified according to three categories:

• IBS-c: Constipation
• IBS-d: Diarrhea
• Mixed: Symptoms of diarrhea alternating with constipation

Serotonin (5-HT) is a neurotransmitter that plays a well-established role in GI function, serving as a physiologic regulator of GI motility and signaling sensations of nausea and discomfort to the brain.  Serotonin is reportedly involved in the pathophysiology of various types of functional GI disorders, as well as contributing to the symptoms experienced by subjects with IBS (Gershon MD 2005).  Also, pharmacological modulation of 5-HT receptors has proven useful in the treatment of IBS and other GI conditions.  Antagonists of the 5-HT3 receptor have demonstrated utility in treating nausea and vomiting resulting from chemotherapy, and agonists of the 5-HT4 receptor have also demonstrated utility in treating constipation-predominant IBS.

Many GI drugs developed for IBS or nausea that target the serotonin pathway affect various serotonin receptor subtypes (e.g., 5-HT3 and 5-HT4 receptors). However, Lexicon’s serotonin synthesis inhibitors target TPH, the enzyme responsible for producing serotonin in the GI tract.

Irritable Bowel Syndrome Prevalence
According to the International Foundation for Functional Gastrointestinal Disorders, IBS is estimated to affect between 25-45 million Americans.  It is the most common diagnosis made by gastroenterologists, and is one of the disorders most frequently treated by primary care physicians.

Related Publications
Click here to view related publications.

 

* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.