Lexicon Pharmaceuticals has successfully completed a phase I clinical trial of LX1033, an orally-delivered small-molecule drug candidate for diarrhea-predominant irritable bowel syndrome (IBS-d). Lexicon plans to move LX1033 forward into a phase II study in patients with IBS-d.
Top-line results demonstrated that LX1033 was well tolerated at all doses and produced a statistically significant reduction in serotonin synthesis compared to placebo, as measured by both plasma (p<0.001) and urinary (p<0.01) 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 and at lower drug exposure levels than was observed with Lexicon's first generation serotonin synthesis inhibitor, LX1031, which had previously demonstrated clinical benefit to IBS patients in a phase IIa clinical trial as measured by both global assessment of adequate relief and stool consistency.
The LX1033 phase I trial was conducted as a randomized, placebo-controlled trial in healthy volunteers. In the multiple-ascending dose portion of the study, doses of 250mg, 500mg and 750mg given three times daily, as well as 1,000mg twice daily, were administered over the course of 14 days. There were eight healthy volunteers (six receiving active compound, two receiving placebo) in each dose group. Study endpoints included safety and tolerability together with pharmacokinetic and pharmacodynamic parameters consisting of measures of both plasma and urinary 5-HIAA. Data from the study showed that LX1033 produced a statistically significant decrease in both plasma and urinary 5-HIAA as compared to placebo at all doses tested. The plasma measures of 5-HIAA in the recent study were obtained from a simple morning blood draw and correlated with results obtained by the traditional 24-hour urine collection method.