Lexicon Pharmaceuticals, Inc (THE WOODLANDS, Texas), a leader in genomics-based drug discovery, announced that it has obtained positive results from its phase 1a clinical trial of LX2931, an orally-delivered, small molecule targeting sphingosine-1-phosphate (S1P) lyase, for the treatment of rheumatoid arthritis (RA) and other autoimmune conditions. The immune system regulation originally observed in animal models was reproduced in 50 healthy volunteers with the administration of single, well-tolerated doses of LX2931. Initial trial results demonstrated a potent, dose-dependent reduction in circulating lymphocytes, suggesting that the target of LX2931 may represent a new mechanism for regulating the immune response. Based on the results, a multiple ascending-dose study with LX2931 in healthy volunteers is planned for mid-2008.

The double-blind, randomized, placebo-controlled trial assessed the safety, tolerability, and pharmacokinetics of seven dose levels of LX2931, ranging from 10 mg/kg to 180 mg/kg. A dose-dependent decrease in absolute lymphocyte counts was observed, with a maximal effect corresponding to ~45% reduction from baseline noted at ~24 hours postdose. Lymphocyte counts approached baseline values by 48 hours postdose. Adverse events were distributed across subjects in each dose group and the placebo group. Adverse events included mild GI upset and leukocytosis, and headache. One subject experienced asymptomatic mild elevations of liver function tests (LFTs) to less than one and one-half times the upper limit of normal and another subject experienced biliary colic with abnormal LFTs. No significant changes in vital signs (including pulse rate) or ECG changes were noted after administration of the agent.

Lexicon has shown previously that genetically “knocking out” or “knocking down” the target of LX2931 substantially reduces the number of circulating lymphocytes, modulating the immune response in multiple animal models of autoimmune disease. S1P lyase, an enzyme in the S1P pathway, is associated with the body's inflammatory response. Mice lacking S1P lyase have increased concentrations of S1P in lymphoid tissues, causing lymphocytes to be retained in the thymus and spleen with a corresponding reduction in the deployment of T-cells and B-cells into the circulating blood. In addition, LX2931 reduced joint inflammation and prevented arthritic destruction of joints in rodent models of arthritis.