Indications
Rheumatoid arthritis and other autoimmune diseases
Stage of Development
Phase 1
Clinical Status
Lexicon initiated Phase 1 clinical trials of LX2931 in December 2007. The initial Phase 1 clinical trial is designed as a double-blind, randomized, placebo-controlled, ascending single-dose study in healthy volunteers, designed to evaluate the safety, tolerability, and pharmacokinetics of LX2931. In April 2008, Lexicon announced positive results from the initial Phase 1 clinical trial of LX2931. Initial results in healthy volunteers 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. For additional information about the results of this study, please view our video presentation  .
Overview
LX2931 is an orally-delivered small molecule under development for the potential treatment of autoimmune diseases such as rheumatoid arthritis.
Inappropriate activation of lymphocytes is associated with autoimmune diseases, a spectrum of disorders in which the immune system malfunctions and causes the body to attack its own organs, tissues, and cells. LX2931 is intended to regulate lymphocyte activity in the body during an inflammatory response.
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The body's own immune system attacks a joint's synovial membrane, which becomes inflamed, secretes fluid, and the cartilage becomes rough and pitted. |
Key Target
The target for LX2931 is sphingosine-1-phosphate lyase (S1P lyase), an enzyme in the sphingosine-1-phosphate (S1P) pathway associated with the body's inflammatory response. From research conducted in the Genome5000TM program, Lexicon scientists discovered that mice lacking this enzyme have increased retention of immune cells in the thymus and spleen with a corresponding reduction in the deployment of T-cells and B-cells into the circulating blood, resulting in a reduced immune response.
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LX2931 regulates lymphocytes by targeting S1P lyase, the enzyme that degrades S1P. The secreted messenger, S1P, interacts with S1P receptors such as S1P1 to regulate lymphocyte migration from lymphoid tissues (e.g., thymus and spleen). In preclinical models, inhibition of S1P lyase by LX2931 caused the concentration of S1P to rise in lymphoid tissues, thereby causing lymphocytes to be retained in the lymphoid tissues. |
Preclinical Data
In preclinical studies, LX2931 produced a consistent reduction in circulating lymphocyte counts in multiple species. In addition, LX2931 reduced joint inflammation and prevented arthritic destruction of joints in mouse and rat models of arthritis.
Related Publications
Brown P, Frazier K, Augeri, D, Walke DW, Pappas C, Brooks B, Donoviel, M, and Oravecz T (2008). LX2931: A Potential Small Molecule Treatment for Autoimmune Disorders. 2008 Annual Meeting of the American College of Rheumatology. Poster  1.31 MB
Oravecz, T., Donoviel, M. S., Anderson, S. J., Carson, K., Sun, W., Swaffield, J., Liu, Q., Kimball, S. D., Piggott, J. R., Main, A. J., Zambrowicz, B. P., Sands, A. S., Turner, C. A., and D. J. Augeri (2007). Genetic and Chemical Inhibition of Sphingosine-1-Phosphate Lyase Results in Peripheral Lymphopenia and Alleviates Disease Development in Animal Models of Inflammation and Autoimmunity. 2007 Annual Meeting of the American Society of Hematology. (5MB)
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