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 and LX2932 are orally-delivered small molecules 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 and LX2932 are 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 and LX2932 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 and LX2932 regulate 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 or LX2932 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. LX2932, a chemically distinct S1P lyase inhibitor, is in preclinical studies as a backup molecule to the LX2931 drug candidate; initial studies demonstrated that LX2932 treatment also produces a consistent reduction in lymphocyte counts in multiple species.
Related Publications
Hait, N. C., C. A. Oskeritzian, S. W. Paugh, S. Milstien, and S. Spiegel. 2006.
Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases.
Biochim. Biophys. Acta. 1758: 2016-2026.
Pyne, S., and N. J. Pyne. 2000.
Sphingosine 1-phosphate signalling in mammalian cells.
Biochem. J. 349: 385-402.
Cyster, J. G. 2005.
Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs.
Annu. Rev. Immunol. 23: 127-159.
Schwab, S. R., J. P. Pereira, M. Matloubian, Y. Xu, Y. Huang, and J. G. Cyster. 2005.
Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients.
Science. 3091: 1735-1739.
Pettus, B. J., C. E. Chalfant, and Y. A. Hannun. 2004.
Sphingolipids in inflammation: roles and implications.
Curr. Mol. Med. 4: 405-418.
Chun, J., and H. Rosen. 2006.
Lysophospholipid receptors as potential drug targets in tissue transplantation and autoimmune diseases.
Curr. Pharm. Des. 12: 161-171.
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