Sunday, November 20, 2011

An Oral S1P Lyase Inhibitor [LX3305 (LX2931)] has been studied in a Phase 2 Trial in Patients with Active Rheumatoid Arthritis

Roy M. Fleischmann and colleagues studied LX3305 (LX2931), an oral S1P lyase inhibitor in patients with active rheumatoid arthritis on stable methotrexate therapy. Sphingosine-1-phosphate (S1P) is a lipid metabolite affecting lymphocyte trafficking and signal transduction pathways. Preclinical studies already showed that the inflammatory response in models of rheumatoid arthritis could be reduced by S1PL activity reduction. The safety, tolerability, and efficacy of LX3305 were evaluated in a multicenter, multinational, randomized, double-blind, placebo-controlled phase 2 trial in patients with active rheumatoid arthritis and an inadequate response to stable doses of methotrexate. LX3305, at 150 mg po QD for 12 weeks, showed a potential clinical benefit in patients with active rheumatoid despite stable-dose methotrexate therapy; but this was only shown n a post-hoc analysis. The results of this study suggest that inhibition of S1PL by LX3305 represents a new mechanism for immune modulation.


[WED] 2593
The Oral S1P Lyase Inhibitor LX3305 (LX2931) Demonstrates Favorable Safety and Potential Clinical Benefit at 12-Weeks in a Phase 2 Proof-of-Concept Trial in Patients with Active Rheumatoid Arthritis on Stable Methotrexate Therapy.
Roy M. Fleischmann1, Jeffrey E. Poiley2, Rumen Stoilov3, Vibeke Strand4, Joel Freiman5, Tamas Oravecz5, Arthur Sands5, Brian Zambrowicz5 and Lexicon Pharmaceuticals RA Clinical Development6.
1University of Texas Southwestern Medical Center and Metroplex Clinical Research Center, Dallas, TX, 2Arthritis Associates, Orlando, FL, 3University Multiprofile Hospital for Active Treatment (UMHAT) St. Ivan Rilski EAD, Sofia, Bulgaria, 4Stanford University, Palo Alto, CA, 5Lexicon Pharmaceuticals, Inc., The Woodlands, TX, 6The +Woodlands, TX
Conclusion: LX3305, at 150 mg po QD for 12 weeks, produced a favorable safety profile and a potential clinical benefit in patients with active RA despite stable-dose methotrexate therapy. These results suggest that inhibition of S1PL by LX3305 represents a new mechanism for immune modulation, and supports further clinical development of LX3305 as a small molecule therapy for rheumatoid arthritis.

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