LX 2931 / Lexicon Pharma - LARVOL DELTA

Dual action of sphingosine 1-phosphate pathway in in vitro models of global cerebral ischemia. (PubMed, Neurobiol Dis) - "In the same model we investigated the effect of the inhibitor of S1P lyase (SPL), LX2931, the selective antagonists of S1P2, JTE-013, and S1P3, CAY10444, quantifying the cell death in the CA1 region by propidium iodide fluorescence, and morphological and tissue organization alterations by immunohistochemistry and confocal microscopy...Our results reveal a dual role of S1P pathway in brain ischemia: intracellular S1P, degraded via SPL, appears to be beneficial whereas signaling via S1P2 and S1P3 is detrimental to the disease. These findings support the notion that SPL, S1P2 and S1P3 are promising therapeutic targets in brain ischemia."

Journal • Preclinical • Cardiovascular • Psychiatry

Sphingosine Phosphate Lyase Is Upregulated in Duchenne Muscular Dystrophy, and Its Inhibition Early in Life Attenuates Inflammation and Dystrophy in Mdx Mice. (PubMed, Int J Mol Sci) - "Transcriptional profiling in the skeletal muscles of LX2931-treated vs. control mdx mice demonstrated changes in innate and adaptive immune functions, plasma membrane interactions with the extracellular matrix (ECM), and axon guidance, a known function of SC. Our cumulative findings suggest that by raising muscle S1P and simultaneously disrupting the chemotactic gradient required for lymphocyte egress, SPL inhibition exerts a combination of muscle-intrinsic and systemic effects that are beneficial in the context of muscular dystrophy."

Journal • Preclinical • Duchenne Muscular Dystrophy • Fibrosis • Genetic Disorders • Immunology • Inflammation • Muscular Dystrophy • Myositis

Is Sphingosine-1-Phosphate a Regulator of Tumor Vascular Functionality? (PubMed, Cancers (Basel)) - "In pancreatic adenocarcinoma PDX models, oral administration of an S1P lyase inhibitor (LX2931) significantly increased plasma S1P levels, decreased tumor expression of the hypoxia marker (CA IX), and enhanced chemotherapy efficacy when combined with gemcitabine treatment. Thus, increasing plasma S1P is a promising strategy to decrease tumor hypoxia and enhance therapy efficacy in solid tumors. S1P may act as a tumor vasculature normalizer."

Journal • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

Agonist-induced activation of the S1P receptor 2 constitutes a novel osteoanabolic therapy for the treatment of osteoporosis in mice. (PubMed, Bone) - "Treatment with a pharmacological S1P2 agonist corrected ovariectomy-induced osteopenia in mice by inducing new bone formation thus constituting a novel osteoanabolic approach to osteoporosis."

Journal • Preclinical • Immunology • Osteoporosis • Rheumatoid Arthritis • Rheumatology

Wedbush Securities LifeSciences Management Access Conference (Lexicon) - LX2931 / Lexicon; Anticipated initiation of dose escalation PoC trial in RA patients in Q3 '11; Anticipated dose ranging study results for RA in H1 '12

Anticipated dose ranging study data • Anticipated PoC study initiation • None • Rheumatoid Arthritis

Lexicon Pharmaceuticals reports preliminary results from two phase 1 studies (Lexicon) - P1, N=10; NCT1417052; LX2931 was well-tolerated at all doses evaluated (beginning at 50mg QD & escalating to 500mg QD), with no serious AEs & no withdrawals due to AEs; 7 of 8 pts on LX2931 achieved drug trough levels greater than 60ng/ml; ACR20 & ACR50 responses were achieved at varying frequencies in both LX2931-treated & placebo patients; 2 of 8 pts dosed with LX2931 achieved an ACR70 response during the course of the study, compared to none on placebo

P1 data • Rheumatoid Arthritis

Jefferies Global Healthcare Conference (Lexicon) - P2a data release

P2a data • Rheumatoid Arthritis

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 (ACR/ARHP 2011) - P2, N=208; ACR20 response at Week 12, the primary endpoint, was achieved by 60% of patients assigned to the 150 mg LX3305 group compared to 49% receiving placebo (not significant)

P2 data • Rheumatoid Arthritis

The oral S1P lyase inhibitor LX3305 (A.K.A. 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 (EULAR 2011) - LX3305, at 150 mg po QD for 12 weeks, produced favorable safety profile & potential clinical benefit in ps with active RA despite stable-dose MTX therapy; 60% of 150 mg LX3305 pts achieved ACR20 response vs. 44.3% of all other pts [p=0.038]

Lexicon Pharmaceuticals reports on clinical program status and 2011 first quarter results (Lexicon) - Lexicon updated its drug development progress & reported financial results for Q1 2011; Lexicon expects to initiate a dose-ranging study in Q3 2011 to explore higher doses of LX2931 in RA; Previously reported P2a results of LX2931 demonstrated favorable safety profile at all doses tested & suggested that RA pts treated with 150 mg of LX2931 once daily showed improvement in primary efficacy endpoint of study

Anticipated dose ranging study

Lexicon phase 2a LX2931 rheumatoid arthritis data confirm safety (Ibtimes) - P2a, N=208; On an intent-to-treat basis, the 150mg dose did not show a statistically significant benefit vs. placebo on ACR20 response (p=0.14); A pooled analysis of the placebo plus low-dose cohorts (70mg and 110mg) vs. the 150mg cohort did show a statistically significant benefit on ACR20 response (60% 150mg vs. 44.3% placebo/70mg/110mg; p=0.038)

P2a data • Rheumatoid Arthritis