Experimental Drug for Rheumatoid Arthritis Targets Immune System Enzyme

An experimental drug designed to treat rheumatoid arthritis by inhibiting sphingosine-1-phosphate (S1P) lyase demonstrated positive results in a phase 2a study.

The drug, LX2931, is developed by Lexicon Pharmaceuticals, Inc., a biopharmaceutical company focused on discovering breakthrough treatments for human disease.

LX2931 is an orally-delivered, small molecule drug candidate. S1P lyase is an enzyme that plays an important role in modulating the immune system by controlling S1P levels in lymphoid tissues. S1P lyase is responsible for the irreversible degradation of S1P, a biologically active lipid that can act as a second messenger in signal transduction pathways important for immune function. Changes in local S1P concentrations and gradients in immune tissues can modify lymphocyte migration, inflammatory cell response, and affect barrier function of endothelial cells.

Inhibiting S1P lyase results in an increase in S1P levels, primarily in lymphoid tissues. The physiological outcome of raising S1P levels in the lymphoid system is immune-modulation, which offers new opportunities for treating autoimmune and inflammatory diseases.

The trial was the first test of this new anti-inflammatory mechanism of action in patients and was designed to obtain safety and tolerability information and signals of efficacy.

Results from the 12-week, randomized, double-blind, placebo-controlled study in 208 patients with RA demonstrated that all three doses tested, 70 mg, 110 mg, and 150 mg given once per day, were well tolerated over the 12-week treatment period. Taken together, the data also suggested that patients treated with 150 mg once daily of LX2931 showed an improvement in the primary efficacy endpoint, the percentage of patients achieving an American College of Rheumatology 20 (ACR20) response at week 12 (60% versus 49% for placebo).

Patients were randomized to receive either placebo (n=49) or LX2931, 70 mg (n=55), 110 mg (n=54), or 150 mg (n=50), once daily for 12 weeks. In addition to measurements to assess the drug's safety, efficacy endpoints included the primary endpoint, ACR20 at week 12, as well as secondary endpoints of ACR20, ACR50, ACR70 and DAS28 at weeks 4, 8 and 12. The trial was conducted at sites within the United States and Eastern Europe.

Patients treated with 70 mg or 110 mg once daily did not indicate improvement in the ACR20 at week 12 (44% and 41% response rates, respectively) relative to placebo. Adverse events for all three LX2931 dose groups were predominantly mild-to-moderate, with frequencies similar to the placebo group.

"We believe the preliminary signal of efficacy and the favorable safety profile observed in this trial supports further study of additional higher doses of LX2931 as an orally-delivered treatment for rheumatoid arthritis," said Dr. Arthur T. Sands, president and chief executive officer of Lexicon. "While we were disappointed by the unusually high placebo effect in this trial, we are encouraged by the excellent overall safety profile observed in the first test of this new mechanism of action in patients with RA."

Source: Lexicon Pharmaceuticals, Inc

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