Lexicon's LX4211 shown to reduce fasting and post-prandial blood sugar in healthy subjects

THE WOODLANDS, Texas -- Lexicon Pharmaceuticals, Inc. (Nasdaq: LXRX) has reported positive data from a recently completed clinical trial and mechanistic study of LX4211, a dual inhibitor of the sodium glucose transporters 1 and 2 (SGLT1 and SGLT2). The favorable safety profile and effects on multiple parameters of glycemic control and cardiovascular health in healthy normal subjects support the broad potential of LX4211 in the treatment of diabetes and associated metabolic conditions.

"Newly observed in this study were the effects of LX4211, in healthy volunteers, of decreasing postprandial glucose levels without hypoglycemia and substantially reducing triglycerides," said Brian Zambrowicz, Ph.D., executive vice president and chief scientific officer. "Notably, the magnitudes of the reductions in triglycerides were similar to current standard of care prescription and clinical-stage medicines. By contrast, reported results of SGLT2-selective compounds have demonstrated minimal or no reductions in postprandial glucose in healthy subjects and minimal or no triglyceride decreases in either healthy normal volunteers or patients with type 2 diabetes."

Results from the study demonstrated that the 400 mg solid oral dose of LX4211 compared to placebo significantly reduced mean changes from baseline in fasting plasma glucose (p=0.005) and post-prandial glucose levels (p<0.001) in parallel with meaningful mean increases from baseline in total and active GLP-1 (p=0.055 and p=0.003, respectively) as well as PYY (p<0.001). GLP-1 is associated with improved glucose control and decreased food intake through reduction of appetite. PYY is a gastrointestinal-derived peptide hormone that has also been associated with reducing food intake and has been studied as an anti-obesity agent. These two gastrointestinal peptides (GLP-1 and PYY) are secreted into circulation by neuroendocrine cells (L cells) as part of a natural homeostatic mechanism that senses nutrient transit through the gastrointestinal tract. Such nutrient sensing and related mechanisms are thought to be enhanced as a result of certain types of bariatric surgery for weight loss and control of diabetes.

LX4211 treatment also produced a 50.2 mg/dL adjusted mean decrease from baseline in triglycerides, consistent with the triglyceride reduction observed in the Phase 2a study in type 2 diabetics. In addition, LX4211, compared to placebo, produced a significant adjusted mean decrease in serum uric acid (1.52 mg/dL from baseline to last study visit, p=0.005). Serum uric acid is an emerging marker for cardiovascular risk and renal disease. These data, together with a trend of improved blood pressure observed in the Phase 2a study, demonstrate that LX4211 has effects on multiple cardiovascular and metabolic risk factors. Also of importance in this study was the safety of LX4211, which showed no hypoglycemia and no abdominal pain or diarrhea, consistent with the favorable safety profile associated with dual inhibition of SGLT1 and SGLT2 by LX4211 in previous clinical trials. Enrollment in Lexicon's ongoing Phase 2b study of LX4211 in patients with type 2 diabetes is on schedule, with results anticipated in the first half of 2012.

"We have now observed results from several clinical studies of LX4211 which consistently support the concept of dual SGLT1/SGLT2 inhibition for the treatment of diabetes and indicate a long-term opportunity in diabetes prevention," said Pablo Lapuerta, M.D., senior vice president of clinical development and chief medical officer. "The favorable metabolic effects in healthy subjects, together with the safety profile observed to date, suggest that LX4211 could be considered earlier in the diabetes treatment paradigm, perhaps including the potential treatment of pre-diabetes in patients with impaired glucose tolerance or impaired fasting glucose (IGT/IFG)."

About the Clinical Trial
The clinical trial was designed to assess the effect of different LX4211 dose schedules relative to meal time in healthy subjects when taken as a single daily dose (400 mg) or a split dose (200 mg twice daily). Subjects were randomized to LX4211 in an ordered sequence to assess the pharmacodynamic effects of different dosing times, ranging from 1 hour prior to meals to immediately prior to meals. Pharmacodynamic effects, include urinary glucose excretion, fasting plasma glucose, insulin, PYY and GLP-1 (total and active) were assessed at multiple time points during the 12-day dosing period.