Lexicon Pharmaceuticals, Inc, has announced data from a recently completed clinical trial and mechanistic study of a solid oral dose formulation for LX4211, a dual inhibitor of sodium-glucose co-transporters 1 and 2 (SGLT1 and SGLT2).
Results from the study demonstrated that administration of a 300 mg solid oral tablet dose of LX4211, administered as two 150 mg tablets, significantly increased total GLP-1 (p=0.001), active GLP-1 (p=0.032) and PYY (p=0.004), important mediators of glycemic and appetite control as well as other metabolic parameters.
Notably, single doses of LX4211 produced rapid and significant improvement in post-prandial glucose (PPG) and fasting plasma glucose (FPG), consistent with results seen in the previous Phase 2 study.
Pharmacokinetic and pharmacodynamic data from the study indicated that the solid oral formulation worked as well as or better than the liquid formulation on key parameters of hormonal release, PPG and FPG. Lexicon plans to move the tablet formulation forward into a Phase 2b study in the second quarter of 2011.
"The significant elevations of GLP-1 levels observed in the study are particularly important given its established relevance in the treatment of diabetes," said Brian Zambrowicz, Ph.D., executive vice president and chief scientific officer. "Newly observed in this study was the effect of LX4211 on increasing circulating levels of PYY. We believe the rapid reduction in blood sugar levels after meals, the increase in GLP-1 and the increase in PYY are all associated with SGLT1 inhibition by LX4211 in the gastrointestinal tract."
PYY and GLP-1 are gastrointestinal-derived peptide hormones that have been associated with producing satiety and reducing food intake. PYY has been studied as an anti-obesity agent, and GLP-1 is a mediator of insulin and glucagon secretion. As nutrients enter the small intestine, PYY and GLP-1 are co-secreted into the circulation by neuroendocrine cells (L cells) of the gastrointestinal tract.
"We have established a solid tablet formulation suitable for further development and will continue to explore LX4211's unique mechanism of action in the treatment of diabetes and the hormonal control of metabolism," said Arthur T. Sands, M.D., Ph.D., president and chief executive officer. "We believe the results of this study provide further evidence that dual inhibition of SGLT1 and SGLT2 may provide enhanced glycemic control over SGLT2 inhibition alone, consistent with the remarkable results observed in our Phase 2a clinical trial of LX4211."