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First in Class SGLT1 Inhibitor – Positive Results

Jan 13, 2011
 

LX4211 rapidly lowered blood sugar and increased GLP-1 and PYY, mediators of glycemic and appetite control….

Lexicon Pharmaceuticals, Inc., a biopharmaceutical company, 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. 

Brian Zambrowicz, Ph.D., executive vice president and chief scientific officer, stated that, “The significant elevations of GLP-1 levels observed in the study are particularly important given its established relevance in the treatment of diabetes.” “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. 

Arthur T. Sands, M.D., Ph.D., president and chief executive officer stated in his news release that, “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.” 

The clinical trial compared a new solid oral dose formulation of LX4211 to the liquid dose formulation used in prior clinical trials of LX4211.  The trial employed a randomized, triple-cross over design during which 12 patients with Type 2 diabetes each received 300 mg of LX4211 in different dose forms.  Patients were administered a single dose of two 150 mg tablets, six 50 mg tablets or a 300 mg liquid dose formulation in varying sequences at 5-day intervals over a total period of 15 days.  Pharmacokinetic and pharmacodynamic measures were monitored at frequent time points at baseline and after administration of each of the three dose forms with baseline measures prior to dosing used as controls. 

LX4211 is an orally-delivered small molecule under development as a potential treatment for diabetes. LX4211 inhibits both sodium-glucose co-transporter Type 1 (SGLT1) and sodium-glucose co-transporter Type 2 (SGLT2).  SGLT2 is a transporter responsible for most of the glucose reabsorption performed by the kidney.  SGLT1 is a transporter responsible for glucose and galactose absorption in the gastrointestinal tract, and to a lesser extent than SGLT2, glucose reabsorption in the kidney.   

Lexicon.com News Release
 
Note from the Editor:

“Unlike LX4211, which works to inhibit both SGLT1 and SGLT2, the other drug that shows promise with a similar mechanism, dapagliflozin, only works on the SGLT2 receptors.”  — DJ