Lexicon Pharmaceuticals of The Woodlands, Texas, has reported that LX4211, an investigational, oral, dual inhibitor of sodium glucose transporters 1 and 2 (SGLT1 and SGLT2), showed substantial, dose-dependent, statistically-significant reductions in hemoglobin A1c (HbA1c) in a phase IIb trial in patients diagnosed with poorly-controlled type 2 diabetes who were concurrently treated with metformin, an established diabetes therapy.
LX4211 also produced significant reductions in body weight and blood pressure. Importantly, LX4211 treatment had a favorable safety profile and was well tolerated in the study.
LX4211, a unique dual inhibitor, reduces the amount of glucose that enters the bloodstream from the gastrointestinal (GI) tract by inhibiting SGLT1, the major transporter responsible for glucose absorption, and enhances glucose excretion in the urine by inhibiting SGLT2, the major transporter responsible for glucose reabsorption by the kidney. Lexicon has previously demonstrated that SGLT1 inhibition by LX4211 increases GLP-1 and PYY, GI hormones associated with glycemic control and appetite.
"New diabetes therapies will need to help patients safely control blood sugar and address other metabolic parameters that play a role in this pervasive disease," said Dr. Arthur Sands, president and CEO of Lexicon. "The positive results obtained when LX4211 is combined with metformin suggest it has the potential to make a meaningful contribution to diabetes care."
The 12-week, dose-ranging study, conducted in over 50 centers in the U.S., randomized 299 patients with poorly controlled type 2 diabetes on metformin therapy to receive either LX4211 or placebo. The primary endpoint of the study was the change in HbA1C, a measure of glycemic control, from baseline to week 12. LX4211 was administered at doses of 75mg QD, 200mg QD, 200mg BID and 400mg QD. Top-line results showed that patients in the LX4211 treatment arms had mean HbA1C reductions from baseline of 0.43%, 0.52%, 0.79% and 0.95%, respectively (p
Adverse events were generally mild to moderate, and the overall incidence of adverse events with LX4211 similar to placebo. There were four serious adverse events, none attributed to treatment, which were equally distributed across treatment groups and placebo. There were no hypoglycemic events reported.
"We believe the encouraging results obtained from this study further differentiate LX4211 from the SGLT2-selective inhibitors currently in development," said Dr. Brian Zambrowicz, CSO at Lexicon. "The enhanced glycemic control and favorable safety profile observed in this study are characteristics we believe are related to LX4211's dual mechanism of action."
Dr. Pablo Lapuerta, CMO at Lexicon, added, "We are targeting phase III initiation for the first half of 2013. Further development of LX4211 in type 2 diabetes will focus on demonstrating long-term benefits in glycemic and metabolic parameters and reduction in cardiovascular risk."