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New First in Class Treatment Shows Significant Improvements in Glucose Lowering

Posted: Sunday, February 07, 2010

The study showed positive results from a recently completed Phase 2 study of LX4211 in patients with Type 2 diabetes.

Lexicon Pharmaceuticals, Inc., a biopharmaceutical company focused on discovering breakthrough treatments for human disease, obtained positive results from a recently completed Phase 2 study of LX4211 in patients with Type 2 diabetes mellitus. LX4211 is a once-per-day, orally-delivered, small molecule drug candidate that inhibits the sodium-dependent glucose transporter 2 (SGLT2), lowering the accumulation of glucose in the body and reducing caloric load. LX4211, dosed as a single agent, provided improvements in glycemic control, demonstrating statistically significant benefits in the primary and multiple secondary efficacy endpoints.

LX4211 was developed at Lexicon as a potent inhibitor of the sodium glucose cotransporter 2 (SGLT2), a transporter responsible for the majority of glucose reabsorption by the kidneys. Lexicon found that mouse knockouts engineered to lack the SGLT2 gene are healthy and require less insulin to manage a glucose challenge. LX4211 may potentially treat diabetes by improving glycemic control as well as providing other metabolic benefits. 

"Results from this important first trial of LX4211 in diabetic patients exceeded our expectations," said Dr. Philip M. Brown, senior vice president of clinical development at Lexicon. "Rapid improvement in multiple parameters of diabetes, meaningful weight loss, a favorable safety profile and the fact that LX4211-treated patients exhibited improvements in clinically-important metabolic and cardiovascular parameters within four weeks on a single agent is remarkable."

The recently completed study was a four-week, randomized, double-blind, placebo-controlled study in 36 patients with Type 2 diabetes. Patients were randomized to receive either placebo (n=12) or LX4211, 150 mg (n=12) or 300 mg (n=12), once daily for 28 days. Patients were sequestered, provided a controlled diet and monitored closely throughout the study period.

There was a marked decrease in fasting plasma glucose throughout the treatment period in both dose groups, with reductions at week four of 53.4 mg/dl and 65.9 mg/dl in the 150 mg and 300 mg dose groups, respectively, as compared to 15.1 mg/dl for placebo. These decreases in fasting plasma glucose relative to placebo were statistically significant for both LX4211 dose groups (p=0.001 and p<0.001, respectively). Notably, a substantial percentage (42%) of patients in the 300 mg dose group achieved fasting plasma glucose levels of <105 mg/dl at week four of dosing as compared to placebo (p=0.037).

Importantly, after only four weeks of dosing, average percent hemoglobin A1c (HbA1c), a measure of blood glucose levels over time, was significantly reduced by 1.15 in the 150 mg dose group (p=0.036) and by 1.25 in the 300 mg dose group (p=0.017), as compared to 0.49 in the placebo group. HbA1c levels were reduced to less than or equal to 7% for half the patients in both dose groups; baseline levels were 8.22%, 8.50% and 8.20% for the 150 mg, 300 mg, and placebo groups, respectively. Patients in both dose groups also exhibited significantly improved glucose tolerance in response to oral glucose tolerance testing as compared to patients receiving placebo (p<0.001 for both dose groups), as measured by area under the curve (AUC). Consistent with the mechanism of action of LX4211, there was also a significant, dose-dependent increase in 24-hour urinary glucose excretion throughout the study period relative to placebo in both dose groups (p<0.001 at all time points measured).

With respect to broader metabolic and cardiovascular safety parameters, patients in both dose groups showed weight reduction accompanied by decreased blood pressure and triglycerides relative to placebo. LX4211 demonstrated a favorable safety profile in the study with no dose-limiting toxicities. Adverse events were generally mild and equally distributed across all groups, including the placebo group.

"The magnitude and rapid response in glycemic control, combined with the triglyceride reduction, may distinguish LX4211 from other agents in this class," said Dr. Brian Zambrowicz, chief scientific officer of Lexicon. "We now believe that the action of LX4211 cannot be entirely explained by glucose excretion in the urine alone, but may also relate to secondary events that both further enhance glycemic control and provide the other metabolic improvements we have witnessed in this study."

Source: Diabetes In Control: Press Release, Lexicon

 
 
 
 
 
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