Indications
Diabetes

Stage of Development
Phase 2



Clinical Status
Lexicon has completed a Phase 2 study of LX4211 in patients with type 2 diabetes mellitus.  In this study, once daily administration of LX4211 lowered the accumulation of glucose in the body, reduced caloric load and provided improvements in glycemic control, demonstrating statistically significant improvements in the primary endpoints as well as demonstrating improvements in multiple secondary efficacy endpoints.

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. 

Previously, Lexicon successfully completed a Phase 1 clinical trial of LX4211.  Initial results in healthy volunteers demonstrated a dose-dependent increase in urinary glucose excretion.  LX4211 also demonstrated a favorable pharmacokinetic profile supporting the potential for once daily dosing.

Overview
LX4211 is an orally-delivered small molecule under development as a potential treatment for diabetes, which functions as a dual inhibitor of both sodium glucose transporter 1 (SGLT1) and sodium glucose transporter 2 (SGLT2). 

SGLT1 is the primary transporter for absorption of glucose and galactose in the gastrointestinal (GI) tract.  Although humans and mice with inactivating mutations in SGLT1 can experience glucose-galactose malabsorption, no GI side effects have been observed with pharmacological inhibition of SGLT1 with LX4211 to date.

SGLT1 is the primary transporter for absorption of glucose and galactose in the gastrointestinal (GI) tract.

This figure depicts a nephron, the basic functional unit of the kidney. The glucose reabsorption transporter, SGLT2, is expressed in the first segment of the proximal convoluted tubule (PCT S1) and is responsible for most of the glucose reabsorption that happens in the kidney. Abbreviations: PCT S1 and S2, proximal convoluted tubule segments 1 and 2; PST S3, proximal straight tubule segment 3.

Preclinical Data
In preclinical studies, animals treated with LX4211 demonstrated increased urinary glucose excretion and decreased blood HbA1c levels.  Importantly, urinary glucose excretion returned to baseline after treatment was discontinued.