Type 1 and type 2 diabetes
Sotagliflozin, or LX4211, is an orally-delivered small molecule compound that we are developing for the treatment of type 1 and type 2 diabetes mellitus. Sotagliflozin was internally generated by our medicinal chemists and inhibits both sodium-glucose cotransporter type 2, or SGLT2, a transporter responsible for most of the glucose reabsorption performed by the kidney, and sodium-glucose cotransporter type 1, or SGLT1, a transporter responsible for glucose and galactose absorption in the gastrointestinal tract, and to a lesser extent than SGLT2, glucose reabsorption in the kidney. Our scientists identified mice lacking SGLT1, SGLT2 or both as having potent anti-diabetic phenotypes across multiple measures of glucose control and metabolism, and found that compounds inhibiting both targets had a favorable preclinical profile relative to compounds selective for SGLT2.
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 where SGLT1 has a lesser role. Abbreviations: PCT S1 and S2, proximal convoluted tubule segments 1 and 2; PST S3, proximal straight tubule segment 3.
SGLT1 is the primary transporter for absorption of glucose and galactose in the gastrointestinal tract.
Phase 2 Clinical Trial
JDRF, the world’s largest non-profit supporter of type 1 diabetes research, is providing funding to support a Phase 2, randomized, double-masked, placebo-controlled clinical trial to evaluate the efficacy and safety of sotagliflozin in a younger population with type 1 diabetes. We have begun enrollment of individuals with T1D, younger than 30 years of age and with A1C levels greater than 9.0%, who are being randomly assigned to receive either placebo or a once daily 400mg dose of sotagliflozin and complete the 12-week treatment period. The primary objective of this study is to demonstrate the superiority of sotagliflozin versus placebo as adjunct to insulin treatment on A1C reduction at 12 weeks as well as several secondary endpoints, including reduced variability in blood glucose levels and lower insulin needs.
Phase 3 Clinical Trials
We have begun enrollment in two pivotal Phase 3 clinical trials of sotagliflozin in patients with type 1 diabetes. Each trial is expected to enroll approximately 750 patients who will be randomized to either 400 mg/once daily, 200 mg/once daily or placebo as an adjunct treatment to insulin. The primary endpoint of both trials is the reduction of A1C versus placebo on optimized insulin. Additional endpoints include reduced variability in blood glucose levels, lower insulin needs, weight loss and other patient-reported outcomes. The Phase 3 development program for sotagliflozin also includes a third Phase 3 clinical trial in approximately 1,400 patients involving a glycemic control primary endpoint and an evaluation of safety.
Current Status on clinicaltrials.gov
Type 1 Diabetes
In April 2014, we announced positive, top-line results in a Phase 2 clinical trial of sotagliflozin in type 1 diabetes, which achieved the primary endpoint of reducing mealtime insulin use as well as several secondary endpoints, including improved glycemic control.
In the placebo-controlled, double-blind, 28-day study, sotagliflozin reduced the total daily mealtime bolus insulin dose by 32% compared to 6% for placebo (p=0.007), while significantly improving glycemic control with a mean HbA1c reduction of 0.55% in the sotagliflozin-treated group compared to a reduction of only 0.06% with placebo (p=0.002). This improvement was accompanied by significant improvement in the time spent in a glucose range of 70-180 mg/dl, a significant reduction in time in hyperglycemic range, and no increase in hypoglycemia. Multiple measures indicated that sotagliflozin treatment resulted in reduced variability in blood glucose levels. Overall, LX4211 was well tolerated with no discontinuations of study medication due to adverse events.
Type 2 Diabetes
We reported top-line data in June 2012 from a Phase 2b clinical trial evaluating the safety and tolerability of sotagliflozin and its effects on glycemic parameters associated with type 2 diabetes. The Phase 2b trial enrolled 299 patients with type 2 diabetes who were not adequately controlled on metformin monotherapy in a double-blind, randomized, placebo-controlled study of 75mg once daily, 200mg once daily, 200mg twice daily and 400mg once daily doses of sotagliflozin, each administered in combination with standard metformin therapy over a 12-week treatment period. The primary efficacy endpoint under evaluation in the trial was the change in hemoglobin A1c, or HbA1c, from baseline to week 12. Secondary efficacy endpoints included percentage of patients achieving HbA1c levels of less than 7%, as well as changes in fasting plasma glucose levels, weight, blood pressure and triglyceride levels. Top-line data from the study showed that treatment with sotagliflozin demonstrated statistically significant benefits in the primary and multiple secondary endpoints. Patients in each of the 75mg once daily, 200mg once daily, 200mg twice daily and 400mg once daily sotagliflozin treatment arms had mean HbA1c reductions from baseline of 0.43, 0.52, 0.79 and 0.95 percent, respectively (p<0.001 for all treatment arms), while in patients randomized to placebo, HbA1C decreased by 0.09 percent. We also observed that patients treated with sotagliflozin showed significant reductions in body weight and blood pressure. Sotagliflozin was well tolerated and adverse events were generally mild to moderate, with the overall incidence of adverse events with sotagliflozin being similar to placebo.
We reported top-line data in October 2013 from a clinical trial evaluating the safety and tolerability of sotagliflozin and its effects on glycemic parameters associated with type 2 diabetes in patients with moderate renal impairment. The clinical trial enrolled 30 patients with type 2 diabetes and moderate to severe renal impairment in a randomized, double-blind, placebo-controlled study of a 400mg once daily dose of sotagliflozin over a seven-day treatment period. The primary efficacy endpoint under evaluation in the trial was the change in postprandial glucose from baseline to day seven, with secondary endpoints including a variety of glycemic control parameters. Top-line data from the study showed that treatment with sotagliflozin provided clinically meaningful and statistically significant reductions (p<0.05) in post-prandial glucose and produced significant elevations in GLP-1, a hormone involved in control of glucose and appetite. Sotagliflozin was well tolerated and adverse events were generally mild to moderate, with the overall incidence of adverse events with sotagliflozin being similar to placebo.
We previously completed a Phase 2a clinical trial in type 2 diabetes patients, in which sotagliflozin provided improvements in glycemic control, demonstrated statistically significant benefits in the primary and multiple secondary efficacy endpoints and demonstrated a favorable safety profile.
We do not intend to continue development of sotagliflozin in type 2 diabetes unless we enter into a collaboration partnership.
Diabetes mellitus is a common metabolic disorder associated with abnormally high blood sugar levels. Diabetes is classified as either type 1, which is characterized by severely diminished insulin production, or type 2, which is characterized by moderately diminished insulin production in conjunction with insulin resistance (insensitivity of the tissues of the body to insulin). Insulin, a hormone that regulates blood glucose levels, is required to convert sugar, starches, and other food into energy needed for daily life. Diabetes can seriously impair overall quality of life and may lead to multiple complications including heart disease, stroke, and kidney failure.
According to the International Diabetes Foundation, more than 246 million people worldwide are afflicted with diabetes, with type 2 diabetes being the most common. The National Institutes of Health (NIH) estimates that more than 20 million Americans have diabetes. Diabetes is increasing as the population ages. Obesity, a leading cause of the disease, is also on the increase. While weight loss can be an effective way to help prevent and treat type 2 diabetes, many diabetics also need to manage the disease with drugs. Most diabetics control blood glucose levels by injecting insulin, or by taking newer drugs that either signal the pancreas to produce the right amount of insulin or reduce resistance to insulin.
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* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.