We are conducting a double-blind, placebo controlled, Phase 3 study known as inTandem1, which enrolled 793 patients in the United States and Canada with type 1 diabetes on insulin pump or multiple daily injection therapy who had an A1C level entering the study between 7.0% and 11.0%. The three-arm study evaluated two doses of sotagliflozin, 200mg and 400mg, each taken once daily before the first meal of the day, against placebo. Prior to randomization, insulin was optimized for all patients over a six-week period, with the objective of improving glycemic control using insulin alone. After completion of this optimization period, patients were maintained on optimized insulin and randomized to one of two doses of sotagliflozin or placebo, and their baseline, post-optimization A1C was measured. The mean baseline A1C level at the time of randomization after the six-week optimization period was 7.6% for all three dose arms.

The primary endpoint of the study was change in A1C from baseline after a 24-week period of treatment. The trial has a double-blind long term extension of 28-weeks, with a total treatment duration of 52-weeks. There were 268 patients in the placebo arm, 263 patients in the 200mg dose arm and 262 patients in the 400mg dose arm. Top-line results from the Phase 3 study showed that patients treated with sotagliflozin had a mean A1C reduction from baseline of 0.43% on 200mg once daily sotagliflozin dose (p<0.001) and a reduction of 0.49% on 400mg once daily sotagliflozin dose (p<0.001) as compared to a reduction of 0.08% on placebo after 24 weeks of treatment, meeting the study’s primary endpoint. This statistically significant and clinically meaningful improvement in A1C for both doses of sotagliflozin was achieved without an increase in severe hypoglycemia, one of the most prevalent serious health challenges in type 1 diabetes, which was seen less frequently in both treatment arms than placebo. The overall mean placebo adjusted A1C reduction was 0.35% in the 200mg dose arm (p<0.001) and 0.41% in the 400mg dose arm (p<0.001).

Sotagliflozin was generally well tolerated. Across all three dose arms (placebo, 200mg, 400mg), the incidence of treatment-emergent adverse events (AEs) were 67.5%, 67.3% and 71.0%, respectively; the incidence of serious AEs (SAEs) were 3.4%, 3.8% and 6.9%, respectively; and discontinuation due to AEs were 1.5%, 1.1% and 3.8%, respectively. There were no reported deaths in the study.

Two primary safety concerns for patients with type 1 diabetes are severe hypoglycemia and diabetic ketoacidosis (DKA). The number of patients with severe hypoglycemic events during the 24-week treatment period was 18 (6.7%), 11 (4.2%), and 12 (4.6%) in the placebo, 200mg and 400mg dose arms, respectively. The number of patients with DKA events during the 24-week treatment period was 0 (0.0%), 3 (1.1%), and 8 (3.1%) in the placebo, 200mg and 400mg dose arms, respectively.

 

Phase 3 inTandem2 Top-Line Results (Europe and Israel)

 

We are conducting a double-blind, placebo controlled, Phase 3 study known as inTandem2 randomized 782 adult patients in Europe and Israel with type 1 diabetes on insulin pump or multiple daily injection therapy who had an A1C level entering the study between 7.0% and 11.0%.  The three-arm study evaluated two doses of sotagliflozin, 200mg and 400mg, each taken once daily before the first meal of the day, against placebo.  Prior to randomization, insulin was optimized for all patients over a six-week period, with the objective of improving glycemic control using insulin alone.  After completion of this optimization period, patients were maintained on optimized insulin and randomized to one of two doses of sotagliflozin or placebo, and their baseline, post-optimization A1C was measured.  The mean baseline A1C levels after the six-week optimization period were 7.80%, 7.74% and 7.71% for patients randomized to the placebo, 200mg and 400mg arms, respectively.  

The primary endpoint of the study was change in A1C from baseline after a 24-week period of treatment.  The trial has a double-blind long term extension of 28 weeks, with a total treatment duration of 52 weeks.  There were 257 patients in the placebo arm, 261 patients in the 200mg dose arm and 263 patients in the 400mg dose arm.  The overall mean placebo-adjusted A1C reduction at week 24 was 0.36% in the 200mg dose arm (p<0.001) and 0.35% in the 400mg dose arm (p<0.001).

Sotagliflozin was generally well tolerated.  Across all three dose arms (placebo, 200mg, 400mg), the incidence of treatment-emergent adverse events (AEs) were 51.4%, 55.9% and 54.4%, respectively; the incidence of serious AEs (SAEs) were 3.5%, 4.2% and 4.2%, respectively; and discontinuation due to AEs were 1.6%, 1.9% and 3.0%, respectively.  There were two deaths in the study in the placebo arm and no deaths in either sotagliflozin arm.  

Two primary safety concerns for patients with type 1 diabetes are severe hypoglycemia and diabetic ketoacidosis (DKA).  The number of patients with severe hypoglycemic events during the 24-week treatment period was seven (2.7%), ten (3.8%), and six (2.3%) in the placebo, 200mg and 400mg dose arms, respectively.  The number of patients with DKA events during the 24-week treatment period was none (0.0%), one (0.4%), and three (1.1%) in the placebo, 200mg and 400mg dose arms, respectively.  

 

Phase 3 inTandem3 Trial

 

We are also conducting a third type 1 diabetes Phase 3 clinical trial, inTandem3, which is studying approximately 1,400 patients treated with sotagliflozin 400mg once daily or placebo on a background of any insulin therapy, but without insulin optimization prior to randomization.  The results from inTandem3 are expected in mid-2017.

 

Phase 2 Trial

 

We previously completed a Phase 2 clinical trial evaluating the safety and tolerability of sotagliflozin and its effects on glycemic parameters associated with type 1 diabetes. The Phase 2 trial enrolled 36 patients with type 1 diabetes. An initial cohort consisted of three patients treated with a 400 mg once daily dose of sotagliflozin for a period of four weeks. A subsequent cohort of 33 patients were enrolled in the randomized, double-blind, placebo-controlled portion of the study and were treated with a 400mg once daily dose of sotagliflozin or placebo for a period of four weeks. The primary efficacy endpoint under evaluation in the trial was reduction in bolus insulin use.  Secondary endpoints included multiple parameters of glycemic control, basal and total insulin use and other metabolic, pharmacodynamic and pharmacokinetic parameters. Data from the study showed that treatment with sotagliflozin demonstrated statistically significant benefits in the primary and multiple secondary endpoints. Patients treated with sotagliflozin experienced a reduction in their total daily mealtime bolus insulin dose of 32% compared to 6% for patients who received placebo (p=0.007). We also observed a significant improvement in glycemic control, with a mean A1C reduction of 0.55% in the sotagliflozin-treated group compared to a reduction of 0.06% in the placebo-treated group (p=0.002). These observations were also 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 (>180 mg/dl) and no increase in time in hypoglycemic range (<70mg/dl). Multiple measures also indicated that patients treated with sotagliflozin experienced reduced variability in blood glucose levels. Sotagliflozin was well tolerated with no discontinuations of study medication due to adverse events.