A pivotal phase 3 study of oral sotagliflozin (Lexicon Pharmaceuticals) has met its primary endpoint, showing a statistically significant reduction in hemoglobin A1c (HbA1c) at 24 weeks in patients with type-1 diabetes on a background of optimized insulin.
Patients treated with sotagliflozin had a mean HbA1c reduction from baseline of 0.43% on a 200-mg once-daily dosage (P < 0.001) and a reduction of 0.49% on a 400-mg once-daily dosage (P < 0.001) compared with a reduction of 0.08% with placebo after 24 weeks of treatment, meeting the study’s primary endpoint. This statistically significant improvement in HbA1c for both dosages of sotagliflozin was achieved without an increase in severe hypoglycemia, one of the most prevalent health challenges in patients with type-1 diabetes, which was seen less frequently in both treatment arms compared with the placebo arm.
Sotagliflozin is a first-in-class, oral dual inhibitor of sodium-glucose co-transporter types 1 and 2 (SGLT1 and SGLT2). SGLT1 is responsible for glucose absorption in the gastrointestinal tract, and SGLT2 is responsible for glucose reabsorption by the kidney. Sotagliflozin improved glycemic control in patients with type-1 diabetes while reducing their need for mealtime insulin in a phase 2 study.
The double-blind, placebo-controlled, phase 3 inTandem1 trial enrolled 793 patients in the United States and Canada with type-1 diabetes on insulin pump or multiple daily injection therapy who had HbA1c levels of between 7.0% and 11.0% at baseline, which corresponded to an estimated average blood sugar level of 154 mg/dL (8.6 mmol/L) to 269 mg/dL (15.0 mmol/L).
The three-arm study evaluated two doses of sotagliflozin, 200 mg and 400 mg, each taken once daily before the first meal of the day, in comparison with placebo. Before randomization, insulin was optimized for all patients during a six-week period, with the objective of improving glycemic control using insulin alone. After the completion of this optimization period, the patients were maintained on optimized insulin; were randomly assigned to one of two doses of sotagliflozin or placebo; and were assessed for baseline HbA1c. The mean baseline HbA1c level at the time of randomization after the six-week optimization period was 7.6% for all three treatment arms.
The study’s primary endpoint was the change in HbA1c from baseline after the 24-week treatment period. The trial had a double-blind long-term extension of 28 weeks, with a total treatment duration of 52 weeks. A total of 268 patients were in the placebo arm; 263 patients were in the 200-mg arm; and 262 patients were in the 400-mg arm. The overall mean placebo-adjusted HbA1c reduction was 0.35% in the 200-mg arm (P < 0.001) and 0.41% in the 400-mg arm (P < 0.001).
Sotagliflozin was generally well tolerated. Across all three treatment arms (placebo, 200 mg, and 400 mg), the rates of treatment-emergent adverse events (AEs) were 67.5%, 67.3%, and 71.0%, respectively; the rates of serious AEs were 3.4%, 3.8%, and 6.9%; and discontinuation rates due to AEs were 1.5%, 1.1%, and 3.8%. 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 numbers of patients with severe hypoglycemic events during the 24-week treatment period were 18 (6.7%), 11 (4.2%), and 12 (4.6%) in the placebo, 200-mg, and 400-mg arms, respectively. The numbers of patients with DKA events during the 24-week treatment period were zero (0.0%), three (1.1%), and eight (3.1%).
Lexicon is conducting a similar pivotal phase 3 study (inTandem2), which is expected to report top-line results by the end of the year. The third phase 3 trial in patients with type-1 diabetes (inTandem3) is under way globally and is studying approximately 1,400 patients treated with sotagliflozin 400 mg once daily or placebo on a background of any insulin therapy, but without insulin optimization before randomization. Phase 3 trials of sotagliflozin in patients with type-2 diabetes are expected to begin by the end of the year.
Source: Lexicon Pharmaceuticals; September 9, 2016.