Memorandum

Lexicon/JDRF report topline results from phase 2 study of SGLT-1/2 dual inhibitor sotagliflozin in younger, less well-managed patients with type 1 – December 7, 2016

Executive Highlights

  • Lexicon/JDRF reported topline results from phase 2 study of SGLT-1/2 dual inhibitor sotagliflozin in younger, less well-managed patients with type 1 diabetes. Although they are being reported as negative topline results from some analyst, we see them as quite positive based on “time in range” and overall absolute A1c loss.  
  • The trial (n=87) demonstrated a total mean A1c reduction of 1.3% in patients treated with a 400 mg daily dose of sotagliflozin for 12 weeks who had a very high baseline A1c of 9.9%. The placebo-adjusted mean A1c reduction was 0.35% in the sotagliflozin arm – although this primary endpoint did not achieve statistical significance, we emphasize that the treated group did very well more easily than the placebo group – after all, in the “real” world, patients do not have a bevy of doctors around making insulin adjustments.
  • Notably, sotagliflozin treatment was associated with a one-third increase in time spent in range of 70-180 mg/dl, as measured by CGM. At week 12, mean proportion of time-in-range was 44% in the sotagliflozin, compared to 33% at baseline. Sotagliflozin was also associated with impressive reductions in postprandial glucose and body weight.

This morning, Lexicon announced topline results from its JDRF-partnered phase 2 study of SGLT-1/2 dual inhibitor sotagliflozin in younger, less well-managed patients with type 1 diabetes (aged 18-30 with baseline A1c ≥9%). The trial (n=87) demonstrated a total mean A1c reduction of 1.33% in patients treated with a 400 mg daily dose of sotagliflozin for 12 weeks (baseline A1c=9.9%). The placebo-adjusted mean A1c reduction was 0.35% in the sotagliflozin arm – this primary endpoint did not achieve statistical significance. From our view, these results just basically reflect that the placebo group did very well with appropriate insulin titration in the study – importantly, these A1c reductions were achieved with increased total insulin dose in the placebo arm and decreased insulin dose in the sotagliflozin arm. Furthermore, sotagliflozin did demonstrate a statistically significant, placebo-adjusted A1c reduction of 0.75% (p=0.006) in a pre-specified subgroup analysis of patients with A1c ≤10% at baseline (mean baseline A1c in this subgroup not specified). Previously, 400 mg sotagliflozin demonstrated a statistically significant, placebo-adjusted A1c reduction in the large, phase 3 inTandem1 trial (n=793, A1c reduction=0.4%, baseline A1c=7.57%, p<0.001). Results from the inTandem4 phase 2 dose-ranging study were also positive. Importantly, the patients in this JDRF-partnered study experienced extremely poor glycemic management prior to the study and, in our view, the lack of statistical significance for the primary endpoint is a reflection of the massive benefits of even standard-of-care diabetes treatment for these individuals – standard of care performed, of course, by experts! The fact that Lexicon and JDRF could even fully enroll this study is a reflection of the poor diabetes care too many patients experience.

The big win in this study is sotagliflozin’s benefit on time-in-range and associated reductions in hypoglycemia and hyperglycemia: sotagliflozin treatment was associated with a one-third increase in time spent in range of 70-180 mg/dl, as measured by CGM. At week 12, mean proportion of time-in-range was 44% in the sotagliflozin, compared to 33% at baseline – this translates into an additional 2.5 hours in range per day, a significant difference for any patient! For comparison, those in the placebo arm averaged 33% of time in range at week 12, down slightly from 34% at baseline. In line with previous results, sotagliflozin was also associated with an impressive placebo-adjusted 57 mg/dl reduction in two-hour postprandial glucose. Patients treated with sotagliflozin experienced a mean weight loss of 0.62 kg (1.4 lbs) at week 12, compared to a 1.75 kg (3.9 lbs) weight gain in the placebo group – a 2.37 kg (5.2 lbs) difference. Lexicon characterized sotagliflozin as well-tolerated, with a lower rate of adverse events than placebo. Notably, in a very closely-watched outcome, no patients experienced DKA, compared to two patients experiencing severe hypoglycemia and one patient experiencing DKA in the placebo arm. One patient in the sotagliflozin arm also experienced a severe hypoglycemic episode, further evidence of how hard it is to manage type 1 diabetes.

Despite the negative finding for the primary endpoint, we view these results as positive overall and further confirmation of sotagliflozin’s added value for many patients with type 1 diabetes, especially in terms of outcomes beyond A1c. We’re very eager to see data on patient-reported outcomes – we believe that the SGLT-1/2 aided results would also probably be easier for doctors to replicate. We’re eagerly look forward to results from the remaining two ongoing phase 3 trials for sotagliflozin in type 1 diabetes, inTandem2 (results expected by end of year) and inTandem3 (expected completion March 2017). We’ll be back soon with a deeper dive into the results.

-- by Helen Gao and Kelly Close