Memorandum

Lexicon’s SGLT-1/SGLT-2 dual inhibitor sotagliflozin reports positive dose-ranging inTandem4 phase 2 data in type 1 diabetes – October 27, 2016

Executive Highlights

  • Lexicon’s SGLT-1/SGLT-2 dual inhibitor sotagliflozin met its primary endpoint of significant A1c-lowering in the dose-ranging phase 2 inTandem4 study, as announced by the company this morning.
  • These results support the potency of a 200 mg or 400 mg dose of sotagliflozin, both of which are being used in ongoing phase 3 trials of the drug candidate.

Earlier this week, Lexicon announced that SGLT-1/2 dual inhibitor sotagliflozin met its primary endpoint of significant A1c reductions in the phase 2 inTandem4 study. This 12-week trial (n=141) investigated three doses of sotagliflozin – 75 mg, 200 mg, or 400 mg once-daily – in adults with type 1 diabetes, and found that the two higher doses were able to lower A1c by statistically significant margins vs. placebo. The mean drop in A1c was 0.84% in the 200 mg arm (p<0.001) and 0.73% in the 400 mg arm (p=0.006) vs. a 0.35% mean A1c reduction with placebo. Patients treated with 75 mg of sotagliflozin experienced a mean A1c-lowering of 0.6%, though this did not reach statistical significance vs. placebo. Baseline A1c across the four arms of the study ranged from 7.95% to 8.07%.  According to the results announcement, the primary purpose of inTandem4 data is two-fold: (i) First, the significant A1c-lowering achieved by the 200 mg and 400 mg doses supports the use of these higher doses in the phase 3 clinical development program for sotagliflozin – indeed, Lexicon reported positive topline results from the phase 3 inTandem1 trial using these doses last month; (ii) Secondly, this new phase 2 data adds to the evidence for the dual mechanisms of action (at the kidneys and in the GI tract) of an SGLT-1/SGLT-2 inhibitor.

  • The company announcement also reported data on four secondary outcomes: (i) post-prandial glucose; (ii) urinary glucose excretion; (iii) body weight; and (iv) blood pressure. Once again, the significant impact of sotagliflozin on each of these measures supports the potential potency of an SGLT-1/SGLT-2 dual inhibitor for the treatment of type 1 diabetes.
    • Results demonstrated dose-dependent two-hour post-prandial glucose reductions of 21 mg/dl, 28 mg/dl, and 50 mg/dl from baseline for the 75 mg, 200 mg, and 400 mg groups, respectively. For comparison, the placebo group experienced a reduction of 0.2 mg/dl. Smaller post-prandial glucose spikes support the SGLT-1 inhibiting effects of sotagliflozin in the GI tract and suggest that sotagliflozin could perhaps reduce glycemic variability. We’re hopeful that sotagliflozin may offer patients more flexibility in their mealtime bolus dose and timing (for instances when patients might forget to bolus pre-meal or when they eat more or less than initially expected).
    • The change in mean 24-hour urinary glucose excretion over 12 weeks was 42 g, 58 g, and 71 g for the 75 mg, 200 mg, and 400 mg groups, respectively. The placebo group, on the other hand, experienced a 0.3 mg mean change. Lexicon’s announcement explained that this dose-dependent relationship is consistent with the SGLT-2 inhibiting effect of sotagliflozin in the kidneys, mitigated somewhat by the agent’s SGLT-1 inhibiting effect in the GI tract.
    • Patients experienced mean weight loss of 0.2 kg (~0.4 lbs), 1.2 kg (~2.6 lbs), and 1.5 kg (~3.3 lbs) in the 75 mg, 200 mg, and 400 mg sotagliflozin treatment arms. Meanwhile, participants given placebo saw an average weight gain of 1.1 kg (2.4 lbs) over the course of the study. Weight loss is an important outcome to consider, especially for new diabetes drugs that seek to go beyond A1c-lowering, so this body weight data is certainly valuable for sotagliflozin’s prospects.
    • In the subset of patients with hypertension at baseline, those taking 400 mg of sotagliflozin daily experienced a placebo-adjusted reduction in systolic blood pressure of 14 mmHg. Lexicon underscored that this result is consistent with what is seen for sotagliflozin in type 2 diabetes treatment, and that this positive data supports further exploration of the blood pressure effects of SGLT-1 inhibition.
  • A few notable adverse events occurred in the trial, though Lexicon characterized the agent as generally well-tolerated. In each treatment arm, there was one incidence of severe hypoglycemia over 12 weeks, in addition to one DKA event in the 400 mg sotagliflozin group. For context, there were no cases of severe hypoglycemia in the placebo group and two separate DKA events in the same patient in the pre-randomization, placebo run-in period of the study. Overall these rates are low and, given the small size of this phase 2 trial, are probably better assessed by the phase 3 data. The safety data from inTandem1 was reassuring, demonstrating lower rates of severe hypoglycemia with sotagliflozin compared to placebo and only slightly increased DKA rates at 1% and 3%. Previously, in a conference call following release of topline phase 3 results from inTandem1, management expressed confidence in low DKA rates associated with sotagliflozin as well as low risk of severe hypoglycemia, attributing both benefits to the drug’s unique mechanism of action: (i) The modest urinary glucose excretion seen with sotagliflozin could explain the low DKA incidence compared to SGLT-2 inhibitors, which have been embroiled in controversy as a type 1 diabetes treatment; (ii) By inhibiting SGLT-1 in the GI tract, the agent limits the magnitude of post-prandial glucose spikes, thereby decreasing the need for insulin adjustments and reducing hypoglycemia risk.
  • Overall treatment-related adverse events for inTandem4 were recorded for 50% of placebo patients, 49% of patients on 75 mg sotagliflozin, 29% of patients on the 200 mg dose, and 34% of patients on the 400 mg dose. No adverse events in the 200 mg or 400 mg arms led to discontinuation, which lends additional support to sotagliflozin’s safety and tolerability profile.
  • Lexicon also shared that inTandem4 is the first of three trials for sotagliflozin that will report topline results in 4Q16. The company confirmed that it plans to share results from the second of three phase 3 trials of sotagliflozin in type 1 diabetes this quarter as well – this most likely refers to inTandem2 (management previously shared the expectation that results from this trial would be available December 2016). The JDRF-partnered phase 2 trial of sotagliflozin in younger, less well-managed patients with type 1 diabetes, inTandem5, is expected to report results in 4Q16 as well (primary completion expected in November 2016, according to ClinicalTrials.gov). Previously, Lexicon shared positive topline results from the first of the phase 3 trials for sotagliflozin in type 1 diabetes, inTandem1, in September. The third and last phase 3 trial of sotagliflozin in type 1 diabetes, inTandem3, has an estimated primary completion date of March 2017, according to ClinicalTrials.gov. We look forward to an update on the progress of all of these trials, plus updates on the progress of the Sanofi-led phase 3 development program for sotagliflozin in type 2 diabetes, during Lexicon’s 3Q16 update November 1.

-- by Payal Marathe, Helen Gao, and Kelly Close