Memorandum

Positive topline results from phase 3 inTandem1 study demonstrate significant A1c reductions for Lexicon/Sanofi’s SGLT-1/2 dual inhibitor sotagliflozin – September 20, 2016

Executive Highlights

  • Lexicon has shared via press release and webcast positive topline results from inTandem1. The double-blind, placebo-controlled trial (n=793 patients with type 1 diabetes) demonstrated a placebo-adjusted mean A1c reduction of 0.35% A1c reduction in participants treated with a once-daily 200 mg dose (baseline A1c=7.6%, p<0.001) after 24 weeks and a placebo-adjusted mean A1c reduction of 0.4% in participants treated with a 400 mg dose (baseline A1c=7.57%, p<0.001).
  • In addition to meeting this primary endpoint (from a low A1c), sotagliflozin was associated with lower risk of severe hypoglycemia (4.2% in the 200 mg group; 4.6% in the 400 mg group; 6.7% in placebo) and with a very slightly increased risk of DKA (1% in the 200 mg group; 3% in the 400 mg group; 0% in placebo). No statistical analyses have yet been reported for either of these diabetes outcomes. We are very eager to see even more outcomes beyond A1c.
  • Management called attention to ways in which sotagliflozin may stand out in a competitive SGLT-2 inhibitor market: (i) low DKA rates in a type 1 population; (ii) mechanism of action in the GI tract, independent of the kidneys; and (iii) decreased risk for severe hypoglycemia.

In an exciting announcement just before EASD, Lexicon shared positive topline results from the phase 3 inTandem1 trial of Sanofi-partnered SGLT-1/2 dual inhibitor sotagliflozin in patients with type 1 diabetes. We’ve been eagerly awaiting this data, and were excited (for type 1 patients who have had so few new options) with what the company reported via press release and webcast. The double-blind, placebo-controlled trial (n=793 patients with type 1 diabetes) demonstrated a placebo-adjusted mean A1c reduction of 0.35% A1c reduction in participants treated with a once-daily 200 mg dose (baseline A1c=7.61%, p<0.001) after 24 weeks and a placebo-adjusted mean A1c reduction of 0.41% in participants treated with a 400 mg dose (baseline A1c=7.57%, p<0.001). Notably, Lexicon management emphasized that all participants underwent six weeks of insulin optimization prior to medication initiation so that sotagliflozin’s benefits would be demonstrated on top of an effective glucose-lowering therapy, providing more compelling efficacy evidence. Furthermore, the agent met its primary A1c endpoint without increasing severe hypoglycemia, which was lower in the sotagliflozin groups (4.2% of 200 mg group; 4.6% of 400 mg group) vs. placebo (6.7%). There was a slightly greater risk of DKA associated with sotagliflozin treatment, with zero events in the placebo group, three events or a ~1% rate in the 200 mg group, and eight events or a ~3% rate in the 400 mg group. No p-value was reported for between-group differences in severe hypoglycemia or DKA, and the company noted that statistical testing for the latter would have been inappropriate given the extremely small numbers.

We’re looking forward to learning more details on hypoglycemia and DKA associated with sotagliflozin treatment when full results from inTandem1 are released, perhaps at ADA 2017. Moreover, inTandem1 is the first phase 3 trial for sotagliflozin to report topline results and we look forward to findings from inTandem2 (expected to report topline results by end of year) and inTandem3 (underway globally and expected to complete in 2017), capping off the type 1 research program for sotagliflozin. We’re also eagerly awaiting a look at sotagliflozin’s efficacy and safety in type 2 diabetes – Sanofi is expected to commence the phase 3 type 2 diabetes program by the end of the year.

  • During Q&A at the end of the webcast, Lexicon management elaborated on the positive clinical features that might distinguish sotagliflozin from SGLT-2 inhibitors. Namely, according to management, the candidate (i) shows low DKA rates in a type 1 patient population, (ii) acts on the GI tract in a manner independent from its impact on the kidneys, and (iii) decreases risk for severe hypoglycemia. Three SGLT-2 inhibitors are currently available on the market in the US and EU: Lilly/BI’s Jardiance (empagliflozin), J&J’s Invokana (canagliflozin), and AZ’s Farxiga (dapagliflozin). Merck/Pfizer’s ertugliflozin will be submitted by the end of the year and is expected to be the fourth-to-market.
    • “We’re satisfied with the 1% and 3% DKA rates at 24 weeks. These low rates may be unique to our product.” Prior to topline results, the company previously acknowledged that DKA would be a concern to look out for in inTandem1 and posited that this risk would have to be weighed against health benefits. Given the topline data, management presented an optimistic view that DKA will not present a major safety concern for sotagliflozin. Management explained that the low DKA rates are possibly due to the modest urinary glucose excretion seen with sotagliflozin compared to SGLT-2 inhibitors. We’ve heard no shortage of controversy over SGLT-2 inhibitor-induced DKA in patients with type 1 diabetes and we’re encouraged by the benefit-risk profile demonstrated by sotagliflozin in this trial.
    • Since many patients experience kidney dysfunction as a comorbidity or complication of diabetes, the less renal-dependent mechanism of action of sotagliflozin could be valuable. Management underscored this point and argued that it will be particularly relevant as the sotagliflozin research program expands into type 2 diabetes. We’re curious if sotagliflozin might have sustained glucose-lowering efficacy at in patients with kidney dysfunction given the renal-independent mechanism of action offered by the SGLT-1 inhibitor component (vs. SGLT-2 inhibitors which are contraindicated in patients with low eGFR due to reduced efficacy). On the other hand, SGLT-2 inhibitors such as Lilly/BI’s Jardiance (empagliflozin) may be renal-protective and we’re curious how the SGLT-1 inhibition component of sotagliflozin affect its potential for renal-protection.
    • Management outlined a mechanism by which sotagliflozin may reduce risk of severe hypoglycemia: First, the drug blocks SGLT-1 in the GI tract, which limits the magnitude of postprandial glucose spikes. “This limits the number of adjustments you have to make to your insulin regimen; that allows you to spend more time in range and avoid severe hypoglycemia.” Management was clearly encouraged by the lower incidence of severe hypoglycemia in the treatment arms vs. placebo arm, and so are we, though we expect the FDA, given its history, might require a more rigorous trial of hypoglycemia rates in order for sotagliflozin’s potential impact on hypoglycemia to make it into the indication.
  • Management did not comment on timing for regulatory filing, or on which dose the company will prioritize for filing. During Q&A, management remarked that Lexicon along with partner Sanofi will wait for further results from the inTandem clinical trial program before making this decision. Previously, management has expressed optimism that the company will be able to file sotagliflozin for type 1 diabetes ahead of completion of the type 2 diabetes program given the lag between the two development programs. On the other hand, the FDA has also previously signaled a preference from a combined type 1 and type 2 diabetes program and may ask Lexicon and Sanofi to wait to file for the two indications together.

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