Lexicon Pharmaceuticals announced new data from the phase 3 inTandem1 and inTandem2 studies of sotagliflozin (Zynquista; Sanofi and Lexicon) in adult patients with type 1 diabetes.

Sotagliflozin is an investigational dual sodium-glucose co-transporter types 1 and 2 (SGLT1, SGLT2) inhibitor. It works by inhibiting the two proteins responsible for glucose regulation: SGLT1 (responsible for glucose absorption in the GI tract) and SGLT2 (responsible for glucose reabsorption by the kidney).

Recent data from the 52-week, double-blind, placebo-controlled phase 3 studies of inTandem1 (N=793) and inTandem2 (N=782) demonstrated changes in clinical biomarkers with sotagliflozin 200mg and 400mg, in combination with insulin, that suggest it may reduce cardiovascular risk and progression to chronic kidney disease.

Results showed that after a modest initial reduction, estimated glomerular filtration rate (eGFR) returned to baseline for patients randomized to sotagliflozin, but not to placebo, 7 days after the last dose, with a placebo-adjusted mean change of +3.0mL/min/1.73m2 (P =.031) for 200mg and +2.7mL/min/1.73m2 (P =.045) for 400mg. Mean serum hematocrit also increased with a mean difference of 1.8% and 1.9% at Week 12 for sotagliflozin 200mg and 400mg, respectively (P <.0001), and persisted throughout the 52-week trial (P <.0001). Moreover, mean serum albumin increased 0.06g/dL and 0.07g/dL with sotagliflozin 200mg and 400mg, respectively, at Week 4 (P <.0001), with the placebo-adjusted LS mean change at Week 52 of 0.03g/dL for 200mg (P = .036) and 0.03g/dL for 400mg (P =.053).

Findings from the study also demonstrated significant reductions in uric acid at Week 52 with a placebo-adjusted mean change of 20.17mg/dL for sotagliflozin 200mg (P =.0003) and 20.28mg/dL for sotagliflozin 400mg (P <.0001). Additionally, a consistent lowering of blood pressure (BP) with sotagliflozin 200mg and 400mg was observed with a placebo-adjusted systolic BP difference of -2.9 and -3.6mmHg, respectively (P <.0001), and a placebo-adjusted diastolic BP difference of -1.4 (P =.0033) and -1.6mmHg (P =.0008), respectively. The urinary albumin-to-creatinine ratio (UACR) decreased by 23.7% with the 200mg dose (P =.054) and 18.3% with the 400mg dose (P =.18) in patients with baseline UACR ≥30mg/g.

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The results were recently published in Diabetes Care and are available here.

In March 2019, the FDA issued a Complete Response Letter (CRL) rejecting the New Drug Application (NDA) for Zynquista due to concerns over the clinical significance of the composite endpoint (HbA1c <7% with no episodes of severe hypoglycemia or diabetic ketoacidosis [DKA]). In addition, the panel noted a “consistent and clinically meaningful increase” in the risk of DKA associated with sotagliflozin treatment.

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