FDA Rejects, EMA Approves: First SGLT-1/2 Dual Inhibitor Zynquista (Sotagliflozin) Authorized for Type 1 Diabetes

On April 26, the European Commission approved the marketing authorization of Zynquista (sotagliflozin), developed by Sanofi and Lexicon Pharmaceuticals, at a once-daily dose of 200 mg or 400 mg as an adjunct to insulin therapy for patients with type 1 diabetes mellitus (BMI ≥27) whose blood glucose is not adequately controlled with optimal-dose insulin alone.

On March 26, one month ago, the EMA approved AstraZeneca’s sodium-glucose cotransporter-2 (SGLT-2) inhibitor Forxiga (dapagliflozin) for the same indication, marking the first time the EMA has approved an oral medication as an adjunct to insulin for patients with type 1 diabetes (see: SGLT-2 Inhibitors Approved for the Treatment of Type 1 Diabetes for the First Time).

SGLT is a family of transporter genes found in the small intestinal mucosa and the proximal convoluted tubules of the kidney, comprising two subtypes: SGLT-1 and SGLT-2. SGLT-1 is primarily distributed in the small intestine and the distal S3 segment of the renal proximal convoluted tubule, with minor expression in the heart and trachea, and is mainly involved in glucose absorption in the gastrointestinal tract. SGLT-2 is predominantly located in the S1 segment of the renal proximal convoluted tubule and plays a key role in renal glucose reabsorption. SGLT inhibitors offer a glucose-lowering therapy that is entirely distinct from insulin-dependent pathways. Sotagliflozin, a dual SGLT-1/2 inhibitor, provides significant therapeutic benefits for patients with type 1 diabetes through its dual inhibition of glucose absorption.

The EU approval of sotagliflozin was primarily based on evidence from the inTandem clinical program. The inTandem program comprised three Phase III clinical trials, enrolling approximately 3,000 patients with type 1 diabetes and inadequate glycemic control. The results demonstrated that sotagliflozin at doses of 200 mg and 400 mg, as an oral adjunct to insulin therapy, significantly improved HbA1c levels, body weight, and systolic blood pressure from baseline after 24 weeks of treatment compared with insulin monotherapy, without a significant increase in severe hypoglycemic events.

Although the EMA approved sotagliflozin for market release, the FDA held a different stance. On March 23, Sanofi and Lexicon Pharmaceuticals announced that the FDA had rejected their marketing application for sotagliflozin for the treatment of type 1 diabetes in adults, without disclosing specific reasons. At an expert advisory committee meeting in January, the FDA panel voted 8:8, expressing uncertainty regarding the benefit-risk profile of sotagliflozin. This hesitation was primarily due to data from the Phase III clinical trial coded as inTandem 1, which showed that after 52 weeks of treatment as an adjunct to insulin, 7.6% of patients experienced suspected or confirmed cases of diabetic ketoacidosis (DKA).

Diabetic ketoacidosis (DKA) is an acute complication of diabetes and one of the common medical emergencies in internal medicine. Typically, patients with type 1 diabetes are predisposed to DKA, carrying a higher risk than those with type 2 diabetes. The American Diabetes Association and most clinical experts believe that the risk of SGLT inhibitor-associated DKA can be managed through patient selection, patient education, and real-time ketone monitoring. Additionally, similar to other SGLT-2 inhibitors, sotagliflozin has also demonstrated an increased risk of genital infections in clinical studies.

Sanofi entered into a collaboration with Lexicon in 2015, acquiring the development and commercialization rights to sotagliflozin for an upfront payment of $300 million and up to $1.4 billion in research, regulatory, and sales milestones. Sotagliflozin is still undergoing clinical studies in patients with type 2 diabetes; currently, there are 11 clinical trials ongoing, including two studies in patients with type 2 diabetes and renal impairment, as well as two large cardiovascular outcome trials.

Source: PharmCube