Lexicon Pharmaceuticals' Zynquista (sotagliflozin), an oral SGLT1/SGLT2 inhibitor, faced a setback as the FDA's Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) voted against its approval for glycemic control in adults with type 1 diabetes (T1D) and chronic kidney disease (CKD). The committee's decision, announced on October 31, 2024, was based on a review of the New Drug Application (NDA) for Zynquista.
The advisory committee voted 11 to 3 that the benefits of Zynquista do not outweigh the risks in adults with T1D and CKD, specifically those with an estimated glomerular filtration rate (eGFR) >45 to <60 mL/min/1.73 m2 or eGFR >60 mL/min/1.73 m2 and a urine albumin-to-creatinine ratio (uACR) > 30mg/g.
Company Response and Expert Commentary
Dr. Mike Exton, CEO of Lexicon Pharmaceuticals, expressed disappointment with the outcome but acknowledged the support for sotagliflozin within certain subpopulations of T1D and CKD patients. He emphasized the urgent need for FDA-approved treatments and clear education on managing risks associated with T1D and CKD.
Dr. Steve Edelman, a professor at the University of California, San Diego (UCSD), highlighted the limitations of insulin alone in managing T1D, noting that only 20% of patients achieve adequate glycemic control. He suggested that Zynquista, if approved, could potentially impact renal and cardiovascular outcomes, especially in those with CKD.
Sotagliflozin: Mechanism of Action and Clinical Studies
Sotagliflozin, discovered using Lexicon’s genomics-based approach, is an oral inhibitor targeting both SGLT2 and SGLT1 proteins. SGLT2 is responsible for glucose and sodium reabsorption in the kidney, while SGLT1 facilitates glucose and sodium absorption in the gastrointestinal tract. Clinical studies involving approximately 20,000 patients have explored sotagliflozin's effects across various populations, including those with heart failure, diabetes, and chronic kidney disease.
Regulatory Context and Future Steps
While the advisory committee's vote is non-binding, the FDA will consider it when making its final decision on the NDA. The FDA has set a Prescription Drug User Fee Act (PDUFA) target action date of December 20, 2024, for Zynquista.
