Sotagliflozin Setback: Cautionary FDA AdComm Vote Reflects Continued Concern for Negative Risk/Benefit Ratio in T1D with CKD

Sotagliflozin received a less-than-confident vote at yesterday’s FDA Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) meeting, with the committee voting 11 to 3 that the benefits of the dual sodium glucose contransporter-1, -2 inhibitor (SGLT1/SGLT2i) do not outweigh the risks of the tablet formulation when added to insulin therapy for reducing hyperglycemia in adults with type 1 diabetes (T1D) and mild-to-moderate chronic kidney disease (CKD). The announcement was made by Lexicon Pharmaceuticals late yesterday.¹

The advisory committee recommendations are not binding but the FDA will factor in the results of the EMDAC discussions when making its final decision on approval of the Lexicon revised new drug application (NDA). The previously assigned date of December 20, 2024, for the Prescription Drug User Fee Act (PDUFA) date has not been changed.

During the discussion, some committee members expressed support for sotagliflozin in alternative subpopulations of people with T1D and CKD, where they believed the benefits potentially outweigh the risks, Lexicon said.¹

“Insulin is essential to managing this disease, but it is not sufficient in keeping patients within appropriate blood glucose ranges,” Steve Edelman, MD, professor of medicine in the division of endocrinology, diabetes, & metabolism at the University of California, San Diego, said in the Lexicon announcement. “Only 20 percent of people with T1D currently achieve adequate glycemic control with insulin alone. [Sotagliflozin], if approved, would be the first oral medication for people with T1D, with potential to impact renal and cardiovascular outcomes, especially in those with CKD who face even greater disease progression risks.”¹

NDA History

The FDA sent a complete response letter to Lexicon following the company’s original NDA in 2019.² In that application Lexicon sought an indication for use of sotagliflozin as an adjunct to insulin in adults with T1D and uncontrolled hyperglycemia. The agency cited concerns about the elevated risk for diabetic ketoacidosis seen during the phase 3 inTandem clinical trial program. Data for the proposed new indication are drawn from post hoc analyses of the population with CKD in the original phase 3 trials. In briefing documents prepared for the October 31 advisory committee meeting, concerns for DKA were raised again along with questions about the durability of treatment response for the target population in the revised indication, defined by the sponsor as adults with T1D and an estimated glomerular filtration rate (eGFR) of 45 to <60 mL/min/1.73 m² or an eGFR ≥60 mL/min/1.73 m² and a urine albumin-creatinine ratio of ≥30 mg/g.

Lexicon continues to believe the risk for DKA can be managed, and may be at least balanced, if not outweighed, by unmet needs in the T1D population.

“We are disappointed in the outcome of today’s Advisory Committee vote. However, we were encouraged by the rich discussion and outpouring of support across the diabetes community in favor of sotagliflozin being made available to appropriate people with T1D and CKD,” Mike Exton, PhD, chief executive officer and director of Lexicon Pharmaceuticals. “It’s clear from today’s discussion that an FDA-approved treatment and clear education on managing risk is urgently needed, and we believe our data supports this need. We look forward to working with the FDA as it completes its review of our NDA, and if approved, making [Sotagliflozin] available to patients who could benefit from this therapy.”

The NDA that now moves on to the FDA for consideration ahead of the December PDUFA date, includes data on the use of Sotagliflozin in adults with type 2 diabetes (T2D) and moderate-to-severe CKD. Last year, the agency granted approval for the SGLT1/SGLT2 inhibitor (marketed as Inpefa) to reduce the risk of cardiovascular (CV) death, emergency visits or hospital admission for heart failure in adults with the condition, and in adults with T2D, CKD, and other CV risk factors.

1. Lexicon announces outcome of FDA advisory committee for Zynquista (sotagliflozin) as an adjunct to insulin therapy for glycemic control in adults wtih type 1 diabetes and chronic kidney disease. News release. Lexicon Pharmaceuticals. October 31, 2024. Accessed November 1, 2024. https://www.lexpharma.com/media-center/news/2024-10-31-lexicon-announces-outcome-of-fda-advisory-committee-for-zynquista-sotagliflozin-as-an-adjunct-to-insulin-therapy-for-glycemic-control-in-adults-with-type-1-diabetes-and-chronic-kidney-disease

2. Halsey G. Sotagliflozin in patients with type 1 diabetes and CKD to be discussed at October FDA adcomm meeting. Patient Care. October 14, 2024. https://www.patientcareonline.com/view/sotagliflozin-in-patients-with-type-1-diabetes-and-ckd-to-be-discussed-at-october-fda-adcomm-meeting

FDA Approves SGLT-2/1 Inhibitor Sotagliflozin, Grants Broad Heart Failure Indication. Patient Care. May 30, 2023. https://www.patientcareonline.com/view/fda-approves-sglt-2-1-inhibitor-sotagliflozin-grants-broad-heart-failure-indication