FDA Advisory Committee Votes Down Sotagliflozin in Type 1 Diabetes and CKD

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 11 to 3 that the benefits of Zynquista (sotagliflozin) do not outweigh the risks in adults with type 1 diabetes (T1D) and chronic kidney disease (CKD).

The FDA is currently reviewing the approval of Zynquista as an adjunct to insulin to help control glycemic levels in adults with type 1 diabetes and chronic kidney disease. The agency’s goal date is Dec. 20, 2024.

Developed by Lexicon Pharmaceuticals, sotagliflozin is an inhibitor of SGLT2 and SGLT1, which are responsible for glucose regulation in the kidney and gastrointestinal tract, respectively.

Sotagliflozin was approved by the FDA as Inpefa in May 2023 as a once-daily oral tablet that reduces the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure or type 2 diabetes, chronic kidney disease, and other cardiovascular risk factors. For the first half of 2024, Inpefa generated sales of $2.7 million. Inpefa is the company’s only revenue-generating product. For the full year 2023, Inpefa generated sales of $1.2 million.

Steve Edelman, M.D.

“Only 20% of people with T1D currently achieve adequate glycemic control with insulin alone. Zynquista, 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," Steve Edelman, M.D., a professor of medicine in the Division of Endocrinology, Diabetes & Metabolism at the University of California, San Diego (UCSD), and founder and director of Taking Control Of Your Diabetes, said in a news release.

Lexicon had resubmitted the application for sotagliflozin for this indication in June 2024. The FDA had issued a complete response letter in 2019 regarding this NDA for sotagliflozin.

Data were presented in March 2024 from the inTandem3 phase 3 trial. The trial found that treatment with sotagliflozin resulted in improved glycemic control in patients with type 1 diabetes and chronic kidney disease. Sotagliflozin lowered A1C, body weight, and systolic blood pressure with safety similar to the total study cohort.

In a briefing document issued ahead of the advisory committee, agency officials expressed concerns about whether there was enough evidence to support the use of sotagliflozin for adults with type 1 diabetes and chronic kidney disease. Regulators suggested that there were uncertainties regarding the magnitude of benefits for patients with type 1 diabetes and mild-to-moderate chronic kidney disease, as well as uncertainty regarding the magnitude of risk for diabetic ketoacidosis.

Diabetic ketoacidosis is a serious complication, where the body is not able to use sugar for energy. The liver will begin to break down fat for fuel, which produces acids called ketones.

In its presentation during the meeting, FDA officials pointed out that two epidemiology sources indicate that patients with chronic kidney disease have an increased risk of diabetic ketoacidosis. But regulators said the data provided by Lexicon doesn’t specifically provide insight into the specific sotagliflozin-related risk, and there are uncertainties about the generalizability of this risk from the overall patient studied in the Tandem trials.

Additionally, committee members, even those who voted yes on the question of whether the benefits outweigh the risk, said there was uncertainty around about the data of sotagliflozin in patients with kidney disease. In the trials, there were fewer patients in the subgroup with kidney disease, those with an estimated glomerular filtration rate (eGFR) of less than 60. GFR estimates how much blood passes through the kidneys to filter waste.

Two phase 3 studies were presented. In Study 300/310, two doses of sotagliflozin in 1,049 patients were compared with 526 receiving placebo. But only 71 patients were in the subgroup of those with less than 60 eGFR. In Study 312, 699 patients treated with the higher dose of sotagliflozin were compared with 703 patients. Just 74 patients had an eGFR of less than 60.

Committee members wanted to see more data about the risk in patients with kidney disease.

Barbara Onumah, M.D.

Barbara Onumah, M.D., a practicing physician at The Diabetes and Endocrine Wellness Center, in Largo, Maryland, voted yes, but she as conflicted. “My yes vote is for the population of patients with eGFR 60 to 90,” she said. “I think the overall benefit of A1c reduction was modest .. but patients with type 1 diabetes have limited options. It’s already happening in the community with other SGLT2s being used without guidance. My yes comes with the caution that should be used with strict risk mitigation.”

Elizabeth A. Chrischilles, Ph.D., professor and Department Head Department of Epidemiology College of Public Health at The University of Iowa, voted no, but said she wanted to vote yes. “I voted no because of the small populations and the uncertainty that left me with. I would have felt differently if we were talking about the eGFR 60 to 90 group of patients,” she said.