FDA Rejects Sotagliflozin for Type 1 Diabetes; Lexicon Shifts Focus

Lexicon Pharmaceuticals received a complete response letter (CRL) from the FDA today, rejecting the company’s application for sotagliflozin (Zynquista) as an adjunct to insulin therapy for glycemic control in adults with type 1 diabetes and chronic kidney disease (CKD), according to a news release.¹

The FDA rejected sotagliflozin as an adjunct to insulin therapy for glycemic control. | Image credit: Postmodern Studio – stock.adobe.com

This decision comes just weeks after an FDA advisory committee voted 11-3 against the drug, citing that its risks outweighed its benefits in this patient population.² While the decision was anticipated, it underscores the regulatory challenges faced by dual sodium-glucose linked transporter 1/2 (SGLT1/2) inhibitors like sotagliflozin, despite the drug's promise in clinical trials.

"We are sincerely grateful to the patients and physicians who participated in our Zynquista clinical trials, and the broader diabetes community who strongly advocated for Zynquista’s approval," said Mike Exton, PhD, CEO and director of Lexicon.¹ “Although this was not our desired outcome for sotagliflozin in this indication, we remain steadfast in our commitment to advancing our clinical pipeline."

The FDA’s rejection aligns with Lexicon’s decision last month to halt launch preparations for sotagliflozin and shift focus towards resources on other pipeline candidates.³ Chief among these is LX9211, a novel AAK1 inhibitor for diabetic neuropathic pain (DPNP), a condition with significant unmet medical needs. Lexicon anticipates releasing top-line data from the PROGRESS phase 2b study in the first quarter of 2025. The global market for DPNP, valued at $3.6 billion, represents a promising opportunity, though it presents different competitive challenges than the diabetes market.

The FDA advisory committee vote held on October 31, 2024, highlighted ongoing concerns about the safety of sotagliflozin, particularly its potential to increase the risk of diabetic ketoacidosis, a life-threatening complication more prevalent in individuals with type 1 diabetes.² Despite this, some panel members acknowledged that the drug could offer benefits to specific subpopulations, such as those with both type 1 diabetes and CKD, who face higher risks of disease progression.

This CRL marks another chapter in sotagliflozin tumultuous regulatory journey. Initially developed in partnership with Sanofi, the drug was rejected for type 1 diabetes by the FDA in 2019 following an 8-8 advisory committee vote, and a subsequent appeal was also denied. In 2022, Lexicon achieved success when the FDA approved sotagliflozin under the brand name Inpefa for heart failure, but type 1 diabetes has proven to be a more elusive indication.

References

1. Lexicon announces receipt of complete response letter for Zynquista (sotagliflozin). News release. Lexicon Pharmaceuticals. December 20, 2024. Accessed December 20, 2024. https://www.lexpharma.com/media-center/news/2024-12-20-lexicon-announces-receipt-of-complete-response-letter-for-zynquista-sotagliflozin
2. Dunleavy K. In FDA adcomm, Lexicon gets another thumbs down for type 1 diabetes hopeful Zynquista. Fierce Pharma. November 1, 2024. Accessed December 20, 2024. https://www.fiercepharma.com/pharma/fda-adcomm-lexicon-gets-another-thumbs-down-sotagliflozin
3. Lexicon to reposition as clinical development-focused company following regulatory update from FDA. News release. Lexicon Pharmaceuticals. November 22, 2024. Accessed December 20, 2024. https://www.lexpharma.com/media-center/news/2024-11-22-lexicon-to-reposition-as-clinical-development-focused-company-following-regulatory-update-from-fda