FDA Issues CRL for Sotagliflozin in Type 1 Diabetes and CKD

Credit: US Food and Drug Administration

The US Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) to Lexicon Pharmaceuticals for sotagliflozin (Zynquista) and their supplemental New Drug Application for treatment of type 1 diabetes with chronic kidney disease (CKD).

Announced on December 20, 2024, the CRL for the SGLT1/2, which received approval for heart failure and is marketed under the brand name Inpefa, comes less than 2 months after the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 11 to 3 that the benefits of the agent do not outweigh the risks among adult patients with type 1 diabetes and CKD.

“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, chief executive officer and director of Lexicon.

This marks the second time Lexicon has pursued an indication in type 1 diabetes for sotagliflozin. In 2019, Lexicon and then-partner Sanofi submitted a New Drug Application (NDA) for an indication among patient populations with type 1 diabetes, but received a Complete Response Letter. Of note, sotagliflozin received approval for this indication in the European Union but was never marketed following approval.

Less than a month prior to receipt of the latest CRL from the FDA, Lexicon announced it would be repositioning as a clinical-development focused company following the receipt of a “deficiencies preclude discussion” letter from the agency. According to the company, this letter claimed deficiencies with the application that preclude discussion of labeling and/or post-marketing requirements and commitments.

Although sotagliflozin has failed to receive approval for a type 1 diabetes indication in the US, it made history in 2023 as the first SGLT1/2 inhibitor to receive approval from the FDA. This approval was based on data from the phase 3 SOLOIST-WHF and SCORED trials.

Stopped early as a result of funding during the COVID-19 pandemic, both the SOLOIST-WHF and SCORED trials were phase 3, double-blind, randomized, placebo-controlled trials. SOLOIST-WHF enrolled and randomized a population of 1222 patients with type 2 diabetes who were recently hospitalized for worsening heart failure. SCORED enrolled and randomized enrolled a population of 10,584with type 2 diabetes, chronic kidney disease, and risks for cardiovascular disease.

The primary endpoint of interest in SOLOIST-WHF was a composite of total cardiovascular deaths and worsening heart failure events. results of the study indicated the rate of primary endpoint events was significantly reduced among those receiving sotagliflozin relative to their counterparts receiving placebo therapy during a median follow-up of 9.0 months (51.0 vs 76.3 events per 100 patient-years; Hazard ratio [HR], 0.67 [95% confidence interval [CI], 0.52-0.85]; P < .001).

As a result of being stopped early due to a loss of funding, the primary endpoint of the SCORED trial was changed from the first occurrence of major adverse cardiovascular events to a composite endpoint of cardiovascular death or worsening heart failure events. Results of the trial indicated the rate of primary endpoint events was significantly reduced among those receiving sotagliflozin relative to their counterparts receive placebo therapy (5.6 vs 7.5 events per 100 patient-years; HR, 0.74 [95% CI, 0.63 to 0.88]; P = .0004).

“Although this was not our desired outcome for sotagliflozin in this indication, we remain steadfast in our commitment to advancing our clinical pipeline, including our near-term focus on LX9211 for diabetic neuropathic pain (DPNP) with top line data from our PROGRESS Phase 2b study anticipated in Q1 2025, and pursuing innovations that we believe can profoundly benefit patients,” Exton added.

References:

Lexicon Pharmaceuticals, Inc. Lexicon announces receipt of Complete Response Letter for zynquistaTM (sotagliflozin). GlobeNewswire News Room. 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.

Campbell P. FDA committee casts negative vote on Sotagliflozin in type 1 diabetes. HCP Live. November 2, 2024. Accessed December 20, 2024. https://www.hcplive.com/view/fda-committee-casts-negative-vote-on-sotagliflozin-in-type-1-diabetes.