The FDA has declined to approve Lexicon Pharmaceuticals' Zynquista (sotagliflozin) as an adjunct to insulin therapy for glycemic control in adults with type 1 diabetes and chronic kidney disease (CKD). This decision follows a previous negative vote by the FDA's advisory committee, which raised concerns about the drug's benefit-risk profile, particularly regarding the increased risk of diabetic ketoacidosis (DKA).
Complete Response Letter Details
Lexicon Pharmaceuticals announced that it has received a complete response letter (CRL) from the FDA regarding its New Drug Application (NDA) for Zynquista. This outcome aligns with the company's prior decision to halt launch preparations for Zynquista and concentrate on its clinical development pipeline. Mike Exton, Ph.D., CEO of Lexicon, expressed gratitude to the patients and physicians involved in the Zynquista clinical trials and reaffirmed the company's commitment to advancing its clinical pipeline.
Concerns Over Diabetic Ketoacidosis
The primary concern cited by regulators and advisory committee members was the uncertainty surrounding the magnitude of benefits for patients with type 1 diabetes and mild-to-moderate CKD, as well as the potential risk of DKA. DKA is a severe complication where the body cannot use sugar for energy, leading the liver to break down fat for fuel, producing harmful acids called ketones.
Lexicon's Strategic Shift
Following the advisory committee hearing, Lexicon initiated a restructuring effort to conserve cash and prioritize its clinical development pipeline. The company has eliminated its commercial field sales team and ceased all promotional activities for Zynquista and Inpefa. Manufacturing of Inpefa will continue to ensure availability for existing prescribers and patients. These measures are projected to reduce 2025 operating costs by $100 million, supplementing the $40 million in savings announced in August as part of a resource realignment.
Ongoing Clinical Development
Lexicon is proceeding with the Phase 2b PROGRESS study, which is evaluating LX9211 for diabetic peripheral neuropathic pain (DPNP), with topline data expected in the first quarter of 2025. The primary endpoint is the reduction of Average Daily Pain Score (ADPS) at eight weeks. Secondary endpoints include changes from baseline in burning pain and pain interference with sleep. Additionally, enrollment is ongoing for the pivotal Phase 3 SONATA HCM study, which is assessing sotagliflozin in hypertrophic cardiomyopathy.
Sotagliflozin's Existing Approval
Notably, sotagliflozin is already FDA-approved under the brand name Inpefa for reducing the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure or type 2 diabetes, CKD, and other cardiovascular risk factors. Inpefa generated $2.7 million in sales during the first half of 2024 and $1.2 million for the full year 2023.
Analyst and Expert Opinions
Several healthcare professionals have expressed disappointment with the FDA's decision, citing the limited non-insulin therapies available for type 1 diabetes. Some experts believe that sotagliflozin could have filled a significant gap in treatment options, particularly given its potential cardiovascular and renal benefits. However, concerns about the increased risk of DKA and the feasibility of effective risk mitigation strategies in real-world settings remain paramount.
