FDA Issues Complete Response for Zynquista in Type 1 Diabetes

The FDA has issued a complete response letter (CRL) for Lexicon Pharmaceuticals’ new drug application (NDA) for Zynquista (sotagliflozin) as an adjunct to insulin therapy for glycemic control in adults with type 1 diabetes and chronic kidney disease (CKD).

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.

In November 2024, a regulatory advisory board said the benefit of Zynquista does not outweigh the risks in adults with type 1 diabetes and chronic kidney disease. FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 11 to 3 against Zynquista for these indications.

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

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. Using data from the 24-week trial, the company said the effects of sotagliflozin 400 mg daily added to insulin therapy on A1C, body weight, systolic blood pressure, eGFR, total insulin dose, adjudicated severe hypoglycemia and DKA were evaluated in a subgroup of 228 patients with type 1 diabetes and CKD.

Compared with placebo, treatment with sotagliflozin led to similar reductions in A1C, body weight and systolic blood pressure in the CKD and total cohorts. Sotagliflozin was associated with similar risks of severe hypoglycemia between the two cohorts.

But regulators and advisory committee members were concerned about the 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.

After the advisory committee hearing, Lexicon began a restructuring effort to preserve cash and focus its resources on advancing its promising clinical development pipeline. The company has eliminated its commercial field teamand stopped all promotional efforts for Zynquista, as well as Inpefa. Inpefa will continue to be manufactured and made available to patients and existing prescribers.

The company has also eliminated about 60% of its employees. These efforts are expected reduce 2025 operating costs by $100 million, the company said in a news release. This amount is in addition to the $40 million in expected 2025 cost savings announced in August as part of a realignment of resources.

Lexicon is continuing the phase 2b PROGRESS study, which is evaluating LX9211 in diabetic peripheral neuropathic pain (DPNP), with topline data anticipated in the first quarter of 2025. The primary endpoint is the reduction of Average Daily Pain Score (ADPS) at eight weeks. Secondary endpoints include change from baseline in burning pain and pain interference with sleep. DPNP is a type of nerve damage caused by chronically high blood sugar and is a major disabling and devastating consequence of long-term diabetes. It can result in pain, numbness, and other symptoms in the hands, feet, legs, and arms. There are approximately 20 million patients in the United Staters who are suffering with some type of neuropathic pain.

Additionally, enrollment of the pivotal phase 3 SONATA HCM study evaluating sotagliflozin in hypertrophic cardiomyopathy is ongoing. Early research of other drug candidates also continues.