Lexicon Pharmaceuticals unveiled the design of its pivotal SONATA-HCM Phase 3 clinical trial at the Heart Failure 2025 Congress in Belgrade, Serbia on May 17. The study is evaluating sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, in patients with both obstructive and non-obstructive hypertrophic cardiomyopathy (HCM).
The trial is actively enrolling patients across 20 countries, with all study sites expected to be operational by September 2025. Lexicon anticipates that positive results could support a supplemental new drug application (sNDA) for sotagliflozin in both forms of HCM.
First Phase 3 Trial Targeting Both HCM Subtypes
SONATA-HCM (SOtaglifloziN in Patients with SymptomATic obstructive And non-obstructive Hypertrophic CardioMyopathy) represents the only ongoing Phase 3 study addressing both obstructive and non-obstructive forms of the disease. The randomized, double-blind, placebo-controlled multicenter trial will evaluate sotagliflozin's efficacy on symptoms, function, and other patient-reported outcomes.
The study will enroll 500 patients worldwide, evenly divided between obstructive and non-obstructive HCM. The primary efficacy endpoint is improvement in symptoms as measured by change from baseline to week 26 in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ CSS).
"There is a huge unmet need for people suffering from HCM, with no approved or effective therapies for non-obstructive HCM," said Dr. Sharlene M. Day, co-principal investigator for SONATA-HCM and Presidential Professor at the University of Pennsylvania Perelman School of Medicine. "I'm very excited to be testing the potential for sotagliflozin to improve symptoms in a broad number of patients across the spectrum of HCM, as has previously been demonstrated in patients with heart failure with reduced and preserved ejection fraction."
Addressing a Significant Treatment Gap
Hypertrophic cardiomyopathy is a chronic, progressive disease that can worsen over time and lead to serious complications including heart failure and stroke. While some treatment options exist for obstructive HCM, patients with the non-obstructive form have no FDA-approved therapies.
Sotagliflozin has already demonstrated efficacy in heart failure treatment, with an established safety profile and significant clinical use. Recent evidence published in The Lancet in February 2025 suggests that the drug's dual inhibition of SGLT1 and SGLT2 reduces the risk of major adverse cardiovascular events (MACE), including heart attack and stroke.
"SONATA-HCM is an important study with the potential to support a broad label to enhance the care of patients with both obstructive and non-obstructive HCM," said Dr. Craig Granowitz, Lexicon's senior vice president and chief medical officer.
Mechanism of Action
Sotagliflozin works by inhibiting two proteins responsible for glucose regulation: sodium-glucose cotransporter types 2 and 1 (SGLT2 and SGLT1). SGLT2 manages glucose and sodium reabsorption in the kidneys, while SGLT1 handles glucose and sodium absorption in the gastrointestinal tract.
The drug was discovered through Lexicon's proprietary Genome5000™ program, the company's genomics target discovery platform. Sotagliflozin has been studied in approximately 20,000 patients across multiple conditions including heart failure, diabetes, and chronic kidney disease.
If successful, the SONATA-HCM trial could establish sotagliflozin as a groundbreaking therapy for HCM patients, particularly those with the non-obstructive form who currently lack effective treatment options.
