Galectin Therapeutics has announced additional findings from its NAVIGATE trial, revealing a statistically significant reduction in new varices among U.S. patients with Metabolic Dysfunction-Associated SteatoHepatitis (MASH) cirrhosis and portal hypertension treated with belapectin. The analysis showed a 68.1% reduction (p=0.02) in the incidence of new varices with belapectin compared to placebo in the per-protocol population (completers) enrolled in the U.S. This finding offers a promising outlook for a patient population with limited treatment options.
NAVIGATE Trial Details
The NAVIGATE trial was a global, multicenter, randomized, double-blind, placebo-controlled study conducted across more than 130 sites in 15 countries. The trial involved 355 patients randomized in a 1:1:1 ratio to receive either belapectin 2mg/kg of lean body mass (LBM), belapectin 4 mg/kg/LBM, or placebo every other week for 18 months. While the top-line results of the NAVIGATE trial indicated a 43.2% lower incidence of varices at 18 months in patients treated with belapectin 2 mg versus placebo, the composite endpoint did not reach statistical significance in the intent-to-treat population (N=355). However, a revised analysis of 287 patients who completed the trial (per-protocol population) showed a 49.3% reduction in varices with belapectin 2 mg compared to placebo (nominal p-value = 0.04).
U.S. Patient Subgroup Analysis
Further analysis focused on the U.S. cohort, comprising two-thirds of the completer population (n=186). In this subgroup, the incidence of varices was significantly reduced by 68.1% (p=0.02) in patients treated with belapectin 2 mg (4 out of 60) compared to placebo (13 out of 62). Notably, all three cohorts of patients in the U.S. had a higher percentage use of GLP-1 agonists and statins compared to the rest of the world; however, the belapectin cohorts demonstrated superior outcomes compared to placebo within the U.S. subgroup.
Clinical Implications and Future Directions
According to recent estimates published in Hepatology, approximately 3 million adults in the U.S. suffer from MASH cirrhosis and clinically significant portal hypertension. Currently, there are no FDA-approved therapies specifically targeting this condition. Joel Lewis, Chief Executive Officer at Galectin Therapeutics, emphasized the urgency for new treatments, stating, "The significant reduction of 68% we see in incidence of new varices in completer patients in the U.S. from the NAVIGATE trial underscores belapectin’s potential as a treatment for MASH cirrhosis and portal hypertension." The company is continuing to analyze the data from the trial, including data from approximately 50 patients who completed 36 months of therapy, with additional clinical updates expected in the first quarter of 2025.
Mechanism of Action and Dosing Considerations
Previous studies suggest that the lack of increased efficacy at the 4 mg dose of belapectin may be due to saturable binding dynamics and interactions with Galectin-3 proteins. The 2 mg dose may provide optimal therapeutic effects, while higher doses may not lead to greater binding and an increase in pharmacodynamic effects, resulting in saturable drug disposition and reduced efficacy.
