Highlights
- Belapectin, a galectin-3 inhibitor, represents a novel therapeutic class for managing portal hypertension in metabolic dysfunction-associated steatohepatitis (MASH).
- The Phase 2b NAVIGATE trial demonstrated that 2 mg/kg of belapectin reduced the development of new esophageal varices by 50% in the per-protocol population (p=0.04).
- Consistent with previous findings, the efficacy of belapectin appears dose-dependent or specific to the 2 mg/kg range, as higher doses (4 mg/kg and 8 mg/kg) did not show significant benefits.
- Belapectin was well-tolerated over 18 months, with no significant safety signals compared to placebo.
Background
Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), has become a leading cause of cirrhosis worldwide. One of the most critical complications of cirrhosis is the development of portal hypertension, which can lead to the formation of esophageal varices. Variceal hemorrhage is a catastrophic event with high mortality, yet current management primarily focuses on secondary prophylaxis or treatment once varices have already formed. There is a profound unmet need for therapies that prevent the initial development of varices in patients with compensated cirrhosis.
Galectin-3, a β-galactoside-binding lectin, has emerged as a key mediator in this pathway. It is upregulated in MASH and plays a central role in hepatic stellate cell activation, fibrogenesis, and the inflammatory response. Belapectin (GR-MD-02) is a complex carbohydrate polymer that inhibits galectin-3, offering a potential mechanism to stabilize the extracellular matrix and reduce the vascular resistance that drives portal hypertension.
Key Content
The Mechanistic Role of Galectin-3 in Liver Pathology
Evidence from recent reviews emphasizes that galectin-3 (encoded by LGALS3) is a central orchestrator of liver inflammation and fibrosis. It facilitates the cross-linking of glycosylated molecules, influencing receptor clustering and downstream signaling. In the context of MASH, galectin-3 contributes to macrophage polarization, inflammasome activation, and the activation of hepatic stellate cells—the primary drivers of collagen deposition. Elevated circulating galectin-3 levels correlate with the severity of liver disease and the risk of hepatocellular carcinoma, making it both a valuable biomarker and a logical therapeutic target.
Evolution of Clinical Evidence: From Initial Phase 2b to NAVIGATE
The development of belapectin has followed a targeted progression. An initial 52-week Phase 2b study involving 162 patients with NASH cirrhosis and portal hypertension (HVPG ≥ 6 mm Hg) initially found no significant difference in the primary endpoint of HVPG change across the total cohort. However, a crucial subgroup analysis of patients without esophageal varices at baseline revealed that 2 mg/kg of belapectin significantly reduced HVPG (p=0.02) and the development of new varices (p=0.03) compared to placebo. Interestingly, the 8 mg/kg dose did not show this effect, suggesting a unique therapeutic window at lower doses.
The NAVIGATE Trial: Methodology and Primary Outcomes
The global NAVIGATE trial was specifically designed to validate these subgroup findings. It enrolled 357 patients with MASH cirrhosis and portal hypertension who did not have varices at baseline. Patients were randomized to receive biweekly intravenous infusions of belapectin at 2 mg/kg or 4 mg/kg, or a placebo, for 18 months.
In the Full Analysis Set (FAS), 17.8% of the placebo group developed varices compared to 10.1% in the 2 mg/kg belapectin group, representing a 43.2% reduction. While the p-value in the FAS was 0.13, the Per-Protocol (PP) population—which included patients who completed the full 18-month treatment and follow-up EGD—showed a more pronounced and statistically significant result. In the PP group, 11.3% of those treated with 2 mg/kg belapectin developed varices versus 22.3% in the placebo group, a 50% reduction (unadjusted p=0.04). Notably, the 4 mg/kg dose did not demonstrate a significant effect, reinforcing the dose-specific efficacy observed in earlier trials.
Methodological Advances: Machine Learning in Histology
Beyond traditional endoscopic and pressure measurements, researchers have begun applying machine learning (ML) to improve the assessment of these patients. Utilizing data from the belapectin trials, ML models (such as the SNOF score—Septa, Nodules, and Fibrosis) have been developed to analyze liver biopsies. These models have shown a high correlation with HVPG and the presence of varices (AUROC of 0.86 for predicting varices). This highlights a shift toward more precise, automated histological assessments that may enhance the sensitivity of future clinical trials in MASH cirrhosis.
Expert Commentary
The NAVIGATE trial provides compelling evidence for the “prevention” paradigm in MASH cirrhosis. While the primary endpoint in the FAS did not reach statistical significance, the clinical signal in the per-protocol analysis is robust and aligns with earlier data. The lack of efficacy at the 4 mg/kg dose remains a point of discussion; researchers hypothesize a potential U-shaped dose-response curve or specific saturable kinetics of galectin-3 inhibition in the liver.
From a safety perspective, belapectin continues to demonstrate an excellent profile. In a patient population often burdened by multiple comorbidities like type 2 diabetes and obesity, the absence of significant adverse events over 18 months of intravenous therapy is highly encouraging. Current clinical guidelines may not yet include galectin-3 inhibitors, but if these results are replicated in Phase 3 trials, belapectin could become a first-in-class therapy for the prevention of varices.
Conclusion
The NAVIGATE trial marks a significant step forward in the pharmacological management of portal hypertension in MASH cirrhosis. Belapectin 2 mg/kg appears to effectively slow the progression of portal hypertensive complications, specifically the development of esophageal varices. Future research should focus on confirming these results in larger Phase 3 cohorts and exploring the long-term impact on clinical outcomes such as variceal bleeding and liver-related mortality. Additionally, integrating AI-driven histological analysis may further refine our ability to identify patients most likely to benefit from galectin-3 inhibition.
References
- Chalasani N, et al. Efficacy and safety of belapectin for the prevention of esophageal varices in patients with MASH cirrhosis: The randomized, placebo-controlled NAVIGATE trial. Hepatology. 2026. PMID: 42065864.
- The Role of Galectin-3 in Liver Inflammation and Fibrosis. J Inflamm Res. 2026. PMID: 41859377.
- Chalasani N, et al. Effects of Belapectin, an Inhibitor of Galectin-3, in Patients With Nonalcoholic Steatohepatitis With Cirrhosis and Portal Hypertension. Gastroenterology. 2020. PMID: 31812510.
- Machine learning liver histology scores correlate with portal hypertension assessments in nonalcoholic steatohepatitis cirrhosis. Aliment Pharmacol Ther. 2023. PMID: 36647687.