Highlights
- Belapectin at a dose of 2 mg/kg demonstrated a clinically significant reduction in the development of new esophageal varices in patients with MASH cirrhosis and portal hypertension.
- The NAVIGATE trial (Phase 2b) showed a 50% reduction in varices within the per-protocol population, suggesting a preventative benefit in patients without pre-existing varices.
- Galectin-3 inhibition represents a novel therapeutic mechanism for portal hypertension, targeting the fibrotic and inflammatory drivers of vascular resistance rather than hemodynamics alone.
- The safety profile of belapectin remains favorable over 18 months of treatment, 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 and the primary indication for liver transplantation in many Western countries. The natural history of MASH cirrhosis is frequently complicated by the development of portal hypertension (PH), defined by an increase in the hepatic venous pressure gradient (HVPG). Clinically significant portal hypertension (CSPH) often leads to the formation of esophageal varices, which carry a high risk of life-threatening hemorrhage.
Current management of portal hypertension primarily focuses on hemodynamic modulation via non-selective beta-blockers (NSBBs) or mechanical intervention. However, there is a profound unmet need for therapies that address the underlying pathophysiology of fibrosis and vascular remodeling. Galectin-3, a β-galactoside-binding lectin, has emerged as a key mediator in these processes. It is overexpressed in fibrotic livers and contributes to myofibroblast activation, macrophage-mediated inflammation, and the progression of cirrhosis. Belapectin (formerly GR-MD-02) is a complex carbohydrate polymer designed to inhibit galectin-3, offering a potential disease-modifying approach to managing MASH-related portal hypertension.
Key Content
Chronological Development of Evidence
The clinical development of belapectin for MASH cirrhosis has followed a nuanced trajectory, characterized by the refinement of patient selection based on disease stage and the presence of portal hypertension complications.
The First Phase 2b Evidence (2020)
In a landmark Phase 2b trial published in Gastroenterology in 2020 (NCT02462967), 162 patients with NASH (MASH) cirrhosis and portal hypertension (HVPG ≥ 6 mm Hg) were randomized to receive biweekly infusions of belapectin (2 mg/kg or 8 mg/kg) or placebo for 52 weeks. The primary endpoint was the change in HVPG from baseline. While the study did not meet its primary endpoint in the overall population, a critical pre-specified subgroup analysis revealed a significant benefit. In patients without esophageal varices at baseline (n=81), the 2 mg/kg dose was associated with a statistically significant reduction in HVPG and a decreased incidence of new variceal development (p=0.03). Conversely, the 8 mg/kg dose and the overall cohort (including those with existing varices) did not show similar benefits, suggesting that the therapeutic window for galectin-3 inhibition may be optimal before the onset of advanced collateral circulation.
The NAVIGATE Trial: Targeted Prevention (2026)
Building on the 2020 subgroup findings, the NAVIGATE trial was designed as a global Phase 2b trial specifically targeting patients with MASH cirrhosis and portal hypertension who had no esophageal varices at baseline. This 18-month, randomized, placebo-controlled trial enrolled 357 patients across multiple international centers.
Study Design and Population: Patients were randomized to receive intravenous belapectin at 2 mg/kg or 4 mg/kg (based on lean body weight) or a placebo every two weeks. Stratification was performed based on the presence of Type 2 diabetes. The primary endpoint utilized a composite approach in the Full Analysis Set (FAS), including the incidence of new varices detected by esophagogastroduodenoscopy (EGD), intercurrent events, or treatment discontinuation.
Efficacy Outcomes: In the FAS, 17.8% of patients in the placebo group developed new varices compared to 10.1% in the 2 mg/kg belapectin group. This represented a 43.2% relative reduction, though the p-value (p=0.13) did not reach conventional statistical significance in the composite primary endpoint. However, in the per-protocol (PP) population—consisting of patients who completed 18 months of treatment and underwent the final EGD—the results were more pronounced. In this group, 22.3% of placebo patients developed varices compared to only 11.3% in the 2 mg/kg group, a 50% relative reduction (unadjusted p=0.04).
Dose-Response Paradox: Interestingly, the 4 mg/kg dose of belapectin did not demonstrate a significant benefit over placebo. This reinforced observations from the earlier Phase 2b study, suggesting a non-linear or “U-shaped” dose-response curve, where lower doses may be more effective at modulating the galectin-3 pathway in the specific context of portal hypertension.
Safety and Tolerability
Across both major Phase 2b trials, belapectin was remarkably well-tolerated. In the 18-month NAVIGATE trial, there were no significant safety signals or differences in the incidence of adverse events between the treatment and placebo arms. The intravenous administration every two weeks was feasible, and the low rate of treatment-related discontinuation highlights the drug’s suitability for long-term chronic management in a cirrhotic population.
Expert Commentary
The NAVIGATE trial represents a pivotal shift in the management of MASH cirrhosis, moving toward the prevention of portal hypertension complications via anti-fibrotic mechanisms. Several factors warrant critical discussion:
1. Mechanism and Timing of Intervention
The consistent finding that belapectin works best in patients without varices at baseline suggests that galectin-3 inhibition is effective at a specific biological “tipping point.” Once varices are established, the structural remodeling of the intrahepatic and extrahepatic vasculature may be too advanced for galectin-3 modulation alone to reverse portal pressures. This underscores the importance of early intervention in compensated MASH cirrhosis.
2. The Dose-Response Challenge
The superior efficacy of 2 mg/kg over 8 mg/kg (in the first trial) and 4 mg/kg (in NAVIGATE) is a pharmacological anomaly often seen with complex carbohydrate polymers. It is hypothesized that higher doses may lead to “receptor saturation” or potentially engage counter-regulatory pathways that negate the anti-fibrotic benefits. Clinicians must be aware that for this class of drug, more is not necessarily better.
3. Statistical vs. Clinical Significance
While the primary composite endpoint in the FAS of NAVIGATE did not achieve statistical significance (p=0.13), the 50% reduction in the per-protocol population is highly clinically relevant. In the context of a Phase 2b trial designed for signal finding, these results provide a strong rationale for a Phase 3 confirmatory trial focusing specifically on the 2 mg/kg dose in the pre-variceal population.
4. Comparative Landscape
Unlike NSBBs (e.g., carvedilol), which reduce portal pressure through heart rate and splanchnic vasoconstriction, belapectin addresses the intrahepatic resistance caused by fibrosis and sinusoidal remodeling. Future guidelines may eventually consider combination therapies that target both hemodynamics and liver structure.
Conclusion
The NAVIGATE trial provides compelling evidence that 2 mg/kg of belapectin can reduce the incidence of new esophageal varices in patients with MASH cirrhosis and portal hypertension. While the primary FAS endpoint fell short of statistical significance, the per-protocol analysis and the cumulative data from preceding studies suggest a robust therapeutic signal for the prevention of varices. Belapectin’s excellent safety profile over 18 months supports its potential as a long-term therapy. Future research must focus on Phase 3 validation and further elucidating the mechanisms behind its dose-specific efficacy. For now, belapectin stands as a promising first-in-class galectin-3 inhibitor that may redefine the preventative care for patients at risk of MASH-related decompensation.
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; doi: 10.1097/HEP.0000000000001774. PMID: 42065864.
- Chalasani N, et al. Effects of Belapectin, an Inhibitor of Galectin-3, in Patients With Nonalcoholic Steatohepatitis With Cirrhosis and Portal Hypertension. Gastroenterology. 2020;158(5):1334-1345.e5. PMID: 31812510.
- Harrison SA, et al. A Phase 2a, Proof-of-Concept Study of GR-MD-02 in Patients with Nonalcoholic Steatohepatitis with Advanced Fibrosis. Aliment Pharmacol Ther. 2017.
