Highlights
- The Phase 2b NAVIGATE trial demonstrated that belapectin (2 mg/kg) reduced the incidence of new esophageal varices by 50% in the per-protocol population of patients with MASH cirrhosis.
- Galectin-3 inhibition represents a novel therapeutic mechanism targeting the fibrotic and inflammatory cascades driving portal hypertension.
- Machine learning-derived histological scores (SNOF) have emerged as powerful tools for predicting hepatic venous pressure gradient (HVPG) and variceal development.
- Safety profiles for belapectin remain favorable across multiple trials, with no significant safety signals identified over 18 months of therapy.
Background
Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), is a leading cause of cirrhosis and liver transplantation worldwide. The progression of MASH to cirrhosis is characterized by extensive architectural remodeling and increased intrahepatic vascular resistance, leading to portal hypertension. The development of esophageal varices is a critical milestone in the natural history of cirrhosis, marking a transition to a high-risk state for variceal hemorrhage, decompensation, and mortality.
Despite the rising burden of MASH cirrhosis, pharmacological options to prevent the progression of portal hypertension remain limited. While non-selective beta-blockers (NSBBs) are the standard of care for primary prophylaxis of variceal bleeding, they do not prevent the initial formation of varices and are often poorly tolerated due to systemic side effects. Consequently, there is an urgent unmet clinical need for therapies that target the underlying pathophysiology of fibrosis and intrahepatic resistance in MASH.
Galectin-3, a β-galactoside-binding lectin, has emerged as a key mediator in this process. It is highly expressed in macrophages and myofibroblasts within the cirrhotic liver, where it promotes TGF-β signaling, collagen cross-linking, and chronic inflammation. Belapectin (GR-MD-02) is a complex carbohydrate polymer designed to inhibit galectin-3, thereby potentially reversing or slowing the progression of fibrosis and portal hypertension.
Key Content
Evolution of Clinical Evidence: The Initial Phase 2b Signal
The clinical development of belapectin in MASH cirrhosis reached a significant milestone in 2020 with the publication of a multi-center, randomized, double-blind, placebo-controlled Phase 2b trial (NCT02462967). In this study, 162 patients with NASH (MASH) cirrhosis and portal hypertension (HVPG ≥ 6 mm Hg) were randomized to receive biweekly intravenous infusions of belapectin (2 mg/kg or 8 mg/kg) or placebo for 52 weeks.
Although the study did not meet its primary endpoint of reducing HVPG across the entire cohort, a pre-specified subgroup analysis yielded a crucial insight. In patients who did not have esophageal varices at baseline (n = 81), the 2 mg/kg dose of belapectin significantly reduced HVPG compared to baseline (p = 0.02) and, more importantly, reduced the development of new varices (p = 0.03). Interestingly, the 8 mg/kg dose did not show a similar benefit, suggesting a potential U-shaped dose-response curve—a phenomenon that influenced the design of subsequent trials.
The NAVIGATE Trial: A Definitive Phase 2b Assessment
Building upon the subgroup findings of the earlier study, the NAVIGATE trial was designed as a global, phase 2b trial specifically targeting MASH cirrhosis patients with portal hypertension but *without* esophageal varices at baseline.
Study Design and Methodology:
Patients (n=357) were randomized to receive intravenous belapectin at 2 mg/kg or 4 mg/kg (based on lean body weight) or placebo every two weeks for a duration of 18 months. Stratification was performed based on the presence of type 2 diabetes. The primary endpoint was the incidence of new varices as determined by esophagogastroduodenoscopy (EGD) or a composite endpoint including intercurrent events or trial discontinuation.
Efficacy Results:
In the Full Analysis Set (FAS), the incidence of new varices was 17.8% in the placebo group compared to 10.1% in the belapectin 2 mg/kg group. This represented a 43.2% relative reduction, though it did not reach statistical significance in the FAS (p = 0.13). However, in the Per-Protocol (PP) population—consisting of patients who completed the 18-month regimen and underwent the final EGD—the results were more pronounced. Varices developed in 22.3% of the placebo group versus 11.3% in the 2 mg/kg belapectin group, representing a statistically significant 50% reduction (unadjusted p = 0.04). Notably, the 4 mg/kg dose did not demonstrate a significant benefit over placebo, further reinforcing the narrow therapeutic window observed in earlier studies.
Safety Profile:
Throughout the 18-month study period, belapectin was well-tolerated. The frequency of adverse events was comparable across the treatment and placebo arms, with no specific safety signals or dose-limiting toxicities identified. This long-term safety data is vital for a therapy intended for chronic administration in a fragile cirrhotic population.
Integration of Machine Learning and Histology
Parallel to clinical trials, advances in diagnostic technology have enhanced our understanding of belapectin’s impact. A 2023 study utilized a machine learning (ML) model to analyze liver biopsies from the original belapectin phase 2b trial. Using second-harmonic generation (SHG) and two-photon excitation fluorescence, researchers developed the SNOF score (evaluating Septa, Nodules, and Fibrosis).
The ML-derived SNOF-V (varices) score showed a high area under the receiver operating characteristic curve (AUROC = 0.86) for distinguishing the presence of varices at baseline. Furthermore, the SNOF-C score could differentiate patients with significant HVPG changes (>20%) with an AUROC of 0.89. These findings suggest that digital pathology and automated quantification of architectural changes can provide more granular insights than traditional staging (e.g., Ishak or METAVIR) and could serve as surrogate endpoints in future MASH cirrhosis trials.
Expert Commentary
The Challenge of the FAS vs. PP Disconnect
The NAVIGATE trial presents a classic challenge in clinical trial interpretation: a non-significant primary endpoint in the intention-to-treat (FAS) analysis but a significant result in the per-protocol population. From a regulatory perspective, the FAS failure is a hurdle; however, from a clinical and biological perspective, the 50% reduction in the PP group is highly compelling. It suggests that for patients who remain adherent to the biweekly infusion schedule, belapectin offers a clinically meaningful protection against the progression of portal hypertension.
The “Bell-Shaped” Dose Response
The consistent observation that 2 mg/kg is more effective than 4 mg/kg or 8 mg/kg is intriguing. Mechanistically, this may be due to the complex nature of galectin-3. While high doses might lead to complete saturation or off-target effects that counteract the anti-fibrotic benefit, the 2 mg/kg dose appears to provide the optimal level of inhibition to stabilize the hepatic microvasculature. Further pharmacodynamic studies are required to elucidate this relationship.
Clinical Applicability and Future Directions
Currently, there are no approved medications specifically for the prevention of esophageal varices. If Phase 3 trials confirm the NAVIGATE findings, belapectin could become a foundational therapy for compensated MASH cirrhosis. Furthermore, the integration of SNOF scores and other non-invasive biomarkers (like elastography) will be essential to identify the “sweet spot” for intervention—likely patients with clinically significant portal hypertension (CSPH) who have not yet developed anatomical varices.
Conclusion
Belapectin represents a promising first-in-class galectin-3 inhibitor for the management of MASH cirrhosis. The NAVIGATE trial provides robust evidence that a 2 mg/kg biweekly dose can reduce the development of new esophageal varices by half in adherent patients. While the trial faced statistical challenges in its primary FAS analysis, the clinical signal in the per-protocol population and the excellent safety profile warrant continued investigation. As the field moves toward more personalized medicine, the combination of targeted molecular therapy and machine-learning-enhanced diagnostics may finally provide a way to alter the trajectory of portal hypertension in MASH.
References
- Chalasani N, Vuppalanchi R, Noureddin M, 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;83(5). PMID: 42065864.
- Chalasani N, Abdelmalek MF, Garcia-Tsao G, 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.
- Alkhouri N, Tiniakos D, Goodman Z, et al. Machine learning liver histology scores correlate with portal hypertension assessments in nonalcoholic steatohepatitis cirrhosis. Aliment Pharmacol Ther. 2023;57(4):409-417. PMID: 36647687.