Background and Aims: Belapectin reduced variceal development in a subgroup of patients with MASH cirrhosis. We report the efficacy and safety of belapectin in patients with MASH cirrhosis and portal hypertension without varices at baseline. Approach and Results: NAVIGATE was a global phase 2b trial. Patients were randomized to intravenous (i.v.) belapectin 2 or 4 mg/kg lean body weight or placebo for 18 months, stratified by type 2 diabetes. The primary endpoint was the incidence of varices with esophagogastroduodenoscopy (EGD) or a composite endpoint (new varices, intercurrent events, or discontinuation) at 18 months with belapectin versus placebo in the full analysis set (FAS). In a pre-specified analysis, new varices were evaluated in all patients who underwent EGD at baseline and 18 months. The per-protocol (PP) population was patients treated for 18 months with EGD at 18 months. Of 357 randomized patients, 291 completed treatment. Baseline characteristics were comparable across cohorts. In the FAS, 17.8% with placebo versus 10.1% with belapectin 2 mg/kg developed varices, a 43.2% reduction ( p =0.13). In the per-protocol population (PP), varices occurred in 22.3% with placebo versus 11.3% with belapectin 2 mg/kg, a 50% reduction (unadjusted p =0.04). Belapectin 4 mg/kg had no significant effect on variceal development. For the composite endpoint at 18 months, no significant difference was observed between belapectin 2 mg/kg ( p =0.14) or 4 mg/kg ( p =0.261) and placebo in the FAS. Belapectin was well-tolerated with no safety signals. Conclusion: Belapectin 2 mg/kg lowered the development of new varices in MASH cirrhosis and portal hypertension.