Effects of Belapectin, an Inhibitor of Galectin-3, in Patients with Nonalcoholic Steatohepatitis With Cirrhosis And Portal Hypertension

Abstract Background & Aims Increased levels of galectin 3 have been associated with nonalcoholic steatohepatitis (NASH) and contributes to toxin-induced liver fibrosis in mice. GR-MD-02 (belapectin) is an inhibitor of galectin 3 that reduces liver fibrosis and portal hypertension in rats and was safe and well tolerated in phase 1 studies. We performed a phase 2b, randomized trial of the safety and efficacy of GR-MD-02 in patients with NASH, cirrhosis, and portal hypertension. Methods Patients with NASH, cirrhosis, and portal hypertension (hepatic venous pressure gradient [HVPG] ≥6 mm Hg) from 36 centers were randomly assigned, in a double-blind manner, to groups that received biweekly infusions of belapectin 2 mg/kg (n=54), 8 mg/kg (n=54), or placebo (n=54) for 52 weeks. The primary endpoint was change in HVPG (-28) at the end of the 52 week period compared with baseline. Secondary endpoints included changes in liver histology and development of liver-related outcomes. Results We found no significant difference in ΔHVPG between the 2 mg/kg belapectin group and placebo group (-0.28 mmHG vs 0.10 mmHG, P=1.0) or between the 8 mg/kg belapectin and placebo group (-0.25 mmHG vs 0.10 mmHG, P=1.0). Belapectin had no significant effect on fibrosis or nonalcoholic fatty liver disease activity score, and liver-related outcomes did not differ significantly among groups. In an analysis of a subgroup of patients without esophageal varices at baseline (n=81), 2 mg/kg belapectin was associated with a reduction in HVPG at 52 weeks compared with baseline (P=.02) and reduced development of new varices (P=.03). Belapectin (2 mg/kg) was well tolerated and produced no safety signals. Conclusions In a phase 2b study of 162 patients with NASH, cirrhosis, and portal hypertension, 1 year of biweekly infusion of belapectin was safe but not associated with significant reduction in HVPG or fibrosis, compared with placebo. However, in a subgroup analysis of patients without esophageal varices, 2 mg/kg belapectin did reduce HVPG and development of varices.