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 contribute 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 (Δ HVPG) 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 mm HG vs 0.10 mm HG, P = 1.0) or between the 8 mg/kg belapectin and placebo group (-0.25 mm HG vs 0.10 mm HG, 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. ClinicalTrials.gov number: NCT02462967.

• Authors: Naga Chalasani, Manal F Abdelmalek, Guadalupe Garcia-Tsao, Raj Vuppalanchi, Naim Alkhouri, Mary Rinella, Mazen Noureddin, Maxmillan Pyko, Mitchell Shiffman, Arun Sanyal, Adam Allgood, Harold Shlevin, Rex Horton, Eliezer Zomer, William Irish, Zachary Goodman, Stephen A Harrison, Peter G Traber, Belapectin (GR-MD-02) Study Investigators
• Journal: Gastroenterology (Gastroenterology) Vol. 158 Issue 5 Pg. 1334-1345.e5 (04 2020) ISSN: 1528-0012 [Electronic] United States
• PMID: 31812510 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Blood Proteins
• Galectin 3
• Galectins
• LGALS3 protein, human
• Placebos
• Pectins
• belapectin

Topics

• Aged
• Biopsy
• Blood Proteins
• Double-Blind Method
• Drug Administration Schedule
• Female
• Galectin 3 (antagonists & inhibitors, metabolism)
• Galectins
• Humans
• Hypertension, Portal (diagnosis, drug therapy, etiology, pathology)
• Infusions, Intravenous
• Liver (drug effects, pathology)
• Liver Cirrhosis (diagnosis, drug therapy, pathology)
• Male
• Middle Aged
• Non-alcoholic Fatty Liver Disease (complications, diagnosis, drug therapy, pathology)
• Pectins (administration & dosage, adverse effects)
• Placebos (administration & dosage, adverse effects)
• Portal Pressure (drug effects)
• Severity of Illness Index
• Treatment Outcome