1. Effects of Belapectin, an Inhibitor of Galectin-3, in Patients With Nonalcoholic Steatohepatitis With Cirrhosis and Portal Hypertension
- Author
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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, Manal Abdelmalek, Luis Balart, Brian Borg, Michael Charlton, Hari Conjeevaram, Michael Fuchs, Reem Ghalib, Pierre Gholam, Dina Halegoua-De Marzio, Stephen Harrison, Christopher Jue, Nyingi Kemmer, Kris Kowdley, Michelle Lai, Eric Lawitz, Rohit Loomba, Angelo Paredes, Don Rockey, Miguel Rodriguez, Raymond Rubin, Michael Ryan, Andrew Scanga, Thomas Sepe, Brent Tetri, Paul Thuluvath, Dawn Torres, John Vierling, Julia Wattacheril, Amanda Weiland, and Donald Zogg
- Subjects
Liver Cirrhosis ,Male ,medicine.medical_specialty ,Cirrhosis ,Portal venous pressure ,Biopsy ,Galectin 3 ,Galectins ,Placebo ,Gastroenterology ,Severity of Illness Index ,Drug Administration Schedule ,Placebos ,Esophageal varices ,Double-Blind Method ,Non-alcoholic Fatty Liver Disease ,Internal medicine ,Nonalcoholic fatty liver disease ,Hypertension, Portal ,Medicine ,Humans ,Infusions, Intravenous ,Aged ,Intention-to-treat analysis ,Hepatology ,business.industry ,Blood Proteins ,Middle Aged ,medicine.disease ,Portal Pressure ,Treatment Outcome ,Liver ,Portal hypertension ,Pectins ,Female ,business ,Varices - 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
- Published
- 2019