TY - JOUR
T1 - Effects of Belapectin, an Inhibitor of Galectin-3, in Patients With Nonalcoholic Steatohepatitis With Cirrhosis and Portal Hypertension
AU - The Belapectin (GR-MD-02) Study Investigators
AU - Chalasani, Naga
AU - Abdelmalek, Manal F.
AU - Garcia-Tsao, Guadalupe
AU - Vuppalanchi, Raj
AU - Alkhouri, Naim
AU - Rinella, Mary
AU - Noureddin, Mazen
AU - Pyko, Maxmillan
AU - Shiffman, Mitchell
AU - Sanyal, Arun
AU - Allgood, Adam
AU - Shlevin, Harold
AU - Horton, Rex
AU - Zomer, Eliezer
AU - Irish, William
AU - Goodman, Zachary
AU - Harrison, Stephen A.
AU - Traber, Peter G.
AU - Balart, Luis
AU - Borg, Brian
AU - Charlton, Michael
AU - Conjeevaram, Hari
AU - Fuchs, Michael
AU - Ghalib, Reem
AU - Gholam, Pierre
AU - Halegoua-De Marzio, Dina
AU - Harrison, Stephen
AU - Jue, Christopher
AU - Kemmer, Nyingi
AU - Kowdley, Kris
AU - Lai, Michelle
AU - Lawitz, Eric
AU - Loomba, Rohit
AU - Paredes, Angelo
AU - Rockey, Don
AU - Rodriguez, Miguel
AU - Rubin, Raymond
AU - Ryan, Michael
AU - Scanga, Andrew
AU - Sepe, Thomas
AU - Tetri, Brent
AU - Thuluvath, Paul
AU - Torres, Dawn
AU - Vierling, John
AU - Wattacheril, Julia
AU - Weiland, Amanda
AU - Zogg, Donald
N1 - Publisher Copyright:
© 2020 AGA Institute
PY - 2020/4/1
Y1 - 2020/4/1
N2 - 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
AB - 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
KW - Carbohydrate-Binding Protein
KW - Inflammation
KW - NAFLD
KW - Steatosis
UR - http://www.scopus.com/inward/record.url?scp=85082061798&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2019.11.296
DO - 10.1053/j.gastro.2019.11.296
M3 - Article
C2 - 31812510
AN - SCOPUS:85082061798
SN - 0016-5085
VL - 158
SP - 1334-1345.e5
JO - Gastroenterology
JF - Gastroenterology
IS - 5
ER -