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
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1334-1345.e5 |
| Journal | Gastroenterology |
| Volume | 158 |
| Issue number | 5 |
| DOIs | |
| State | Published - Apr 1 2020 |
Funding
We sincerely thank the study participants and their families and the study coordinators for their commitment to completing this study. This study would not have been completed without their participation. We thank Ms Julianne Nanzer for her assistance with this manuscript. Author contributions: study design: Peter G. Traber, Naga Chalasani, Guadalupe Garcia-Tsao, Zachary Goodman, Stephen A. Harrison, Harold Shlevin, Adam Allgood, Rex Horton, and William Irish; study conduct: all authors; preparation of the manuscript: Naga Chalasani, Adam Allgood, Raj Vuppalanchi, Stephen A. Harrison, Guadalupe Garcia-Tsao, and Harold Shlevin; critical review of the manuscript: all authors; guarantors of the article: Naga Chalasani and Harold Shlevin. The Belapectin (GR-MD-02) Study Investigators (arranged alphabetically): Manal Abdelmalek,1 Luis Balart (deceased),2 Brian Borg,3 Naga Chalasani,4 Michael Charlton,5 Hari Conjeevaram,6 Michael Fuchs,7 Reem Ghalib,8 Pierre Gholam,9 Dina Halegoua-De Marzio,10 Stephen Harrison,11 Christopher Jue,12 Nyingi Kemmer,13 Kris Kowdley,14 Michelle Lai,15 Eric Lawitz,16 Rohit Loomba,17 Mazen Noureddin,18 Angelo Paredes,19 Mary Rinella,20 Don Rockey,21 Miguel Rodriguez,22 Raymond Rubin,23 Michael Ryan,24 Arun Sanyal,25 Andrew Scanga,26 Thomas Sepe,27 Mitchell Shiffman,28 Mitchell Shiffman,29 Brent Tetri,30 Paul Thuluvath,31 Dawn Torres,32 John Vierling,33 Julia Wattacheril,34 Amanda Weiland,35 and Donald Zogg36, 1Duke University Medical Center, Durham, North Carolina; 2Tulane University Health Sciences Center, New Orleans, Louisiana; 3University of Mississippi Medical Center, Jackson, Mississippi; 4Indiana University School of Medicine, Indianapolis, Indiana; 5Intermountain Medical Center, Murray, Utah; 6University of Michigan, Ann Arbor, Michigan; 7McGuire Veterans Affairs Medical Center, Richmond, Virginia; 8Texas Clinical Research Institute, Arlington, Texas; 9UH Cleveland Medical Center, Cleveland, Ohio; 10Thomas Jefferson University, Philadelphia, Pennsylvania; 11Pinnacle Clinical Research PLLC, San Antonio, Texas; 12Digestive Health Specialists, Seneca, Pennsylvania; 13Tampa General Medical Group, Tampa, Florida; 14Swedish Medical Center, Englewood, Colorado; 15Beth Israel Deaconess Medical Center, Boston, Massachusetts; 16The Texas Liver Institute, San Antonio, Texas; 17University of California San Diego Medical Center, La Jolla, California; 18Cedars Sinai Medical Center, Los Angeles, California; 19Brooke Army Medical Center, San Antonio, Texas; 20 Northwestern University Feinberg School of Medicine, Chicago, Illinois; 21Medical University of South Carolina, Charleston, South Carolina; 22International Medical Investigations Center, Palmetto Bay, Florida; 23Piedmont Hospital, Atlanta, Georgia; 24Digestive and Liver Disease Specialists, Norfolk, Virginia; 25Virginia Commonwealth University, Richmond, Virginia; 26Vanderbilt University Medical Center, Nashville, Tennessee; 27University Gastroenterology, Providence, Rhode Island; 28Bon Secours Richmond Health System, Richmond, Virginia; 29Liver Institute of Virginia, Richmond and Newport News, Virginia; 30Saint Louis University, Saint Louis, Missouri; 31Mercy Medical Center, Baltimore, Maryland; 32Walter Reed National Military Medical Center, Bethesda, Maryland; 33Baylor College of Medicine, Houston, Texas; 34Columbia University Medical Center, New York, New York; 35University of Colorado, Denver, Colorado; and 36Minnesota Gastroenterology P.A. St Paul, Minnesota. Funding This study was funded by Galectin Therapeutics, Inc.
Keywords
- Carbohydrate-Binding Protein
- Inflammation
- NAFLD
- Steatosis
ASJC Scopus subject areas
- Gastroenterology
- Hepatology