Belapectin misses endpoints in NASH trial

For patients with nonalcoholic steatohepatitis (NASH) with cirrhosis and portal hypertension, belapectin therapy was safe but did not significantly improve fibrosis or hepatic venous pressure gradient, compared with placebo, according to the results of a multicenter phase 2b study.

After 52 weeks of infusions, the change in hepatic venous pressure gradient did not significantly differ between the 2-mg/kg group (–0.28 mm Hg) and the placebo group (0.10 mm Hg) or between the 8-mg/kg group (–0.25 mm Hg) and the placebo group (P = .1 for both comparisons). Belapectin also did not significantly improve fibrosis, nonalcoholic fatty liver disease activity score, or the frequency of various complications of cirrhosis. “However, in a subgroup analysis of patients without esophageal varices, 2 mg/kg belapectin did reduce hepatic venous pressure gradient and development of varices,” wrote Naga Chalasani, MD, of Indiana University in Indianapolis and his associates. The findings were published in Gastroenterology.

NASH leads to portal hypertension, variceal bleeding, ascites with bacterial peritonitis, hepatic encephalopathy, and liver-related death and is a leading reason for liver transplantation among women and men. Galectin-3, which is primarily secreted by macrophages, is elevated in patients with NASH and has been linked to the pathophysiology of liver fibrosis in mice. Belapectin (GR-MD-02), a complex carbohydrate that targets and disrupts galectin-3, has been found to reduce liver fibrosis and portal hypertension in rats and was safe and well tolerated in phase 1 studies.

For this double-blind trial, the researchers randomly assigned 162 patients with NASH, cirrhosis, and portal hypertension (hepatic venous pressure gradient at least 6 mm Hg) to receive biweekly infusions of belapectin 2 mg/kg (54 patients), belapectin 8 mg/kg (54 patients), or placebo (54 patients). Patients were treated for 52 weeks. The primary endpoint was change from baseline in hepatic venous pressure gradient.

In a post-hoc analysis of the 81 patients who had no esophageal varices at baseline, 2 mg/kg belapectin was associated with an average 1.61-mm Hg reduction in hepatic venous pressure gradient from baseline (P = .02) and with a reduction in the development of new varices (P = .03).These effects did not extend to subgroups of patients with varices at baseline, clinically significant portal hypertension, or mild portal hypertension. Moreover, 2 mg/kg belapectin did not improve fibrosis, and the higher dose of belapectin (8 mg/kg) met neither the primary endpoint nor the secondary endpoints in the overall cohort or in subgroup analyses. In the subgroup with no varices at baseline, Galectin Technologies is proceeding to initiating a phase 3 clinical trial.

“Interestingly and somewhat unexpectedly, belapectin was associated with an improvement in hepatocyte ballooning,” which “is considered fundamental to the pathogenesis of disease progression in nonalcoholic steatohepatitis,” the researchers wrote. “The significance of such improvement in hepatocyte ballooning in the absence of improvement of other histological components, especially inflammation, is unknown.”

Galectin Therapeutics provided funding. Dr. Chalasani disclosed grant support from Galectin Therapeutics and relevant consulting relationships with NuSirt, AbbVie, Afimmune (DS Biopharma), and several other pharmaceutical companies. Sixteen coinvestigators also disclosed relationships with pharmaceutical companies, of whom eight disclosed consulting relationships, received research funding, or were employed by Galectin.

SOURCE: Chalasani N et al. Gastroenterology. 2019 Dec 5. doi: 10.1053/j.gastro.2019.11.296.

*This story was updated on 3/18/2020.

For patients with nonalcoholic steatohepatitis (NASH) with cirrhosis and portal hypertension, belapectin therapy was safe but did not significantly improve fibrosis or hepatic venous pressure gradient, compared with placebo, according to the results of a multicenter phase 2b study.

After 52 weeks of infusions, the change in hepatic venous pressure gradient did not significantly differ between the 2-mg/kg group (–0.28 mm Hg) and the placebo group (0.10 mm Hg) or between the 8-mg/kg group (–0.25 mm Hg) and the placebo group (P = .1 for both comparisons). Belapectin also did not significantly improve fibrosis, nonalcoholic fatty liver disease activity score, or the frequency of various complications of cirrhosis. “However, in a subgroup analysis of patients without esophageal varices, 2 mg/kg belapectin did reduce hepatic venous pressure gradient and development of varices,” wrote Naga Chalasani, MD, of Indiana University in Indianapolis and his associates. The findings were published in Gastroenterology.

NASH leads to portal hypertension, variceal bleeding, ascites with bacterial peritonitis, hepatic encephalopathy, and liver-related death and is a leading reason for liver transplantation among women and men. Galectin-3, which is primarily secreted by macrophages, is elevated in patients with NASH and has been linked to the pathophysiology of liver fibrosis in mice. Belapectin (GR-MD-02), a complex carbohydrate that targets and disrupts galectin-3, has been found to reduce liver fibrosis and portal hypertension in rats and was safe and well tolerated in phase 1 studies.

For this double-blind trial, the researchers randomly assigned 162 patients with NASH, cirrhosis, and portal hypertension (hepatic venous pressure gradient at least 6 mm Hg) to receive biweekly infusions of belapectin 2 mg/kg (54 patients), belapectin 8 mg/kg (54 patients), or placebo (54 patients). Patients were treated for 52 weeks. The primary endpoint was change from baseline in hepatic venous pressure gradient.

In a post-hoc analysis of the 81 patients who had no esophageal varices at baseline, 2 mg/kg belapectin was associated with an average 1.61-mm Hg reduction in hepatic venous pressure gradient from baseline (P = .02) and with a reduction in the development of new varices (P = .03).These effects did not extend to subgroups of patients with varices at baseline, clinically significant portal hypertension, or mild portal hypertension. Moreover, 2 mg/kg belapectin did not improve fibrosis, and the higher dose of belapectin (8 mg/kg) met neither the primary endpoint nor the secondary endpoints in the overall cohort or in subgroup analyses. In the subgroup with no varices at baseline, Galectin Technologies is proceeding to initiating a phase 3 clinical trial.

“Interestingly and somewhat unexpectedly, belapectin was associated with an improvement in hepatocyte ballooning,” which “is considered fundamental to the pathogenesis of disease progression in nonalcoholic steatohepatitis,” the researchers wrote. “The significance of such improvement in hepatocyte ballooning in the absence of improvement of other histological components, especially inflammation, is unknown.”

Galectin Therapeutics provided funding. Dr. Chalasani disclosed grant support from Galectin Therapeutics and relevant consulting relationships with NuSirt, AbbVie, Afimmune (DS Biopharma), and several other pharmaceutical companies. Sixteen coinvestigators also disclosed relationships with pharmaceutical companies, of whom eight disclosed consulting relationships, received research funding, or were employed by Galectin.

SOURCE: Chalasani N et al. Gastroenterology. 2019 Dec 5. doi: 10.1053/j.gastro.2019.11.296.

*This story was updated on 3/18/2020.

For patients with nonalcoholic steatohepatitis (NASH) with cirrhosis and portal hypertension, belapectin therapy was safe but did not significantly improve fibrosis or hepatic venous pressure gradient, compared with placebo, according to the results of a multicenter phase 2b study.

After 52 weeks of infusions, the change in hepatic venous pressure gradient did not significantly differ between the 2-mg/kg group (–0.28 mm Hg) and the placebo group (0.10 mm Hg) or between the 8-mg/kg group (–0.25 mm Hg) and the placebo group (P = .1 for both comparisons). Belapectin also did not significantly improve fibrosis, nonalcoholic fatty liver disease activity score, or the frequency of various complications of cirrhosis. “However, in a subgroup analysis of patients without esophageal varices, 2 mg/kg belapectin did reduce hepatic venous pressure gradient and development of varices,” wrote Naga Chalasani, MD, of Indiana University in Indianapolis and his associates. The findings were published in Gastroenterology.

NASH leads to portal hypertension, variceal bleeding, ascites with bacterial peritonitis, hepatic encephalopathy, and liver-related death and is a leading reason for liver transplantation among women and men. Galectin-3, which is primarily secreted by macrophages, is elevated in patients with NASH and has been linked to the pathophysiology of liver fibrosis in mice. Belapectin (GR-MD-02), a complex carbohydrate that targets and disrupts galectin-3, has been found to reduce liver fibrosis and portal hypertension in rats and was safe and well tolerated in phase 1 studies.

For this double-blind trial, the researchers randomly assigned 162 patients with NASH, cirrhosis, and portal hypertension (hepatic venous pressure gradient at least 6 mm Hg) to receive biweekly infusions of belapectin 2 mg/kg (54 patients), belapectin 8 mg/kg (54 patients), or placebo (54 patients). Patients were treated for 52 weeks. The primary endpoint was change from baseline in hepatic venous pressure gradient.

In a post-hoc analysis of the 81 patients who had no esophageal varices at baseline, 2 mg/kg belapectin was associated with an average 1.61-mm Hg reduction in hepatic venous pressure gradient from baseline (P = .02) and with a reduction in the development of new varices (P = .03).These effects did not extend to subgroups of patients with varices at baseline, clinically significant portal hypertension, or mild portal hypertension. Moreover, 2 mg/kg belapectin did not improve fibrosis, and the higher dose of belapectin (8 mg/kg) met neither the primary endpoint nor the secondary endpoints in the overall cohort or in subgroup analyses. In the subgroup with no varices at baseline, Galectin Technologies is proceeding to initiating a phase 3 clinical trial.

“Interestingly and somewhat unexpectedly, belapectin was associated with an improvement in hepatocyte ballooning,” which “is considered fundamental to the pathogenesis of disease progression in nonalcoholic steatohepatitis,” the researchers wrote. “The significance of such improvement in hepatocyte ballooning in the absence of improvement of other histological components, especially inflammation, is unknown.”

Galectin Therapeutics provided funding. Dr. Chalasani disclosed grant support from Galectin Therapeutics and relevant consulting relationships with NuSirt, AbbVie, Afimmune (DS Biopharma), and several other pharmaceutical companies. Sixteen coinvestigators also disclosed relationships with pharmaceutical companies, of whom eight disclosed consulting relationships, received research funding, or were employed by Galectin.

SOURCE: Chalasani N et al. Gastroenterology. 2019 Dec 5. doi: 10.1053/j.gastro.2019.11.296.

*This story was updated on 3/18/2020.