Belapectin shows signs of benefit in MASH Phase 2b clinical trial
Lower dose reduced new varices in patients with cirrhosis
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Belapectin, Galectin Therapeutics’ investigational therapy, significantly reduced the development of new enlarged blood vessels in the esophagus among people with metabolic dysfunction-associated steatohepatitis (MASH), a severe form of steatotic liver disease, who completed the 1.5-year treatment period of a global clinical trial.
The therapy also was associated with favorable changes in noninvasive markers related to liver scarring, or fibrosis, and portal hypertension relative to placebo. The trial involved people with MASH-related cirrhosis, or advanced liver scarring, and portal hypertension at the study’s start.
Varices can develop with portal hypertension
Portal hypertension, a marker of advanced liver fibrosis, refers to abnormally high pressure in the portal vein, a major blood vessel that carries blood from digestive organs to the liver. It can lead to esophageal varices, which are enlarged blood vessels in the tube that carries food from the mouth to the stomach. These vessels are prone to breaking, which can lead to fatal bleeding.
That’s according to final data from the Phase 2b NAVIGATE trial (NCT04365868) that were published in Hepatology in a study titled, “Efficacy and safety of belapectin for the prevention of esophageal varices in patients with MASH cirrhosis: The randomized, placebo-controlled NAVIGATE trial.” The work was funded by Galectin.
Previous top-line data had shown the study failed to meet its main goal of demonstrating that belapectin was superior to placebo at reducing new esophageal varices in the whole study population. That main analysis also accounted for certain liver-related or treatment-related events and for patients who discontinued treatment or did not have an end-of-treatment endoscopy.
“The consistency across clinical outcomes and noninvasive biomarkers, including signals of reduced risk of clinically significant portal hypertension and variceal development, reinforces our confidence in belapectin’s potential to modify disease progression,” Khurram Jamil, MD, Galectin’s chief medical officer, said in a company press release. “We believe these data meaningfully support continued advancement of our program, while positioning belapectin as a differentiated therapeutic candidate in MASH cirrhosis with portal hypertension—a market with significant unmet need and limited treatment options.”
Additional biomarker analyses from the NAVIGATE study will be presented later this month at the European Association for the Study of the Liver Congress in Barcelona, Spain.
Galectin plans FDA talks on next steps
Galectin is scheduled to meet with the U.S. Food and Drug Administration in coming months to discuss next clinical development plans for belapectin, according to a company press release announcing its latest financial results and business updates.
MASH is a severe form of steatotic liver disease in which the buildup of fat triggers inflammation and fibrosis in the liver. This can lead to complications including cirrhosis, portal hypertension, and esophageal varices.
Belapectin, administered directly into the bloodstream via infusion, is designed to inhibit galectin-3, a protein involved in MASH and liver fibrosis.
The global NAVIGATE study was designed to test belapectin in adults with MASH-related compensated cirrhosis, meaning the liver can still perform its main functions, and portal hypertension, but no esophageal varices at the study’s start.
A total of 357 participants were randomly assigned to receive one of two doses of belapectin, 2 or 4 mg/kg, or a placebo, for 18 months (about 1.5 years). The full analysis set included 355 participants, and 287 were included in the per-protocol population, meaning they completed 18 months of treatment and had endoscopy data at the start and end of the study.
The study’s main goal was to see if belapectin treatment would reduce the development of new esophageal varices in the whole study population. As previously reported, the trial missed this goal.
While rates of varices were lower in participants given the 2 mg/kg dose of belapectin than in those on the placebo in the full analysis set, the difference was not statistically significant, meaning it could be due to random chance.
Lower dose reduced varices in completers
The final published data showed, however, that in the subset of participants who completed 1.5 years of treatment and had endoscopy data at the start and end of the study, rates of new varices were significantly lower with 2 mg/kg belapectin than with placebo (11.3% vs. 22.3%). The higher belapectin dose showed no significant effect on rates of varices in any analysis.
“In the [per-protocol population], belapectin 2 mg/kg demonstrated a significant and meaningful reduction in the development of new esophageal varices in patients with MASH cirrhosis and portal hypertension,” the researchers wrote.
A key secondary goal of the study was to see if belapectin would reduce rates of a composite outcome that included varices, treatment discontinuation, and liver-related health problems. In the full analysis set, neither dose of belapectin showed a significant difference from the placebo for this measure.
In addition, average liver stiffness, used as a proxy of liver fibrosis, increased in participants given placebo, but decreased in those given belapectin, particularly the 2 mg/kg dose. The clinical significance of that average change was uncertain. Patients given the lower belapectin dose also were generally more likely than those on placebo to experience reductions in risk scores related to portal hypertension.
The therapy was generally safe and well tolerated. The most common treatment-related adverse events were diarrhea, fatigue, headache, and itching.
The findings “provide clinically meaningful evidence for the potential role of belapectin in addressing portal hypertension and reducing the risk of clinically significant complications in patients with MASH cirrhosis,” said Naga Chalasani, MD, NAVIGATE’s principal investigator at Indiana University. “The observed reduction in variceal development, together with consistent biomarker findings and a favorable safety profile, supports continued development of belapectin in patients with MASH cirrhosis and portal hypertension—a population with substantial unmet medical need.”
