Belapectin Misses Primary Endpoint in Phase 3 MASH Cirrhosis, Portal Hypertension Trial

Khurram Jamil, MD

Credit: Khurram Jamil on LinkedIn

The phase 2b/3 NAVIGATE trial of Galectin Therapeutics’ belapectin in patients with metabolic dysfunction-associated steatohepatitis (MASH) cirrhosis and portal hypertension missed its composite primary endpoint for the prevention of varices, according to a press release from the company.¹

Topline results showed that although belapectin in both 2 mg/kg and 4 mg/kg doses reduced the incidence of varices in the intent-to-treat population, the difference over placebo was not statistically significant. According to a December 20, 2024, release from Galectin, the Company is conducting a full analysis of the NAVIGATE trial data and anticipates having additional data from approximately 50 patients with 36 months of belapectin treatment in early 2025, at which point they will provide clinical updates and determine next steps for its development.¹

“While we had hoped that the NAVIGATE trial would meet its composite primary endpoint, we are highly encouraged by trends we have seen at only 18 months of treatment in the ITT population and by the statistically significant 48.9% reduction in new varices noted in the per-protocol population with belapectin 2 mg,” Khurram Jamil, MD, chief medical officer at Galectin Therapeutics, said in a press release.¹ “All enrolled subjects transitioned into a 36-month treatment period, with approximately 50 subjects completing the full 36 months to date. We are still analyzing the extensive data from the trial and anticipate providing multiple clinical updates from the subjects completing 36-month therapy, as well as additional biomarker data in Q1 2025.”

A global, multicenter, randomized, double-blind, placebo-controlled study conducted in over 130 sites across 15 countries, the NAVIGATE trial included 355 patients who were randomly assigned in a 1:1:1 ratio to receive intravenous belapectin 2mg/kg of lean body mass (LBM; n = 119), belapectin 4 mg/kg/LBM (n = 118), or placebo (n = 118) every other week for 18 months.¹

The primary endpoint was the prevention of varices, assessed as a composite clinical outcome including subjects with any varices, those with intercurrent events, or those without an endoscopy or intercurrent events at 18 months.¹

In the intent-to-treat population (n = 355), the incidence of varices was reduced by 43.2% in the belapectin 2 mg/kg dose group compared with placebo, but the composite endpoint did not reach statistical significance. In the per-protocol population (n = 290), which comprised subjects who completed 18 months of therapy with upper endoscopy performed at both baseline and 18 months, the incidence of varices was reduced by 48.9% compared to the targeted 52.5% reduction in the belapectin 2 mg/kg dose group (P <.05). Of note, these clinical outcomes were supported by noninvasive measures.¹

Results additionally showed the incidence of adverse events and serious adverse events were comparable across the 3 cohorts. Rates of discontinuation, adverse events, and serious adverse events were similar to placebo, with no drug-related severe adverse events reported in the trial.¹

“I am encouraged by the results demonstrating an approximately 49% reduction in the development of varices in patients with MASH cirrhosis with the previously studied belapectin dose of 2 mg in such a large, global trial,” Naim Alkhouri, MD, chief medical officer and director of the Steatotic Liver Program at Arizona Liver Health, said in a press release.¹ “I believe the results warrant further clinical development as belapectin could become a pivotal therapeutic option for these patients that currently do not have any treatment options.”

According to the release from Galectin, based on results from previous clinical and preliminary nonclinical studies as well as preliminary data from the NAVIGATE trial, the lack of increased efficacy at the 4 mg dose of belapectin is likely attributable to saturable binding dynamics and interactions with Galectin-3 proteins. Specifically, the 2 mg dose may provide optimal therapeutic effects, while doses ≥ 4 mg may not lead to greater binding and an increase in pharmacodynamic effects, leading to saturable drug disposition and the appearance of reduced efficacy.¹

Galectin is performing further analysis of the pharmacodynamic data from the NAVIGATE trial and is conducting a full analysis of the NAVIGATE data, with additional data from approximately 50 patients that have completed 36 months of treatment with belapectin anticipated in early 2025.¹

“I have been involved with the belapectin development program in MASH cirrhosis since the beginning and am very pleased to see that prevention of esophageal varices in patients with MASH cirrhosis in this large NAVIGATE clinical trial confirmed the results that were seen in the previous trial conducted by Galectin in the 2 mg/kg cohort,” Naga Chalasani, MD, David W. Crabb Professor of Gastroenterology and Hepatology and adjunct professor of anatomy, cell biology, and physiology at Indiana University School of Medicine, said.¹ “Belapectin clearly is offering a reproducible benefit and should be continued in clinical development as there is a significant unmet need for patients with MASH cirrhosis.”

References

1. ^{Galectin Therapeutics. Galectin Therapeutics Announces Top-Line Results of NAVIGATE Clinical Trial Evaluating Belapectin in Patients with Cirrhotic Portal Hypertension Caused by MASH. December 20, 2024. Accessed December 20, 2024. https://investor.galectintherapeutics.com/news-releases/news-release-details/galectin-therapeutics-announces-top-line-results-navigate}
2. ^{Galectin Therapeutics. Belapectin: Targeting Galectin-3. Accessed December 20, 2024. https://galectintherapeutics.com/about-belapectin/}