Investigational Gal3 inhibitor NAVIGATEs MASH treatment field

The galectin-3 (Gal3) inhibitor belapectin, given at the established 2-mg dose, demonstrates its treatment potential for metabolic dysfunction-associated steatohepatitis (MASH) cirrhosis and portal hypertension (PH) in the phase IIb/III NAVIGATE trial.

“Compensated MASH cirrhosis with clinically significant PH remains a high-risk and underserved population with a significant unmet need. Currently, there are no FDA-approved therapies to reverse fibrosis in MASH cirrhosis,” said Dr Naim Alkhouri from Arizona Liver Health, Phoenix, Arizona, US, at EASL 2025.

Belapectin 2 mg has shown efficacy in improving portal pressure and reducing the incidence of oesophageal varices in individuals without baseline varices at week 52 in a phase IIb trial. [Gastroenterology 2020;158:1334-1345.e5]

The team sought to evaluate the treatment effect of belapectin in individuals with MASH cirrhosis* and PH** but no gastroesophageal varices at baseline. A total of 357 participants (mean age 60 years, ~65 percent women) were randomized 1:1:1 to belapectin 2 or 4 mg/kg/lean body mass Q2W or placebo for 78 weeks. [EASL 2025, abstract LBO-006]

Neither belapectin dose achieved statistical significance relative to placebo for the composite primary endpoint (ie, new varices and/or intercurrent events or dropout) in the intention-to-treat analysis (37.8 percent vs 47.5 percent; p=0.139 [2 mg] and 43.2 percent vs 47.5 percent; p=0.552 [4 mg]).

Looking at the individual components of the composite primary endpoint, fewer participants on belapectin 2 mg/kg had new varices vs those on placebo, but the between-group comparison also fell short of statistical significance (10.1 percent vs 17.8 percent; p=0.13).

Per-protocol analysis

In the per-protocol (PP) population comprising completers at 18 months plus those with endoscopic assessments, the incidence of new varices was halved with the lower belapectin dose vs placebo (11.3 percent vs 22.3 percent; p=0.04), and most were small*** varices (10.3 percent vs 13.8 percent). The 4 mg/kg dose showed no significant effect relative to placebo (13.5 percent vs 22.3 percent; p=0.13).

The improvements in liver stiffness measure (LSM) between baseline and month 18 were greater with belapectin vs placebo (LS kPa mean change, -12.3 percent [2 mg] and -12.1 percent [4 mg] vs -3.1 percent). There were significantly fewer belapectin 2 mg/kg vs placebo recipients who had worsening of LSM, ie, LSM increase of >30 percent (11.7 percent vs 23.9 percent; p=0.03) or >10 kPa (4.3 percent vs 12.5 percent; p=0.02) from baseline.

Fewer belapectin-treated patients progressed to high-risk ELF^# category at 18 months (2.1 percent [2 mg] and 3.2 percent [4 mg] vs 5.6 percent [placebo]). The ELF score predicts hepatic decompensation and mortality; a score of ≥13 denotes the highest risk of disease progression. [JHEP Rep 2024;6:101062]

Safety summary

Both belapectin doses were well tolerated. All cohorts (belapectin 2 mg, belapectin 4 mg, and placebo) had comparable incidences of treatment-emergent adverse events (TEAEs; 97.5, 96.7, and 94.9 percent, respectively), serious TEAEs (22.7, 20.8, and 19.5 percent), and study discontinuation (4.2, 6.7, and 5.9 percent).

There were no drug-related SAEs reported during the entire study, nor were there any adjudicated drug-induced liver events, noted Alkhouri.

Takeaways

“While the study did not meet the composite primary endpoint, belapectin 2 mg/kg significantly reduced the incidence of new oesophageal varices after 18 months of treatment in individuals with MASH cirrhosis and PH [in the PP analysis]. The categorical changes in LSM mirror the higher incidence of new varices with placebo vs belapectin 2 mg,” Alkhouri said, adding that these validate the previously reported favourable observations.

“[Taken together,] belapectin has the potential to address the critical unmet need of patients with MASH cirrhosis and PH,” Alkhouri concluded. Readout of the 3-year data is planned in the latter part of 2025.