Zabopegdutide shows 62.5% MASH resolution rate at 48 weeks

Zabopegdutide, an investigational long-acting GLP-1/glucagon agonist, reduced fibrosis and resolved metabolic dysfunction-associated steatohepatitis (MASH), according to results of a phase 2 trial.

At 48 weeks, biopsies showed that 62.5% of patients achieved MASH resolution with no worsening of fibrosis, compared with 5.3% for placebo, and 50% of patients had improvement in fibrosis compared with 15.8% of those given placebo. Additionally, 37.5% achieved both fibrosis improvement and MASH resolution, compared with 5.3% for placebo.

“For clinicians managing progressive MASH, the absolute priority is to stop or reverse fibrosis before it leads to irreversible cirrhosis or hepatic decompensation,” Mazen Noureddin, M.D., MHSc, professor of Medicine at Houston Methodist Hospital, said in a news release. He is also director of the Houston Research Institutes. “Coupled with a well-tolerated safety profile and low discontinuation rates, zabopegdutide is positioning itself as an incredibly robust and viable next-generation therapeutic option for individuals living with advanced metabolic liver disease.”

MASH is a serious liver disease that causes the liver to swell and can lead to cirrhosis, liver cancer and liver failure. It is linked to Type 2 diabetes and other metabolic conditions such as obesity and affects about 7% of the global population. MASH is primarily treated with medications, lifestyle, and the management of metabolic conditions. Medications given to patients include Wegovy (semaglutide), a GLP-1 medication that was approved for MASH in August 2025, and Rezdiffra (resmetirom), which was granted an accelerated approval in April 2025 specifically for MASH.

Developed by D&D Pharmatech, zabopegdutide is a once-weekly dual agonist targeting both GLP-1 and glucagon receptors. By targeting both receptors, zabopegdutide aims to reduce liver fat, resolve inflammation, and reverse fibrosis more effectively than GLP-1 therapies alone.

The phase 2 DD01-DN-02 trial enrolled 67 overweight or obese patients with MASLD/MASH who received a two-week titration of zabopegdutide 20 mg followed by a 40 mg once-weekly maintenance dose. The 48-week analysis included 35 patients who were adherent to the treatment regimen.

Results at 12 weeks were recently published in Lancet Gastroenterology & Hepatology. The primary endpoint was the proportion of participants having at least a 30% relative reduction in liver fat by MRI-proton density fat fraction at week 12. Safety analyses included all participants who received at least one dose of study drug.

The 12-week results showed that 75.8% of patients treated with zabopegdutide achieved at least a 30% reduction in liver fat, and 72.7% of patients achieved greater than 50% reduction in liver fat. Additionally, 48.5% of treated patients achieved normalization of liver fat. Patients also experienced a reduction in liver stiffness and fibrosis biomarkers.

Zabopegdutide also produced weight loss, 3.8% at 12 weeks and 6.4% at 24 weeks, and improved glycemic control and favorable effects on liver enzymes and lipid parameters. Among patients who achieved less than 5% of body weight loss by week 12, zabopegdutide still produced significant reductions in liver fat and liver stiffness.

Zabopegdutide was generally well tolerated. Treatment-emergent adverse events occurred in 28 of 33 patients who received zabopegdutide and 23 of 34 participants who received placebo. The most common adverse events were nausea, diarrhea, and vomiting. Four patients discontinued treatment, including three in the treatment group. Two serious adverse events occurred in the treatment group (abdominal pain and acute cholecystitis).