Survodutide treatment for MASH with fibrosis scores high in mid-stage trial

The investigational dual agonist of glucagon receptor and glucagon-like peptide-1 (GLP-1) receptor survodutide helps reduce the histological activity of metabolic dysfunction-associated steatohepatitis (MASH) as well as improve fibrosis, according to the phase II 1404-0043 trial.

After 48 weeks of treatment, the proportion of patients who met the primary endpoint of histologic improvement, defined as a ≥2-point decrease in Nonalcoholic fatty liver disease Activity Score (NAS) with ≥1-point decrease in lobular inflammation or ballooning subscores without worsening of fibrosis, was significantly higher with survodutide than with placebo, reported first author Dr Arun Sanyal from the Virginia Commonwealth University School of Medicine in Richmond, Virginia, US.

Sanyal noted that the superior effect of survodutide on the primary endpoint was seen in both the actual treatment dataset (the actual dose received at the start of the maintenance phase [per protocol]; 38.7 percent with 2.4 mg, 63.8 percent with 4.8 mg, and 55.8 percent with 6.0 mg vs 15.2 percent with placebo; p=0.0010, p<0.0001, and p<0.0001, respectively) and the planned treatment dataset (the maintenance dose assigned at randomization; 46.6 percent with 2.4 mg, 62.5 percent with 4.8 mg, and 43.2 percent with 6.0 mg vs 13.5 percent with placebo; p<0.0010, p<0.0001, and p=0.0001, respectively). Results were similar when analysis was limited to patients with paired baseline and end-of-treatment biopsies. [EASL 2024, abstract GS-006]

Additionally, paired biopsy results for patients with F2/F3 fibrosis in the actual treatment dataset showed that liver fibrosis regression by ≥1 stage (with no worsening in MASH) occurred in a significantly higher proportion of those in the survodutide groups than in the placebo group (56.1 percent with 2.4 mg and 64.5 percent with 6.0 mg vs 25.9 percent with placebo; p=0.0041 and p=0.0007, respectively), as did MASH resolution (with no worsening in fibrosis; 63.4 percent with 2.4 mg, 61.4 percent with 4.8 mg, and 64.5 percent with 6.0 mg vs 13.0 percent with placebo; p<0.0001 for all).

As for safety, “the side effect profile [of survodutide] is quite similar to other GLP-1-based therapies,” Sanyal noted. “As expected, nausea (65.8 percent) was the most commonly reported adverse event (AEs),” followed by diarrhoea (48.9 percent) and vomiting (40.6 percent).

Furthermore, heart rate increased by up to 3.4 beats per minute in survodutide-treated patients, in line with observations for other GLP-1 agonists, he added.

The rate of investigator-defined drug-related AE was 81.7 percent with survodutide vs 48.6 percent with placebo. Serious AEs occurred in 7.8 percent of patients in the combined survodutide dose groups vs 6.8 percent of those in the placebo group. AEs led to treatment discontinuation in 20.1 percent and 2.7 percent of patients, respectively.

“Overall, survodutide was generally well tolerated and showed benefit in fibrosis management in participants suffering from MASH and advancing fibrosis,” Sanyal concluded, adding that the drug was the first to show the observed level of fibrosis benefit in a phase II MASH trial after 48 weeks of treatment.

The glucagon agonist component in the drug has the potential to increase energy expenditure and exerts a direct impact in the liver, which could contribute to the improvement in fibrosis, Sanyal explained. Meanwhile, the GLP-1 agonist component increases glucose-dependent insulin secretion and suppresses appetite while promoting fullness and satiety, he added.

The 1404-0043 trial

A total of 293 patients (mean age 50.8 years, 52.9 percent female, mean BMI 35.81 kg/m²) with biopsy-confirmed MASH and F1-F3 fibrosis participated in the trial. They were randomly assigned to receive once-weekly subcutaneous injections of survodutide at 2.4 mg (n=73), 4.8 mg (n=72), or 6.0 mg (n=74) or placebo (n=74). The 48-week treatment period consisted of a 24-week dose-escalation phase followed by a 24-week maintenance phase. The first 24 weeks of the study comprised a rapid dose-escalation phase, followed by a 24-week maintenance phase.

The total NAS at baseline was 5.2. Liver fibrosis stage was F2 in 41.0 percent of patients, F3 in 35.2 percent, and F1B in 16.0 percent. More than a third of the population (38.6) had type 2 diabetes.

Over 48 weeks of treatment, liver fat content decreased by 50.9–64.3 percent with survodutide vs 7.3 percent with placebo, NAS decreased by 2.8–3.3 vs 0.4, ALT decreased by 37.5–38.0 vs 6.2 U/L, aspartate aminotransferase decreased by 2.8.1–30.9 vs 2.9 U/L, body weight decreased by 10.03–13.82 vs 0.89 kg, respectively. Finally, HbA1c dropped by 0.67–0.78 percent with survodutide but increased by 0.11 percent with placebo.

Survodutide is advancing into a phase III MASH study and is being investigated in several phase III studies of people with overweight and obesity, including those with a confirmed or presumed diagnosis of MASH.