Novel GLP-1/GCG receptor agonist shows promise against noncirrhotic MASH with fibrosis

Dual glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptor agonism with cotadutide has shown a signal of benefit in the treatment of noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis, according to the phase II PROXYMO trial.

A total of 74 patients with biopsy-proven noncirrhotic MASH with fibrosis were randomly assigned to receive treatment with placebo (n=24) or cotadutide at 300 μg (n=25) or 600 μg (n=25) for 19 weeks.

The primary objective was to evaluate the safety and tolerability of the study drug through the 4-week follow-up period. Secondary objectives included assessment of effect of treatment on hepatic fat fraction (HFF; assessed using MRI-derived proton density fat fraction), markers of hepatic injury, and metabolic parameters. Analyses were conducted in intent-to-treat and modified intent-to-treat populations.

Compared with placebo, cotadutide 600 μg yielded significant improvements in markers of liver health at 19 weeks. The least squares mean difference was –5.0 percent for absolute HFF, –23.5 U/L for alanine aminotransferase, and –16.8 U/L for aspartate aminotransferase.

The frequency of any-grade treatment-emergent adverse events (TEAEs) was 91.7 percent with cotadutide 600 μg, 76.9 percent with cotadutide 300 μg, and 37.5 percent with placebo. Most TEAEs were gastrointestinal, mild to moderate in severity, and largely consistent with other incretins at this stage of development.

TEAEs led to treatment discontinuation in 16.7 percent of patients on cotadutide 600 μg, 7.7 percent of those on cotadutide 300 μg, and 4.2 percent of those on placebo.

Overall, the findings support further evaluation of this novel drug in MASH.