Pegozafermin improves stage 4 fibrosis, noninvasive markers in MASH patients

Key takeaways:

• Fibrosis improved by at least one stage in 82% patients with MASH and well-compensated cirrhosis who were treated with pegozafermin.
• Noninvasive markers such as ALT, AST, VCTE, Pro-C3 and FAST also improved.

BOSTON — Pegozafermin improved fibrosis and other key noninvasive tests at 24 weeks in patients with metabolic dysfunction-associated steatohepatitis-related cirrhosis, according to data presented at The Liver Meeting.

“Pegozafermin is a glycopegylated form of synthetic FGF21,” Rohit Loomba, MD, MHSc, professor of medicine and chief of the division of gastroenterology and hepatology at the University of California at San Diego, said during his presentation. “It has a nanomolar potency against FGF receptors 1c, 2c and 3 c and is similar to native FGF21. It has comparable [pyruvate kinase] profiles between patients with noncirrhotic and well-compensated cirrhotic NASH patients.”

In the 24-week, phase 2b ENLIVEN trial, Loomba and colleagues aimed to assess the treatment effect of three doses of pegozafermin (15 mg, 30 mg and 44 mg) compared with placebo on liver histology endpoints in 192 patients with MASH with stage f2 to f3 fibrosis. At week 24, patients underwent a repeat liver biopsy. Loomba noted that the study will continue to week 48 in a blinded extension phase.

Biopsies were first examined by one of two central pathologists, followed by the introduction of a novel three-panel consensus scoring method to increase objectivity in the readings. The panel reread the baseline biopsies enrolled prior to the addition of the scoring method.

“There was a systematic predetermined central analysis of histology for all patients,” Loomba said. “At the end of the trial, we found there were 14 patients who were classified as having stage 4 fibrosis.”

At week 24, follow-up biopsies were available for 12 of those patients (placebo, n = 1; pooled pegozafermin, n = 11). In 82% of those with well-compensated cirrhosis at baseline, pegozafermin led to a one stage or greater improvement in fibrosis, and in 45% of patients it led to an improvement of at least one stage without worsening of MASH. The placebo group did not improve, results showed.

Additionally, pegozafermin improved alanine transaminase (–53%) and aspartate aminotransferase (–31%) and increased adiponectin (38%). Improvements were also noted in other noninvasive fibrosis markers, including vibration controlled transient elastography, Pro-C3, FibroScan-AST and FIB-4.

Pegozafermin was well-tolerated, Loomba noted, with no drug-related adverse events leading to discontinuation. “That is important in the setting of cirrhosis,” he added.

“Improvement in key noninvasive tests for NASH, along with high correlation between [noninvasive test] responders and fibrosis improvement, support the observed improvement in histology,” Loomba said. “These promising results are hypothesis-generating and need to be validated in the future in a large, dedicated study of patients with well-compensated cirrhosis. We are planning a pegozafermin phase 3 program, which is underway for steatohepatitis.”