Aldafermin 3 mg significantly reduced Enhanced Liver Fibrosis score in MASH

Key takeaways:

• Aldafermin 3 mg and 1 mg reduced Enhance Liver Fibrosis score by 0.5 and 0.1, respectively.
• Fibrosis improvement occurred among 23% and 21%, respectively, vs. 15% in placebo.

BOSTON — Treatment with aldafermin 3 mg appeared to be well-tolerated and significantly reduced Enhance Liver Fibrosis score after 48 weeks among patients with metabolic dysfunction-associated steatohepatitis, according to a presenter.

“There have been numerous failures in advanced development in the context of MASH cirrhosis,” Mary E. Rinella, MD, professor of medicine and director of metabolic and fatty liver disease at University of Chicago Medicine, said at The Liver Meeting. “Partly there have been low efficacy with respect to the compounds that have been tested ... cirrhosis represents a very big spectrum of collagen burden and categorical scoring really may not accurately reflect changes, even significant changes, in collagen.

Rinella continued: “Noninvasive markers such as ELF correlate with outcomes and they may reflect a reduction in the fibrogenic drivers at an earlier disease stage.”

Previous phase 2 trials have demonstrated that aldafermin, an engineered analog of the human hormone FGF19, improved liver histology among patients with MASH and no cirrhosis. In the phase 2b ALPINE-4 study, Rinella and colleagues evaluated 160 patients (mean age, 60 years; 75% type 2 diabetes) with biopsy-confirmed MASH with stage 4 fibrosis and compensated cirrhosis.

Participants were randomized to subcutaneous aldafermin 0.3 mg (n = 7), 1 mg (n = 42) or 3 mg (n = 55) or placebo (n = 56) and underwent liver biopsy at baseline and week 48. The primary endpoint was change in Enhanced Liver Fibrosis (ELF) score at week 48, while secondary measures included fibrosis improvement of at least one stage, C4, serum bile acids, Pro-C3, alanine transaminase and aspartate aminotransferase.

“The 3 mg dose achieved a very statistically significant reduction in ELF to a 0.5 reduction in ELF with a 0.1 reduction in ELF in the 1 mg group,” Rinella noted. “This is the first late stage randomized controlled trial in compensated MASH cirrhosis that met its primary endpoint.”

Further, 15% of patients in the placebo group achieved at least one-stage improvement in fibrosis compared with 21% in the 1 mg aldafermin group and 23% in the 3 mg group. Patients in the treatment arms also had dose-dependent reductions in C4 (least-squares mean difference vs. placebo = –67% and –74%, respectively), serum bile acids (–36% and –51%), Pro-C3 (–54% and –60%), ALT (–36% and –42%) and AST (–19% and –28%).

Six patients in the aldafermin groups discontinued due to treatment-related adverse events and 16 experienced serious adverse events, although none required treatment. The most common adverse events in any group were diarrhea and nausea.

“Aldafermin 3 mg significantly reduced ELF compared to placebo at 48 weeks of treatment,” Rinella concluded. “Secondary NIT endpoints, such as Pro-C3, ALT, AST, all improved in the same direction. Dose-dependent trend in histologic findings was also noted though did not meet statistical significance.”

Rinella continued: “Aldafermin treatment for up to 1 year seemed to be fairly well-tolerated and safe.”