Author information

¹University of Chicago Pritzker School of Medicine, Chicago, Illinois, USA.

²NGM Biopharmaceuticals, South San Francisco, California, USA.

³Washington State University, Spokane, Washington, USA.

⁴Liver Institute Northwest, Seattle, Washington, USA.

⁵Inova Health System, Falls Church, Virginia, USA.

⁶Arizona Liver Health, Tucson, Arizona, USA.

⁷Texas Liver Institute, University of Texas Health San Antonio, San Antonio, Texas, USA.

⁸Sorbonne Université, ICAN Institute for Cardiometabolism and Nutrition, Assistance Publique Hôpitaux de Paris, INSERM UMRS 1138 CRC.

⁹Mayo Clinic, Rochester, Minnesota, USA.

¹⁰The Chinese University of Hong Kong, Hong Kong, China.

¹¹Gastro One, Germantown, Tennessee, USA.

¹²GI Specialists of Georgia, Atlanta, Georgia, USA.

¹³Gastrointestinal Associates, Flowood, Mississippi, USA.

¹⁴Kansas City Research Institute, Kansas City, Missouri, USA.

¹⁵DHR Health Transplant Institute, McAllen, Texas, USA.

¹⁶Austin Health, Heidleberg, Australia.

¹⁷Virginia Commonwealth University, Richmond, Virginia, USA.

¹⁸Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

¹⁹Pinnacle Clinical Research, San Antonio, Texas, USA.

Abstract

Background and aims: Aldafermin, an engineered analog of the human hormone FGF19, improves liver histology in patients with noncirrhotic NASH; however, its efficacy and safety in compensated cirrhosis is unknown. No drug has yet to demonstrate benefit in the compensated NASH population.

Approach and results: In this multicenter, double-blind, placebo-controlled, phase 2b trial, 160 patients with compensated NASH cirrhosis were randomized to aldafermin 0.3 mg (n = 7), 1 mg (n = 42), 3 mg (n = 55), or placebo (n = 56) for 48 weeks. The 0.3 mg group was discontinued to limit exposure to suboptimal doses. The primary end point was a change in Enhanced Liver Fibrosis from baseline to week 48. The analyses were performed in the intention-to-treat population. At week 48, the least-squares mean difference in the change in Enhanced Liver Fibrosis was -0.5 (95% CI, -0.7 to -0.2; p = 0.0003) between the 3 mg group and the placebo group. 15%, 21%, and 23% of patients in the placebo, 1 mg, and 3 mg group, respectively, achieved fibrosis improvement ≥ 1 stage; and 13%, 16%, and 20% achieved fibrosis improvement ≥ 1 stage without NASH worsening. Improvement in alanine aminotransferase, aspartate aminotransferase, neoepitope-specific N-terminal pro-peptide of type III collagen, and liver stiffness favored aldefermin groups over placebo. Diarrhea was the most frequent adverse event, occurring at 26% and 40% in the 1 mg and 3 mg groups, respectively, compared to 18% in the placebo group. Overall, 0%, 2%, and 9% of patients in the placebo, 1 mg, and 3 mg group, respectively, discontinued due to treatment-related adverse events.

Conclusions: Aldafermin 3 mg resulted in a significant reduction in Enhanced Liver Fibrosis in patients with compensated NASH cirrhosis.