Stephen A Harrison1, Guy Neff2, Cynthia D Guy3, Mustafa R Bashir4, Angelo H Paredes5, Juan P Frias6, Ziad Younes7, James F Trotter8, Nadege T Gunn9, Sam E Moussa10, Anita Kohli11, Kristin Nelson12, Mildred Gottwald12, William C G Chang12, Andrew Z Yan12, Alex M DePaoli12, Lei Ling13, Hsiao D Lieu12. 1. Radcliffe Department of Medicine, University of Oxford, United Kingdom; Pinnacle Clinical Research, San Antonio, Texas. Electronic address: stephenharrison87@gmail.com. 2. Covenant Research, Sarasota, Florida. 3. Pathology, Duke University, Durham, North Carolina. 4. Radiology and Medicine (Gastroenterology), Duke University, Durham, North Carolina. 5. San Antonio Military Medical Center, San Antonio, Texas. 6. National Research Institute, Los Angeles, California. 7. Gastro One Research, Germantown, Tennessee. 8. Clinical Research and Education, Texas Digestive Disease Consultants, Dallas, Texas. 9. Pinnacle Clinical Research, Austin, Texas. 10. Adobe Clinical Research, Tucson, Arizona. 11. Arizona Liver Health, Chandler, Arizona. 12. NGM Biopharmaceuticals, South San Francisco, California. 13. NGM Biopharmaceuticals, South San Francisco, California. Electronic address: lling@ngmbio.com.
Abstract
BACKGROUND & AIMS:Aldafermin, an engineered analog of fibroblast growth factor 19, inhibits bile acid synthesis and regulates metabolic homeostasis. We report results from a 24-week, phase 2 study, with serial liver biopsies, of patients with nonalcoholic steatohepatitis (NASH). METHODS: We performed a double-blind study of 78 patients with NASH at 9 centers in the United States. Key inclusion criteria were biopsy-proven NASH with Nonalcoholic Fatty Liver Disease Activity Score ≥4, stage 2 or 3 fibrosis by NASH Clinical Research Network classification, and absolute liver fat content ≥8%, measured by magnetic resonance imaging-proton density fat fraction. Patients were randomly assigned (1:2) to groups given subcutaneous placebo (n = 25) or aldafermin 1 mg (n = 53) daily for 24 weeks. The primary outcome was change in absolute liver fat content from baseline at week 24. Secondary outcomes included serum markers and histologic measures of fibrosis improvement and NASH resolution. RESULTS: At week 24, the aldafermin group had a significant reduction in absolute liver fat content (reduction of 7.7%) compared with placebo (reduction of 2.7%; difference, reduction of 5.0%; 95% confidence interval, reduction of 8.0%-1.9%; P = .002). Aldafermin produced significantly greater decreases in levels of 7α-hydroxy-4-cholesten-3-one, bile acids, alanine and aspartate aminotransferases, and neoepitope-specific N-terminal pro-peptide of type III collagen (Pro-C3) than placebo. Fibrosis improvement (≥1 stage) with no worsening of NASH was achieved in 38% of patients receiving aldafermin vs 18% of patients receiving placebo (P = .10). NASH resolution with no worsening of fibrosis was observed in 24% of patients given aldafermin vs 9% of patients given placebo (P = .20). Discontinuations due to adverse events occurred in no patients in the aldafermin group and 4% of patients in the placebo group. CONCLUSIONS: In a phase 2 trial of patients with NASH, aldafermin reduced liver fat and produced a trend toward fibrosis improvement. ClinicalTrials.gov, Number: NCT02443116.
RCT Entities:
BACKGROUND & AIMS:Aldafermin, an engineered analog of fibroblast growth factor 19, inhibits bile acid synthesis and regulates metabolic homeostasis. We report results from a 24-week, phase 2 study, with serial liver biopsies, of patients with nonalcoholic steatohepatitis (NASH). METHODS: We performed a double-blind study of 78 patients with NASH at 9 centers in the United States. Key inclusion criteria were biopsy-proven NASH with Nonalcoholic Fatty Liver Disease Activity Score ≥4, stage 2 or 3 fibrosis by NASH Clinical Research Network classification, and absolute liver fat content ≥8%, measured by magnetic resonance imaging-proton density fat fraction. Patients were randomly assigned (1:2) to groups given subcutaneous placebo (n = 25) or aldafermin 1 mg (n = 53) daily for 24 weeks. The primary outcome was change in absolute liver fat content from baseline at week 24. Secondary outcomes included serum markers and histologic measures of fibrosis improvement and NASH resolution. RESULTS: At week 24, the aldafermin group had a significant reduction in absolute liver fat content (reduction of 7.7%) compared with placebo (reduction of 2.7%; difference, reduction of 5.0%; 95% confidence interval, reduction of 8.0%-1.9%; P = .002). Aldafermin produced significantly greater decreases in levels of 7α-hydroxy-4-cholesten-3-one, bile acids, alanine and aspartate aminotransferases, and neoepitope-specific N-terminal pro-peptide of type III collagen (Pro-C3) than placebo. Fibrosis improvement (≥1 stage) with no worsening of NASH was achieved in 38% of patients receiving aldafermin vs 18% of patients receiving placebo (P = .10). NASH resolution with no worsening of fibrosis was observed in 24% of patients given aldafermin vs 9% of patients given placebo (P = .20). Discontinuations due to adverse events occurred in no patients in the aldafermin group and 4% of patients in the placebo group. CONCLUSIONS: In a phase 2 trial of patients with NASH, aldafermin reduced liver fat and produced a trend toward fibrosis improvement. ClinicalTrials.gov, Number: NCT02443116.
Authors: Giada Sebastiani; Keyur Patel; Vlad Ratziu; Jordan J Feld; Brent A Neuschwander-Tetri; Massimo Pinzani; Salvatore Petta; Annalisa Berzigotti; Peter Metrakos; Naglaa Shoukry; Elizabeth M Brunt; An Tang; Jeremy F Cobbold; Jean-Marie Ekoe; Karen Seto; Peter Ghali; Stéphanie Chevalier; Quentin M Anstee; Heather Watson; Harpreet Bajaj; James Stone; Mark G Swain; Alnoor Ramji Journal: Can Liver J Date: 2022-02-04