Efficacy and Safety of Aldafermin, an Engineered FGF19 Analog, in a Randomized, Double-Blind, Placebo-Controlled Trial of Patients With Nonalcoholic Steatohepatitis

  • Gastroenterology. 2021 Jan;160(1):219-231.e1. doi: 10.1053/j.gastro.2020.08.004.
Stephen A Harrison  1 ,  Guy Neff  2 ,  Cynthia D Guy  3 ,  Mustafa R Bashir  4 ,  Angelo H Paredes  5 ,  Juan P Frias  6 ,  Ziad Younes  7 ,  James F Trotter  8 ,  Nadege T Gunn  9 ,  Sam E Moussa  10 ,  Anita Kohli  11 ,  Kristin Nelson  12 ,  Mildred Gottwald  12 ,  William C G Chang  12 ,  Andrew Z Yan  12 ,  Alex M DePaoli  12 ,  Lei Ling  13 ,  Hsiao D Lieu  12
Affiliations
  • 1. Radcliffe Department of Medicine, University of Oxford, United Kingdom; Pinnacle Clinical Research, San Antonio, Texas. Electronic address: [email protected].
  • 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: [email protected].
PMID: 32781086 DOI: 10.1053/j.gastro.2020.08.004
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.

Keywords
Lipid; Metabolism; NAFLD; Nonalcoholic Fatty Liver Disease.
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