Cilofexor, a Nonsteroidal FXR Agonist, in Patients With Noncirrhotic NASH: A Phase 2 Randomized Controlled Trial

  • Hepatology. 2020 Jul;72(1):58-71. doi: 10.1002/hep.31205.
Keyur Patel  1 ,  Stephen A Harrison  2 ,  Magdy Elkhashab  3 ,  James F Trotter  4 ,  Robert Herring  5 ,  Sergio E Rojter  6 ,  Zeid Kayali  7 ,  Vincent Wai-Sun Wong  8 ,  Susan Greenbloom  9 ,  Saumya Jayakumar  10 ,  Mitchell L Shiffman  11 ,  Bradley Freilich  12 ,  Eric J Lawitz  13 ,  Edward J Gane  14 ,  Eliza Harting  15 ,  Jun Xu  15 ,  Andrew N Billin  15 ,  Chuhan Chung  15 ,  C Stephen Djedjos  15 ,  G Mani Subramanian  15 ,  Robert P Myers  15 ,  Michael S Middleton  10 ,  Mary Rinella  16 ,  Mazen Noureddin  17
Affiliations
  • 1. University of Toronto, Toronto, ON, Canada.
  • 2. Pinnacle Clinical Research, San Antonio, TX.
  • 3. Toronto Liver Center, Toronto, ON, Canada.
  • 4. Texas Digestive Disease Consultants, Dallas, TX.
  • 5. Quality Medical Research, Nashville, TN.
  • 6. Ruane Clinical Research, Los Angeles, CA.
  • 7. Inland Empire Liver Foundation, Rialto, CA.
  • 8. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
  • 9. Toronto Digestive Disease Associates, Woodbridge, ON, Canada.
  • 10. University of California San Diego, San Diego, CA.
  • 11. Bon Secours Mercy Health, Richmond, VA.
  • 12. Kansas City Research Institute, Kansas City, MO.
  • 13. Texas Liver Institute, University of Texas Health San Antonio, San Antonio, TX.
  • 14. Liver Unit, Auckland City Hospital, Auckland, New Zealand.
  • 15. Gilead Sciences, Inc., Foster City, CA.
  • 16. Feinberg School of Medicine, Northwestern University, Chicago, IL.
  • 17. Cedars-Sinai Medical Center, Los Angeles, CA.
PMID: 32115759 DOI: 10.1002/hep.31205
Abstract

Background and aims: We evaluated the safety and efficacy of cilofexor (formerly GS-9674), a small-molecule nonsteroidal agonist of farnesoid X receptor, in patients with nonalcoholic steatohepatitis (NASH).

Approach and results: In this double-blind, placebo-controlled, phase 2 trial, 140 patients with noncirrhotic NASH, diagnosed by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) ≥8% and liver stiffness ≥2.5 kPa by magnetic resonance elastography (MRE) or historical liver biopsy, were randomized to receive cilofexor 100 mg (n = 56), 30 mg (n = 56), or placebo (n = 28) orally once daily for 24 weeks. MRI-PDFF, liver stiffness by MRE and transient elastography, and serum markers of fibrosis were measured at baseline and week 24. At baseline, median MRI-PDFF was 16.3% and MRE-stiffness was 3.27 kPa. At week 24, patients receiving cilofexor 100 mg had a median relative decrease in MRI-PDFF of -22.7%, compared with an increase of 1.9% in those receiving placebo (P = 0.003); the 30-mg group had a relative decrease of -1.8% (P = 0.17 vs. placebo). Declines in MRI-PDFF of ≥30% were experienced by 39% of patients receiving cilofexor 100 mg (P = 0.011 vs. placebo), 14% of those receiving cilofexor 30 mg (P = 0.87 vs. placebo), and 13% of those receiving placebo. Serum gamma-glutamyltransferase, C4, and primary bile acids decreased significantly at week 24 in both cilofexor treatment groups, whereas significant changes in Enhanced Liver Fibrosis scores and liver stiffness were not observed. Cilofexor was generally well-tolerated. Moderate to severe pruritus was more common in patients receiving cilofexor 100 mg (14%) than in those receiving cilofexor 30 mg (4%) and placebo (4%).

Conclusions: Cilofexor for 24 weeks was well-tolerated and provided significant reductions in hepatic steatosis, liver biochemistry, and serum bile acids in patients with NASH. ClinicalTrials.gov No. NCT02854605.

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