1 University of Toronto, Toronto, ON, Canada.
2 Pinnacle Clinical Research, San Antonio, TX, United States.
3 Toronto Liver Centre, Toronto, ON, Canada.
4 Texas Digestive Disease Consultants, Dallas, TX, United States.
5 Quality Medical Research, Nashville, TN, Hong Kong.
6 Ruane Clinical Research, Los Angeles, CA, Hong Kong.
7 Inland Empire Liver Foundation, Rialto, CA, United States.
8 Department of Medicine and Therapeutics, The Chinese University of 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.
We evaluated the safety and efficacy of cilofexor (formerly GS-9674), a small molecule nonsteroidal agonist of farnesoid X receptor (FXR), in patients with nonalcoholic steatohepatitis (NASH). In this double-blind, placebo-controlled, phase 2 trial, 140 non-cirrhotic patients with 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 ELF 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%). CONCLUSION: 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 number, NCT02854605.