TY - JOUR
T1 - Cilofexor, a Nonsteroidal FXR Agonist, in Patients With Noncirrhotic NASH
T2 - A Phase 2 Randomized Controlled Trial
AU - Patel, Keyur
AU - Harrison, Stephen A.
AU - Elkhashab, Magdy
AU - Trotter, James F.
AU - Herring, Robert
AU - Rojter, Sergio E.
AU - Kayali, Zeid
AU - Wong, Vincent Wai Sun
AU - Greenbloom, Susan
AU - Jayakumar, Saumya
AU - Shiffman, Mitchell L.
AU - Freilich, Bradley
AU - Lawitz, Eric J.
AU - Gane, Edward J.
AU - Harting, Eliza
AU - Xu, Jun
AU - Billin, Andrew N.
AU - Chung, Chuhan
AU - Djedjos, C. Stephen
AU - Subramanian, G. Mani
AU - Myers, Robert P.
AU - Middleton, Michael S.
AU - Rinella, Mary
AU - Noureddin, Mazen
N1 - Funding Information:
The study was approved by the institutional review board or independent ethics committee at participating sites and conducted in compliance with the Declaration of Helsinki, Good Clinical Practice guidelines, and local regulatory requirements. The study was designed and conducted by the sponsor (Gilead Sciences) in collaboration with the principal investigator (K.P.) according to the protocol. The sponsor collected the data, monitored the study conduct, and performed all statistical analyses. An independent data safety monitoring committee reviewed the progress of the study. All authors had access to the data, assumed responsibility for the integrity and completeness of the reported data, and reviewed and approved the manuscript. The study enrolled adults ages 18 to 75?years with suspected NASH based on a clinical diagnosis of NAFLD along with an estimated magnetic resonance imaging?proton density fat fraction (MRI-PDFF) value of ?8% and liver stiffness by magnetic resonance elastography (MRE) of ?2.5?kPa, or a historical biopsy within 12?months of screening consistent with NASH and F1-F3 fibrosis (ClinicalTrials.gov No. NCT02854605).
Publisher Copyright:
© 2020 by the American Association for the Study of Liver Diseases.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - 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.
AB - 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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U2 - 10.1002/hep.31205
DO - 10.1002/hep.31205
M3 - Article
C2 - 32115759
AN - SCOPUS:85087881628
SN - 0270-9139
VL - 72
SP - 58
EP - 71
JO - Hepatology
JF - Hepatology
IS - 1
ER -