Fenofibrate Mitigates Hypertriglyceridemia in Nonalcoholic
Steatohepatitis Patients Treated With
Q9
Cilofexor/Firsocostat
Q1
Q10
Eric J. Lawitz, * Bal Raj Bhandari,
‡
Peter J. Ruane,
§
Anita Kohli,
jj
Eliza Harting,
¶
Dora Ding,
¶
Jen-Chieh Chuang,
¶
Ryan S. Huss,
¶
Chuhan Chung,
¶
Robert P. Myers,
¶
and Rohit Loomba
#
*Texas Liver Institute and University of Texas Health, San Antonio, Texas;
‡
Delta Research Partners, LLC, Bastrop, Louisiana;
§
Ruane Clinical Research Group, Inc, Los Angeles, California;
||
Arizona Liver Health, Chandler, Arizona;
¶
Gilead Sciences, Inc,
Foster City, California; and
#
UC San Diego, La Jolla, California
BACKGROUND & AIMS: Patients with advanced fibrosis due to nonalcoholic steatohepatitis (NASH) are at high risk of
morbidity and mortality. We previously found that a combination of the farnesoid X receptor
agonist cilofexor (CILO) and the acetyl-CoA carboxylase inhibitor firsocostat (FIR) improved
liver histology and biomarkers in NASH with advanced fibrosis but was associated with
hypertriglyceridemia. We evaluated the safety and efficacy of icosapent ethyl (Vascepa) and
fenofibrate to mitigate triglyceride elevations in patients with NASH treated with CILO and FIR.
METHODS: Patients with NASH with elevated triglycerides (‡150 and <500 mg/dL) were randomized to
Vascepa 2 g twice daily (n [ 33) or fenofibrate 145 mg daily (n [ 33) for 2 weeks, followed by
the addition of CILO 30 mg and FIR 20 mg daily for 6 weeks. Safety, lipids, and liver
biochemistry were monitored.
RESULTS: All treatments were well-tolerated; most treatment-emergent adverse events were Grade 1 to 2
severity, and there were no discontinuations due to adverse events. At baseline, median
(interquartile range [IQR]) triglycerides were similar in the Vascepa and fenofibrate groups
(median, 177 [IQR, 154–205] vs 190 [IQR, 144–258] mg/dL, respectively). Median changes from
baseline in triglycerides for Vascepa vs fenofibrate after 2 weeks of pretreatment were L12
mg/dL (IQR, L33 to 7 mg/dL; P [ .09) vs L32 mg/dL (IQR, L76 to 6 mg/dL; P [ .010) and at 6
weeks were D41 mg/dL (IQR, 16–103 mg/dL; P < .001) vs L2 mg/dL (IQR, L42 to 54 mg/dL;
P [ .92). In patients with baseline triglycerides <250 mg/dL, fenofibrate was more effective vs
Vascepa in mitigating triglyceride increases after 6 weeks of combination treatment (D6
vs D39 mg/dL); similar trends were observed in patients with baseline triglycerides ‡250 mg/
d(L61 vs D99 mg/dL).
CONCLUSIONS: In patients with NASH with hypertriglyceridemia treated with CILO and FIR, fenofibrate was
safe and effectively mitigated increases in triglycerides associated with acetyl-CoA carboxylase
inhibition. ClinicalTrials.gov , Number: NCT02781584.
Keywords: Nonalcoholic Fatty Liver Disease; Peroxisome Proliferator-Activated Receptor-a; Very Low Density Lipoprotein.
N
onalcoholic steatohepatitis (NASH)
Q5
is a leading
cause of end-stage liver disease and liver trans-
plantation in the United States.
1,2
The pathogenesis of
NASH is multifactorial and includes contributions from
metabolic and other pro-inflammatory insults that
contribute to the development of fibrosis and disease
progression.
3,4
Targeting multiple relevant pathogenic
mechanisms through a combination treatment approach
may, therefore, provide optimal efficacy in NASH, partic-
ularly among patients with advanced fibrosis.
4–6
In the
recent phase II ATLAS study, treatment with a combina-
tion of the farnesoid X receptor (FXR) agonist cilofexor
Abbreviations used in this paper: ACC, acetyl-coenzyme A carboxylase;
AE, adverse event; ALP, alkaline phosphatase; ALT, alanine aminotrans-
ferase; ANGPTL4, angiopoietin-like 4; AST, aspartate aminotransferase;
CILO, cilofexor; FABP1, fatty acid binding protein 1; FAP, fibroblast acti-
vation protein; FGF21, fibroblast growth factor 21; FIR, firsocostat; FXR,
farnesoid X receptor; IQR, interquartile range; GGT, g-glutamyl trans-
ferase; LDL, low-density lipoprotein; NASH, nonalcoholic steatohepatitis;
PPAR, peroxisome proliferator-activated receptor; SREBP-1c, sterol
regulatory element-binding transcription factor 1c; VLDL, very low-density
lipoprotein.
© 2022 by the AGA Institute. Published by Elsevier Inc. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.
org/licenses/by-nc-nd/4.0/).
1542-3565
https://doi.org/10.1016/j.cgh.2021.12.044
Clinical Gastroenterology and Hepatology 2022;-:-–-
FLA 5.6.0 DTD YJCGH58258_proof 22 January 2022 4:55 am ce JO
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