TY - JOUR
T1 - Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis
T2 - A randomised, open-label phase II trial
AU - Alkhouri, Naim
AU - Herring, Robert
AU - Kabler, Heidi
AU - Kayali, Zeid
AU - Hassanein, Tarek
AU - Kohli, Anita
AU - Huss, Ryan S.
AU - Zhu, Yanni
AU - Billin, Andrew N.
AU - Damgaard, Lars Holm
AU - Buchholtz, Kristine
AU - Kjær, Mette Skalshøi
AU - Balendran, Clare
AU - Myers, Robert P.
AU - Loomba, Rohit
AU - Noureddin, Mazen
N1 - Funding Information:
This trial was funded by Gilead Sciences Inc., CA, USA, and Novo Nordisk A/S, Denmark.
Funding Information:
We thank the patients, investigators, trial site staff, and all Gilead and Novo Nordisk employees involved in the trial. We also thank Andy Bond of Spirit Medical Communications Group Ltd, for medical writing and editorial assistance (funded by Gilead Sciences Inc. and Novo Nordisk A/S).
Publisher Copyright:
© 2022 European Association for the Study of the Liver
PY - 2022/9
Y1 - 2022/9
N2 - Background & Aims: Non-alcoholic steatohepatitis (NASH) is associated with increased risk of liver-related and cardiovascular morbidity and mortality. Given the complex pathophysiology of NASH, combining therapies with complementary mechanisms may be beneficial. This trial evaluated the safety and efficacy of semaglutide, a glucagon-like peptide-1 receptor agonist, alone and in combination with the farnesoid X receptor agonist cilofexor and/or the acetyl-coenzyme A carboxylase inhibitor firsocostat in patients with NASH. Methods: This was a phase II, open-label, proof-of-concept trial in which patients with NASH (F2–F3 on biopsy, or MRI-proton density fat fraction [MRI-PDFF] ≥10% and liver stiffness by transient elastography ≥7 kPa) were randomised to 24 weeks’ treatment with semaglutide 2.4 mg once weekly as monotherapy or combined with once-daily cilofexor (30 or 100 mg) and/or once-daily firsocostat 20 mg. The primary endpoint was safety. All efficacy endpoints were exploratory. Results: A total of 108 patients were randomised to semaglutide (n = 21), semaglutide plus cilofexor 30 mg (n = 22), semaglutide plus cilofexor 100 mg (n = 22), semaglutide plus firsocostat (n = 22) or semaglutide, cilofexor 30 mg and firsocostat (n = 21). Treatments were well tolerated – the incidence of adverse events was similar across groups (73–90%) and most events were gastrointestinal in nature. Despite similar weight loss (7–10%), compared with semaglutide monotherapy, combinations resulted in greater improvements in liver steatosis measured by MRI-PDFF (least-squares mean of absolute changes: −9.8 to −11.0% vs. −8.0%), liver biochemistry, and non-invasive tests of fibrosis. Conclusions: In patients with mild-to-moderate fibrosis due to NASH, semaglutide with firsocostat and/or cilofexor was generally well tolerated. In exploratory efficacy analyses, treatment resulted in additional improvements in liver steatosis and biochemistry vs. semaglutide alone. Given this was a small-scale open-label trial, double-blind placebo-controlled trials with adequate patient numbers are warranted to assess the efficacy and safety of these combinations in NASH. Clinical Trial registration number: NCT03987074. Lay summary: Non-alcoholic fatty liver disease and its more severe form, non-alcoholic steatohepatitis (NASH), are serious liver conditions that worsen over time if untreated. The reasons people develop NASH are complex and combining therapies that target different aspects of the disease may be more helpful than using single treatments. This trial showed that the use of 3 different types of drugs, namely semaglutide, cilofexor and firsocostat, in combination was safe and may offer additional benefits over treatment with semaglutide alone.
AB - Background & Aims: Non-alcoholic steatohepatitis (NASH) is associated with increased risk of liver-related and cardiovascular morbidity and mortality. Given the complex pathophysiology of NASH, combining therapies with complementary mechanisms may be beneficial. This trial evaluated the safety and efficacy of semaglutide, a glucagon-like peptide-1 receptor agonist, alone and in combination with the farnesoid X receptor agonist cilofexor and/or the acetyl-coenzyme A carboxylase inhibitor firsocostat in patients with NASH. Methods: This was a phase II, open-label, proof-of-concept trial in which patients with NASH (F2–F3 on biopsy, or MRI-proton density fat fraction [MRI-PDFF] ≥10% and liver stiffness by transient elastography ≥7 kPa) were randomised to 24 weeks’ treatment with semaglutide 2.4 mg once weekly as monotherapy or combined with once-daily cilofexor (30 or 100 mg) and/or once-daily firsocostat 20 mg. The primary endpoint was safety. All efficacy endpoints were exploratory. Results: A total of 108 patients were randomised to semaglutide (n = 21), semaglutide plus cilofexor 30 mg (n = 22), semaglutide plus cilofexor 100 mg (n = 22), semaglutide plus firsocostat (n = 22) or semaglutide, cilofexor 30 mg and firsocostat (n = 21). Treatments were well tolerated – the incidence of adverse events was similar across groups (73–90%) and most events were gastrointestinal in nature. Despite similar weight loss (7–10%), compared with semaglutide monotherapy, combinations resulted in greater improvements in liver steatosis measured by MRI-PDFF (least-squares mean of absolute changes: −9.8 to −11.0% vs. −8.0%), liver biochemistry, and non-invasive tests of fibrosis. Conclusions: In patients with mild-to-moderate fibrosis due to NASH, semaglutide with firsocostat and/or cilofexor was generally well tolerated. In exploratory efficacy analyses, treatment resulted in additional improvements in liver steatosis and biochemistry vs. semaglutide alone. Given this was a small-scale open-label trial, double-blind placebo-controlled trials with adequate patient numbers are warranted to assess the efficacy and safety of these combinations in NASH. Clinical Trial registration number: NCT03987074. Lay summary: Non-alcoholic fatty liver disease and its more severe form, non-alcoholic steatohepatitis (NASH), are serious liver conditions that worsen over time if untreated. The reasons people develop NASH are complex and combining therapies that target different aspects of the disease may be more helpful than using single treatments. This trial showed that the use of 3 different types of drugs, namely semaglutide, cilofexor and firsocostat, in combination was safe and may offer additional benefits over treatment with semaglutide alone.
KW - cilofexor
KW - fibrosis
KW - firsocostat
KW - NASH
KW - non-alcoholic steatohepatitis
KW - semaglutide
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U2 - 10.1016/j.jhep.2022.04.003
DO - 10.1016/j.jhep.2022.04.003
M3 - Article
C2 - 35439567
AN - SCOPUS:85130972078
SN - 0168-8278
VL - 77
SP - 607
EP - 618
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 3
ER -