Combination therapies impact NAFLD more than singular therapy
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Combining therapies with different mechanisms of action to treat non-alcoholic fatty liver disease resulted in greater reduction in liver-related measures, according to a presenter at The Liver Meeting Digital Experience.
“In this randomized, 24-week, phase 2a trial, both semaglutide and combination regimens including semaglutide, firsocostat and/or cilofexor were well tolerated in NASH patients with mild-to-moderate fibrosis,” Naim Alkhouri, MD, from Arizona Liver Health, said. “Despite similar relative reductions in body weight vs. semaglutide, the combination regimens led to greater improvement in ALT, AST, hepatic steatosis as assessed by MRI PDFF and the CAPS score, liver stiffness by transient elastography and the FAST score.”
Alkhouri and colleagues evaluated the safety and efficacy of a GLP-1 receptor agonist (semaglutide, Ozempic, Novo Nordisk) alone and in combination with an farnesoid X receptor agonist (cilofexor, Gilead Sciences) and/or an acetyl-CoA carboxylase inhibitor (firsocostat, Gilead Sciences).
The study comprised five groups: semaglutide alone (n = 21), semaglutide with firsocostat 20 mg (n = 22), semaglutide with cilofexor 30 mg (n = 22), semaglutide with cilofexor 100 mg (n = 22) and semaglutide with firsocostat 20 mg and cilofexor 30 mg (n = 21). The main endpoint of the 24-week study was safety and tolerability with exploratory endpoints in liver imaging and biomarkers. Alkhouri noted that despite the COVID-19 pandemic, 89% of participants completed the study.
“Overall, the regimens were well tolerated,” Alkhouri said. “Serious adverse events were rare.” He said gastrointestinal side effects were most common. Pruritus was lower in cilofexor-containing arms.
Treatment groups showed general improvement in laboratory abnormalities and lipid changes, but Alkhouri noted mild triglyceride elevations in firsocostat groups and LDL increases in the semaglutide-cilofexor 100 mg group.
“Low-dose cilofexor did not increase LDL,” he said. “It also seems that adding semaglutide to the firsocostat containing arms led to mitigation in the known increase in triglycerides that happens particularly when you give fisocostat monotherapy.”
Alkhouri reported weight reductions across all groups, with the greatest reduction seen in the cilofexor-containing arms. He said weight loss continued through week 24.
“There is potential for further weight loss with longer treatment duration,” Alkhouri said.
ELF, liver stiffness and glycemic parameters similarly improved in all groups.
“It seems that a higher percentage of patients in the combination arms achieved that 25% reduction in transient elastography compared to semaglutide monotherapy,” he said.
Using MRI-PDFF, all groups saw declines from baseline, but the combination treatments showed greater improvement, Alkhouri said. Firsocostat-containing regimens reached significance, he added.
“It seems that the combination arms were more successful than semaglutide monotherapy in reducing liver fat by 50% or higher and 70% or higher,” he said. “luckily it seems that all the regimens were associated with achieving that 30% relative fat reduction and in some of the combination arms, this was more than 90%.”
Similarly, there was more improvement in ALT, AST and CK-19 with combination treatments.
FAST score changes were most improved with combination treatment.
“The pathogenesis of NASH is multifactorial, providing rationale for combination therapy,” Alkhouri said. “These three medications target distinct and complementary mechanisms of NASH development and progression.”