In another phase II study, Dr Naim Alkhouri of Arizona Liver Health and
colleagues compared regimens of semaglutide alone or in combination with Gilead
cilofexor or both.
Firsocostat (GS-0976) is an
acetyl-CoA carboxylase (ACC) inhibitor; ACC is involved in lipogenesis, or conversion of
carbohydrates to fatty acids in the liver. Cilofexor (GS-9674) is a nonsteroidal farnesoid X
receptor (FXR) agonist; FXR regulates bile acid synthesis and plays a
role in lipid and glucose metabolism.
As reported at the recent
Digital International Liver Congress, the ATLAS trial showed that firsocostat, cilofexor and
signal-regulating kinase 1 inhibitor selonsertib (GS-4997), alone or in
combination regimens, failed to
significantly improve liver fibrosis without worsening NASH. However, one combo
in particular – firsocostat
plus cilofexor – led to improvements
in other measures of fibrosis and liver health.
The present study design was similar to that of ATLAS,
but substituted semaglutide for selonsertib, which was found to be ineffective
in the phase III STELLAR 3 and 4 trials presented at last year's Liver Meeting.
The trial included 108 people with
NASH and stage F2 to F3 fibrosis according to biopsies or an MRI liver fat
fraction of 10% or higher and a liver stiffness measurement of 7 kPa according
to FibroScan. About 70% were women, a
third to a half were Hispanic or Latino (a group with a higher prevalence of
NASH) and the median age was 54 years. A majority were overweight or had
obesity and more than half had diabetes.
Participants were randomised to receive semaglutide
in one of the following regimens for 24 weeks:
- semaglutide monotherapy
- semaglutide plus 20mg firsocostat
- semaglutide plus 30mg cilofexor
- semaglutide plus 100mg cilofexor
- semaglutide plus 20mg firsocostat
plus 30mg cilofexor.
Semaglutide was given as a once-weekly
injection at escalating doses ranging from 0.24mg to 2.4mg. Firsocostat and
cilofexor were taken orally once daily.
All groups lost
weight, with percentage loss ranging from -7% to -10%. MRI liver fat fraction
decreased more in all the combination groups (-10% to -13%, with the greatest
loss in the triple therapy arm) compared with the semaglutide monotherapy group
Liver stiffness declined in all groups,
with the greatest improvement seen in the triple therapy arm. Enhanced liver fibrosis (ELF)
score, a composite index of fibrosis biomarkers, showed similar
improvement across all treatment groups. FAST score, another composite measure,
showed greater improvement in the combination groups, especially those containing
The combination groups saw greater
improvements in ALT, AST and the biomarker cytokeratin 18 (CK18). The largest
drops in ALT occurred in the dual and triple regimens containing firsocostat.
All treatment groups had similar
improvements in glycaemic parameters including HbA1c, plasma glucose and
insulin levels. Looking at lipid changes, harmful LDL
cholesterol increased in the group taking the higher dose of cilofexor – though
it did not change in the lower dose group – and triglycerides rose in the
groups that used firsocostat.
The combination therapies were
generally safe and well tolerated. Rates of moderate or worse side effects
ranged from 14% to 32%, but few people stopped treatment due to adverse events.
Gastrointestinal symptoms were again most common, with about two-thirds of
participants reporting nausea in the triple therapy group. Mild pruritus, or
itching, was reported by a small number of people taking cilofexor.
with NASH, combinations of semaglutide with cilofexor or firsocostat may
provide additional benefits compared with semaglutide alone, Alkhouri and