GS-0976, an acetyl-CoA carboxylase (ACC) inhibitor being developed
by Gilead Sciences, led to significant reductions in liver fat accumulation and
fibrosis in people with non-alcoholic steatohepatitis (NASH),
according to phase 2 study results presented at the 2017 AASLD
Liver Meeting last week in Washington, DC.
and its less severe form, non-alcoholic fatty liver disease (NAFLD), refer to the
build-up of fat in the liver in people who do not drink heavily. Fatty liver
disease, which is often associated with obesity and metabolic syndrome, is a
common cause of chronic liver disease worldwide. Over time, fat accumulation in
the liver (steatosis) and the accompanying inflammation and build-up of scar
tissue (fibrosis and cirrhosis) can interfere with normal liver function and
lead to liver cancer. While weight loss and exercise can improve fatty liver
disease, to date there are no approved therapies for NASH.
Loomba of the University of California at San Diego and colleagues evaluated the safety of efficacy of GS-0976 for
people with NASH in a phase 2 clinical trial.
A non-invasive test, used instead of a biopsy, to measure the stiffness
or elasticity of the liver using an ultrasound probe.
Abnormal fat deposits in the liver.
Acetyl-CoA carboxylase plays a key role in de novo lipogenesis, or conversion of carbohydrates into fatty
acids in the liver, which are stored as triglycerides to provide energy when
food is unavailable, Loomba explained as background. If food is plentiful, de
novo lipogenesis can contribute to steatosis, NAFLD and NASH.
GS-0976, which blocks the first chemical step in the
process (conversion of acetyl-CoA to malonyl-CoA),
inhibits de novo lipogenesis. It was shown
to improve liver steatosis, inflammation and fibrosis in pre-clinical studies,
and it was associated with reduced de novo lipogenesis and liver fat
accumulation in a previous proof-of-concept study of NASH patients, Loomba
2 trial enrolled 126 people with NAFLD at 41 sites in the US. Participants had
to have a liver fat proportion of at least 8% according to magnetic
resonance imaging (known as MRI-estimated proton density fat fraction or MRI-PDFF),
liver stiffness of at least 2.5 kPa according to magnetic resonance
elastography (MRE) or a liver biopsy showing NASH and mild to moderate fibrosis
(stage F1-F3). However, people with liver cirrhosis (stage F4) were excluded.
About two-thirds of participants were
women, the median age was approximately 56 years, about 85% were white and more
than a third were Latino/Hispanic (a group with a high rate of fatty liver
disease). The median body mas index was 33 (considered obese), about 60% had
diabetes and about 40% had advanced fibrosis.
Study participants were randomly
assigned to receive GS-0976 at daily oral doses of 5mg or 20mg, or else a
placebo, for 12 weeks.
study endpoints were a reduction in MRI-PDFF of at least 30%, an MRE liver
stiffness reduction of at least 15% or a reduction in liver stiffness by FibroScan. The researchers also looked
liver enzyme levels including ALT and AST and the enhanced
liver fibrosis (ELF) score, a biomarker index that includes serum levels of tissue
inhibitor of metalloproteinases 1 (TIMP-1), amino-terminal propeptide of type
III procollagen (PIII-NP) and hyaluronic acid.
the 12-week treatment the amount of liver fat by MRI-PDFF fell by a median of
29% from the baseline level in the 20mg GS-0976 group, by 13% in the 5mg group
and by 8% in the placebo group. Nearly half (48%) of people in the 20mg
group, 23% in the 5mg group and 15% in the placebo group saw at least a 30% reduction.
The decline in the 20mg group – but not in the 5mg group – was statistically and
clinically significant, Loomba reported.
stiffness according to FibroScan fell
by 11% in the 20mg group, 8% in the 5mg group and 3% in the placebo group.
Conversely, MRE stiffness showed the least improvement in the higher-dose
GS-0976 group (6%, 10% and 13%, respectively). However, the differences in liver
stiffness by either method were not statistically significant.
Although ALT, TIMP-1 and PIII-NP decreased more in the 20mg GS-0976 group
than in the 5mg or placebo groups, only the TIMP-1 decline was statistically significant,
and the composite ELF score did not fall significantly in any group.
In an analysis restricted to those who had at least a 30% MRI-PDFF
response, liver stiffness by MRE, liver enzyme levels and some fibrosis markers
fell more than they did in MRI-PDFF non-responders, with some of these
differences reaching statistical significance.
Treatment with GS-0976 was generally safe and well tolerated, and almost
all participants completed treatment. Serious adverse events and
discontinuations due to adverse events were rare and did not appear to be
drug-related. The most frequently reported adverse events were nausea,
abdominal pain and diarrhoea, which were more common in the 20mg group than in
the 5mg or placebo groups.
The laboratory abnormality of most concern was increased triglycerides
and, interestingly, elevations were greater among those receiving the lower
GS-0976 dose. Triglyceride levels rose by 11% in the 20mg group and by 13% in
the 5mg group, while falling by 4% in the placebo group. Ten per cent of
people in both the 20mg and 5mg groups developed grade 3 triglyceride
elevations (500-1000 mg/dl), while 4% and 8%, respectively, had grade 4
elevations (over 1000 mg/dl). No one in the placebo group had seriously
elevated triglycerides. People with triglyceride levels over 250 mg/dl at
baseline and higher MRE liver stiffness were more likely to see substantial
Among 16 people with asymptomatic triglyceride elevation who continued
on GS-0976, the four people who took fish oil or fibrates (medications to
reduce blood lipid levels) all saw their levels fall below 500 mg/dl at week
12. Seven of the 12 who were not treated with lipid-lowering therapy still spontaneously
fell below the 500 mg/dl threshold by week 12.
People treated with 20mg GS-0976 in this study saw a
"significant improvement in hepatic steatosis" by MRI-PDFF, a
significant improvement in TIMP-1 and dose-dependent reductions in ALT and
PIII-NP, the researchers summarised.
Although they concluded that treatment with GS-0976 was "safe and
well tolerated," they said that its effect on triglyceride levels requires
this first randomized, placebo-controlled, phase 2 study of an ACC inhibitor in
NASH, the data suggest that GS-0976 has the potential to play an important role
in treating patients with this disease," Loomba said in a Gilead press release.
Future studies of GS-0976, both alone and in combinations, are planned, according