Resmetirom, a thyroid hormone receptor agonist, appeared to reduce
liver fat and fibrosis, as determined by biomarkers and non-invasive imaging, in
people with non-alcoholic steatohepatitis
to a presentation at the 2021 International Liver Congress.
Non-alcoholic fatty liver disease (NAFLD) and
NASH, its more severe form, are a growing concern worldwide. The build-up of
fat in the liver triggers inflammation and production of scar tissue
(fibrosis), which over time can lead to cirrhosis, liver cancer and the need
for a liver transplant. With no effective therapies, management currently relies on lifestyle changes such as
Developing treatments for NAFLD and
NASH has proved challenging. Several drugs that have produced favourable biomarker
changes in early studies did not show significant benefits in larger clinical
- compensated cirrhosis
The earlier stage of
cirrhosis, during which the liver is damaged but still able to perform most of
its functions. See also ‘cirrhosis’ and ‘decompensated cirrhosis’.
A non-invasive test, used instead of a biopsy, to measure the stiffness
or elasticity of the liver using an ultrasound probe.
MGL-3196) is a liver-directed selective thyroid hormone receptor-beta agonist.
Thyroid hormones play an important role in metabolism, and agents that promote
receptor-beta activity can reduce blood lipid levels and liver fat by breaking
down fatty acids. Selective agonists like resmetirom
aim to stimulate receptor-beta activity without triggering receptor-alfa activity,
which can lead to side effects like increased heart rate and bone loss.
At last week's virtual conference,
Prof. Stephen Harrison of Oxford University and Pinnacle Clinical Research in
Texas presented findings from the phase III MAESTRO-NAFLD-1
trial (NCT04197479). At the 2018 International
Liver Congress, Harrison
presented promising results from a
smaller phase II trial of resmetirom.
MAESTRO-NAFLD-1 enrolled around 1200 people with NASH, as determined by non-invasive
biomarker and imaging tests, at some 65 sites in the United States. Harrison
described this as a 'real-life' NASH study that does not require liver biopsies
to verify eligibility or monitor outcomes.
Eligible participants had at least
three metabolic risk factors, transient elastometry (FibroScan) imaging showing at least some fibrosis (≥5.5 kPa) and
substantial liver fat (CAP ≥280) and MRI-PDFF (magnetic resonance imaging estimation of proton density fat fraction)
showing at least 8% liver fat.
Three-quarters of the participants
were randomised to receive 80mg or 100mg resmetirom
or placebo for 52 weeks. The rest entered an open-label arm in which they all
received 100mg resmetirom without
blinding. The latter group included those found to have compensated cirrhosis,
considered a special safety population.
Harrison presented results for the
open-label arm, which included 115 people who had completed 52 weeks of
treatment and undergone follow-up laboratory tests, FibroScan, magnetic resonance elastography (MRE) and MRI-PDFF
imaging. Just over 70% were women and the mean age was approximately 58 years.
The mean body mass index was 36.2
(≥30 denotes obesity). A majority had metabolic co-morbidities including type 2
diabetes (41%), hypertension (64%) and abnormal blood lipids (>70%); nearly
half used statins. One in four had hypothyroidism. At baseline, the mean FibroScan transient elastometry score was
7.4 kPa, the mean MRE was 2.7 kpA, the mean CAP score was 341 and the mean
MRI-PDFF fat fraction was 18%. ALT and AST liver enzyme levels were generally
within the normal range.
reduced liver fat as determined by both MRI-PDFF and CAP at week 52, Harrison
reported. MRI-PDFF fell by an average of 53% overall. People with high levels
of sex hormone-binding globulin (SHBG), a protein linked to insulin resistance
and lipid metabolism, saw a reduction of 65%, and among those who lost at least
5% of body weight, there was a 63% decline. The corresponding decreases in CAP
scores were -45.2, -52.2 and -72.1 points, respectively.
Turning to fibrosis, FibroScan imaging showed an overall
reduction of -2.8 kPa, or 26%. MRE showed an
improvement of -11.9% overall, rising to -16.1% among those with high SHBG
levels. Harrison noted that approximately half of patients saw at least a 25%
reduction according to FibroScan or a
15% reduction according to MRE.
Various fibrosis and inflammation
biomarkers showed improvement. This was also the case for biomarkers of
cardiovascular risk, including reductions in LDL cholesterol (-20%),
triglycerides (-27%) and blood pressure. While 21% of participants lost at
least 5% of body weight, 9% gained a similar amount.
Resmetirom was safe and well
tolerated; only one person withdrew from the study due to adverse events. Side
effects were generally mild, including transient loose stools that did not
lead to discontinuation. Interestingly, the most common serious adverse event
in this study was COVID-19. There were no notable changes in thyroid function
or vital signs.
While non-invasive imaging and
biomarker tests can only provide an estimate of liver pathology, Harrison said
the observed improvements could reflect favourable changes that would be
apparent in liver biopsies.
A companion phase III trial, MAESTRO-NASH (NCT03900429), is currently enrolling NASH patients
with moderate to advanced fibrosis (stage F2-F3) who have not yet progressed to
cirrhosis. Unlike MAESTRO-NAFLD-1, this trial will include pre- and post-treatment biopsies, considered the
gold standard for assessing liver health.