Non-alcoholic
steatohepatitis (NASH) refers to liver inflammation and fibrosis caused by
non-alcoholic fatty liver disease (NAFLD). Left untreated, NASH may lead to the
development of cirrhosis and hepatocellular carcinoma. NASH is often
accompanied by obesity and other metabolic disorders such as type 2 diabetes
and dyslipidemia.
A
meta-analysis of studies carried out in Europe shows that around one in 20 people have
advanced fibrosis due to NAFLD or NASH, and NASH is the fastest-growing
reason for a liver transplant in the United States.
There is no
approved form of treatment for NASH. Numerous pharmaceutical companies are
working to develop treatments targeting a variety of metabolic pathways.
Several
companies reported results of phase 2 efficacy studies of experimental NASH
treatments at the AASLD Liver Meeting in November.
Efruxifermin
Efruxifermin reduced liver fat and improved liver inflammation and fibrosis in
the majority of people with NASH who received it in a phase 2a trial but nausea and vomiting led
10% of people who received the drug to drop out of the trial, Professor Stephen
Harrison of the University of Oxford reported at the conference.
Efruxifermin
is designed to treat NASH by regulating levels of FGF-21. FGF-21 is involved in
the regulation of numerous metabolic pathways governing glucose and lipid
levels. Levels of FGF-21 are elevated in people with NAFLD, type 2 diabetes and
obesity. Efruxifermin is an analogue of FGF-21, designed to normalise FGF-21
levels.
The phase 2a
study randomised 80 people to one of three doses of efruxifermin or placebo for
16 weeks.
Liver fat
declined significantly at all doses compared to the placebo group. Liver fat
reduced substantially in more patients in the 50mg and the 70mg groups compared
to the 28mg group. Participants in the 70mg group were more likely to
experience a normalisation in liver fat content (< 5%).
Forty-eight
per cent of responders in the efruxifermin arms achieved resolution of NASH and
there was no difference between dosing groups.
As with
several other drugs being investigated for NASH treatment, gastrointestinal
side effects were common in people who received efruxifermin and 10% of people
receiving the drug stopped due to nausea and vomiting.
A phase 2b/3
clinical trial of efruxifermin in NASH patients is due to begin recruiting in
early 2021, drug developer Akero Therapeutics said in a press release.
Semaglutide
Semaglutide is a glucagon-like peptide-1 (GLP-1)
receptor agonist that mimics the action of natural GLP-1, which increases
insulin secretion and plays a role in appetite regulation and glucose and lipid
metabolism. Several studies of semaglutide as a
treatment for NASH were presented at the Liver Meeting.
A phase 2 study of semaglutide alone
as NASH treatment randomised 230 people to receive one of three doses or
placebo.
People who received semaglutide were
significantly more likely to experience NASH resolution. A slightly higher
number also had improvement in liver fibrosis. Improvements in metabolic
markers were also observed more frequently compared with placebo.
In another phase II study, Dr Naim
Alkhouri of Arizona Liver Health and colleagues compared regimens of
semaglutide alone or in combination with Gilead Science's firsocostat,
cilofexor or both.
All groups
lost weight, with percentage loss ranging from -7% to -10%. Liver fat decreased
more in all the combination groups, with the greatest loss in the triple
therapy arm.
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.
Lanifibranor
Lanifibranor is a PPAR
agonist. It activates all three types of PPAR and is dosed orally, once a day.
PPARs
regulate the expression of genes and are involved in the regulation of numerous
metabolic and inflammatory pathways. PPARs appear
to play a role in the development of NAFLD and NASH and levels of PPARs are
reduced in people with NASH.
Various PPAR
agonists are being tested in clinical trials. Lanifibranor is the only PPAR
agonist which activates all forms of PPAR.
The NATIVE phase 2b study randomised 247 people with
biopsy-confirmed NASH to either 800mg or 1200mg of lanifibranor or placebo for 24
weeks.
The study
used a new outcome measure, changes in steatosis-activity-fibrosis (SAF) score.
SAF score is calculated differently from NAFLD Activity Score, using only liver
tissue inflammation and ballooning of hepatocytes to assess the severity of
disease. After
24 weeks of treatment, participants in the lanifibranor 1200mg group were
significantly more likely to experience a 2-point reduction in SAF score
compared to the placebo group.
Lanifibranor 1200mg also resulted in
improvement of fibrosis by one stage and no worsening of NASH in 42% compared
to 24% in the placebo group and resolution of NASH and improvement of fibrosis
in 31%, compared to 7% in the placebo group.
Lanifibranor will enter phase 3
studies in 2021.
Cotadutide
Cotadutide, an experimental therapy that alters glucose
and lipid metabolism, led to weight loss and improvements in metabolic,
cardiovascular and liver fibrosis biomarkers in overweight people with diabetes
and fatty liver disease, but nausea was a common side effect, another study reported at the conference.
The phase 2b study included 834 people
who were overweight or obese and had type 2 diabetes treated with metformin.
Participants were randomly assigned to receive one of three doses of cotadutide
(100, 200 or 300mcg) via once-daily subcutaneous injection, daily injections of
the diabetes drug liraglutide (a GLP-1 agonist) or a placebo.
After 54 weeks of treatment, people
assigned to all three doses of cotadutide and liraglutide lost significantly
more weight than those in the placebo arm. Those in the high-dose cotadutide
group saw a weight reduction of 5%, which is considered clinically beneficial.
All three doses of cotadutide and
liraglutide reduced NAFLD fibrosis scores, but the difference was only
significant for the high-dose group.
Nausea, vomiting and diarrhoea were
common side effects. More than one in five people (22%) taking the high dose of
cotadutide stopped treatment due to adverse events, as did 13% taking the low
dose and 15% taking the intermediate dose.
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