A novel type of experimental therapy led to a significant reduction in
liver fat and improvement in liver health among people with non-alcoholic steatohepatitis
according to study presented at the recent AASLD
Aramchol, from Galmed Pharmaceuticals, is a fatty acid-bile acid conjugate that inhibits stearoyl
coenzyme A desaturase 1 (SCD1). This enzyme plays a role in lipid metabolism in
the liver, converting saturated fatty acids to monounsaturated fatty acids.
Animal studies showed that it reduces steatosis (liver fat build-up),
inflammation and fibrosis characteristic of NASH.
higher proportion of resolution of steatohepatitis together with the potential
for direct fibrosis improvement and excellent safety and tolerability place aramchol
among the most promising candidates in development for NASH patients," Prof. Vlad Ratziu of Sorbonne University in Paris said
in a Galmed press
Cell of the liver.
Abnormal fat deposits in the liver.
and its milder form, non-alcoholic fatty liver disease (NAFLD), are often
associated with obesity and the metabolic syndrome. The build-up of fat in the
liver triggers inflammation and development of scar tissue, which over time can
lead to cirrhosis, liver cancer and the need for a liver transplant. Now that
direct-acting antivirals can cure most people with hepatitis C, fatty liver
disease accounts for a growing share of advanced liver disease. But to date there are no good
therapies and management relies on lifestyle changes such as weight loss.
Prof. Ratziu presented late-breaking results from the phase IIb ARREST
trial, which tested aramchol in 247 people with NASH in 11 countries in Europe,
the United States and Latin America.
About two-thirds of
study participants were women and the mean age was 54 years. They were
overweight or obese and had type 2 diabetes or pre-diabetes, which are
components of the metabolic syndrome. Over half had high blood pressure and
elevated blood lipid levels. They had NAFLD activity scores of 4 or higher
according to baseline biopsy specimens. People with liver cirrhosis were
excluded, but about 60% had moderate to severe fibrosis.
randomly assigned to receive once-daily oral
aramchol at doses of 400mg or 600mg or a placebo for 52 weeks. A second biopsy
was performed after a year on treatment.
paired biopsies showed that both doses of aramchol reduced liver fat by around
3.5% on average, while there was no notable change in the placebo group. A total of 36.7%
of people in the 400mg aramchol arm, 47.0% in the 600mg arm and 24.4% in the
placebo group had at least a 5% absolute reduction in liver fat from baseline; 25.6%,
30.1% and 14.6%, respectively, had at least a 30% relative reduction.
resolution (no hepatocyte ballooning and little or no inflammation) without
worsening of fibrosis was seen in 7.5% of people in the 400mg aramchol arm,
16.7% in the 600mg arm and 5.0% in the placebo group. Fibrosis improvement (at
least a one-stage reduction) without worsening of NASH was seen in 21.3%, 29.5%
and 17.5%, respectively.
and AST liver enzyme levels – an indicator of liver inflammation – fell significantly
in the aramchol arms but rose in the placebo group. ALT normalisation was seen
in 21.9% and 29.0% of people in the aramchol 400mg and 600mg arms, compared
with 13.3% in the placebo group. Haemoglobin A1c (a measure of blood glucose
over time) also fell in the aramchol arms while rising in the placebo group. There were no
notable changes in body weight or blood lipid levels.
Aramchol was generally safe and well tolerated. Most adverse events
occurred with similar frequency in the aramchol and placebo groups. About 9% of
aramchol recipients in both dose groups and 13% of placebo recipients had
serious adverse events. Fewer than 5% in any group discontinued treatment due
to adverse events.
one year study, aramchol showed liver fat reduction, biochemical improvement,
NASH resolution and fibrosis reduction in a dose-response pattern," the
Based on these
findings, the 600mg dose was chosen for further testing in a phase III clinical
trial called ARMOR, which is expected to start in mid-2019, according to Galmed.