Aramchol reduces liver fat in people with NASH

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 (NASH), according to study presented at the recent AASLD Liver Meeting.

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.

"The 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 release.

NASH 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.

Participants were 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.

The 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.

NASH 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.

ALT 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.

"In a one year study, aramchol showed liver fat reduction, biochemical improvement, NASH resolution and fibrosis reduction in a dose-response pattern," the researchers concluded.

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.