Fatty liver: therapy from the sea

Researchers have developed a novel drug that could be used to effectively treat nonalcoholic steatohepatitis: an omega-3 fatty acid. So far there is no established therapy.

In industrialized countries around the world, more and more people are suffering from metabolic diseases such as obesity, impaired lipid metabolism or type 2 diabetes. Many of these patients develop fatty liver disease, non-alcoholic fatty liver disease (NAFL). In Germany alone, about 30 percent of the population has an NAFL. The NAFL causes no complaints. However, around one in six NAFL patients develops fatty liver inflammation, known as non-alcoholic steatohepatitis (NASH).

Weight loss difficult for patients

If fatty liver inflammation becomes chronic, it leads to liver fibrosis. The collagenous connective tissue in the liver increases and the liver becomes scarred. Complications of fibrosis caused by NASH can be liver cirrhosis, liver failure and even hepatocellular carcinoma. The previous treatment of NAFL and NASH initially aimed at changing the diet of those affected and prescribing more physical activity. Among other things, this is intended to achieve weight loss. This can improve the NASH.

However, as with the treatment of obesity, weight loss is often inadequate in most NASH patients. Drug therapy is currently not available. Although research is being carried out on numerous active ingredients, their approval often fails due to insufficient effectiveness or because they cause undesirable side effects.

Daily capsule shows success

“Together with Northsea Therapeutics, we have developed a potential drug against NASH and tested it extensively in vitro and in vivo with regard to its effectiveness: the structurally modified omega-3 fatty acid icosabutate. This is a completely new class of substances. Icosabutate improved both liver inflammation and liver fibrosis. In a first study with patients who were at high risk for NASH, a daily capsule of our active substance icosabutate very convincingly and quickly normalized elevated blood values ​​of liver inflammation and liver fibrosis.

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consequences

Based on these promising results, a clinical phase IIb study (‘ICONA’) was initiated in the USA, in which patients with severe NASH and liver fibrosis are treated with icosabutate over a period of one year. Here, the success of the therapy is assessed at the beginning and at the end by means of a liver biopsy,” explains Prof. Detlef Schuppan, Director of the Institute for Translational Immunology at the University Medical Center Mainz.

Problem: High doses required

The development of the new drug is based on known substances from fish oil, the omega-3 fatty acids. In addition to the positive effect on the cardiovascular system, omega-3 fatty acids are also involved in several processes that can regulate liver inflammation and fibrosis. This served as a starting point for the search for a drug that could be used to treat chronic liver inflammation.newsimage363961_original.jpgResearchers at the Mainz University Medical Center have developed the modified omega-3 fatty acid icosabutate for the treatment of non-alcoholic fatty liver hepatitis (NASH). The innovative active ingredient inhibits inflammation and scarring of the liver. Credit: University Medicine Mainz

The challenge of making an effective drug against NASH from omega-3 fatty acids is that omega-3 fatty acids are needed almost everywhere in the body for general energy metabolism. The liver also uses the fatty acids to generate energy and build up its cells. As a result, the omega-3 fatty acids are quickly used up by the body, which is why they no longer have sufficient potential to inhibit liver inflammation. The high doses of omega-3 fatty acids required for clinical efficacy are poorly tolerated and have undesirable side effects.

With modification to the goal

“With our substance icosabutate, we have modified the structure of the omega-3 fatty acid in such a way that this active ingredient cannot be incorporated into the liver cells or used up as ‘fuel’. There is enough unused icosabutate fatty acid in the liver to dampen inflammation and fibrosis. The modified omega-3 fatty acid icosabutate is 50 times stronger than the natural omega-3 fatty acid. We are optimistic that the active ingredient we have developed will lead to the first effective therapy with clear benefits for the many people affected by NASH,” says Schuppan.

This article is based on a press release from the University Medical Center of Johannes Gutenberg University Mainz. We have linked the original publication in the text and here.

Image source: Sebastian Pena Lambarri, unsplash

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