Exploring the growing burden of liver disease

© iStock / magicmine

With one in five people at risk for developing liver disease, Dr Michael Lutz discusses what can be done to combat this growing threat.

According to the British Liver Trust, liver disease is the leading cause of death in adults aged 35 to 49. Yet while this statistic is indeed shocking, it is equally disturbing to read that 90% of cases of liver disease are in fact preventable. Our liver is an integral part of our overall well-being, responsible for over 500 essential functions in the body, such as helping us detoxify harmful substances in our blood, process food, regulate hormones and fight infections.

Excess alcohol, a diet rich in processed foods, and sedentary behavior are some of the main risk factors associated with liver disease. the liver is severely damaged. Talk to Health Europe, Dr Michael Lutz, CEO and Managing Director of HepaRegenix, reflects on the growing burden of disease, the challenges of diagnostic procedures, and the need for reliable and innovative therapies that can help patients with acute and chronic liver problems.

Can you describe some common types of liver disease and their current burden on health systems?

There are a number of diseases related to the liver and two key factors that can strongly influence their development: food and alcohol, or a combination of both. As the disease progresses, the first stages of deterioration are called non-alcoholic fatty liver disease (NAFLD), including non-alcoholic steatohepatitis (NASH). These define a range of conditions caused by a buildup of fat in the liver and are commonly seen in overweight people. NAFLD / NASH has four key stages (F1-F4), each with different clinical manifestations and requiring different diagnostic procedures. As the liver becomes inflamed you may see the first signs of steatosis where fat builds up in liver cells (F1), and if left untreated or undiagnosed it may progress. in fibrosis which can cause scarring of the liver and adjacent blood vessels (F2).

The early stages of liver disease are called non-alcoholic fatty liver disease (NAFLD), including non-alcoholic steatohepatitis (NASH) © iStock / Jan-Otto

The most severe cases of liver disease are stage F3 (advanced liver fibrosis) and stage F4 (cirrhosis). Also known as end-stage liver disease, cirrhosis manifests as scarring and irregular lumps or nodules that can affect the functionality of the liver. There are two types of cirrhosis called “compensated” and “decompensated”. One of the main difficulties at this stage of liver disease is that patients who have compensated cirrhosis may not have any symptoms because their liver is able to function relatively well despite the damage. Conversely, the decompensated stage means the damage to the liver is so severe that it cannot function properly, which in turn can lead to many other health complications, including hepatic encephalopathy and bleeding varicose veins. . At this point, patients would need a liver transplant within two to three years.

Patients with advanced fibrosis, or even early stage cirrhosis, may be stable for 10 to 20 years. However, the impact of other health problems incurred, such as hepatic encephalopathy, can lead to deterioration of the liver, as well as other organs, and lead to acute liver failure.

Are there certain demographics or groups that are particularly susceptible to the disease or is lifestyle the main driver of the disease?

The impact of diet and lifestyle on the liver has been well documented for many years. There are reports that have hinted at fast food as the source of the next US pandemic and that over the next 10 to 20 years there will be a huge increase in the number of people with non-alcoholic steatohepatitis (NASH). , advanced stage fibrosis or cirrhosis. This means that there may be an organ shortage as more people will need a liver transplant.

The impact of the COVID-19 pandemic has also seen a substantial increase in the number of people turning to alcohol to overcome the ‘COVID blues’, particularly in the UK and US.

Can you describe some of the main challenges associated with diagnosis and screening? Should more be done to raise awareness?

Diagnosing the severity of the fibrosis or cirrhosis would require a liver biopsy and subsequent histopathological evaluations, which can be very difficult to determine where to do the liver biopsy in order to get a clear and valid result.

Although NASH can create opportunities for innovation, for regulatory reasons, many pharmaceutical companies have failed in advanced NASH trials due to the difficult nature of liver biopsies and histopathology. Our company is part of the Liver Forum which was created by the pharmaceutical industry and a few other partners to facilitate the development of drugs for the treatment of liver disease. Last year there was a session where people said that histopaths, and the results are like rolling the dice; three pathologists can take a sample, and each can give different results.

In terms of awareness, there are effective initiatives to encourage healthier lifestyles; we have seen a gradual decline in the number of people who smoke over the past 10 to 15 years and we are now seeing similar initiatives regarding sugar taxes. Advocating a healthy lifestyle that incorporates more exercise, less alcohol and red meat is a starting point, but in some countries like the United States, the scale of liver disease is increasing so rapidly that interventions are urgently needed. In the past 10 years alone, cases of liver disease in the United States have increased by around 25% and we expect this to continue to rise if left unchecked.

On your website, you state that there is a huge unmet medical need, mainly due to the lack of treatment options. Can you share any innovations or recent developments that could improve the success rate of treatment for liver disease?

When I joined HepaRegeniX in 2019, the NASH space was very crowded with over 200 companies developing treatments. However, since then many of these companies’ attempts have failed and they have left the NASH space. Our company has embarked on other projects focused on more advanced liver diseases. In the early stages of some liver diseases, regulators are still convinced that if you make changes to your diet and lifestyle, you can stop the disease and essentially heal yourself. Therefore, they are reluctant to motivate and fund companies to create drugs for these patients. Supporting patients with acute or chronic liver failure is another story, and more and more people will need this type of advanced care. We already hear the term “liver tsunami” reflecting the rapid increase in the number of people in need of treatment. Likewise, some reports predict that liver cancer will be the most important cancer over the next 20 years.

There are still companies developing treatments for NASH as well as those trying to “cleanse” fat from the liver or reduce the impact and early symptoms of NAFLD, including treatments for obesity. There are also companies that try to roll back and prevent fibrosis from growing further. Regenerative medicine companies like ours are studying the more severe stages of liver disease to support patients who need it and that is our goal with upcoming clinical trials.

In development, HepaRegenix only works on advanced liver diseases. Can you explain how your therapeutic approach differs from currently approved therapies and more advanced compounds currently in clinical development?

Current therapies for chronic liver disease focus on reducing or eliminating harmful exogenous agents and thus may slow the progression of the disease. For terminal liver disease, transplantation is currently the only curative option. Currently, no therapy can restore the almost infinite regenerative capacity of healthy liver cells. Yet this is exactly the approach we follow at HepaRegeniX: we aim to unlock the regenerative capacity of hepatocytes. Our target is the Mitogen Activated Protein (MAP) Kinase Kinase 4 – in short: MKK4. The foundations of this “first-in-class” approach were laid in the laboratory of Professor Lars Zender at the University Hospital of Tübingen. In cooperation, we have developed a small molecule platform of MKK4 inhibitors. From extensive preclinical studies, we know that restoration of regenerative capacity through inhibition of MKK4 is possible even in severely affected livers. In fact, the evidence we were able to gather in acute and chronic liver disease was very convincing and fully confirmed the therapeutic rationale. More recently, we reported significant benefits in terms of survival and improvement of key liver function parameters in collaboration with the Mayo Clinic. As we embark on our Phase 1 First-In-Human trial which began in August 2021, we see the great potential of MKK4 to treat patients with advanced liver disease.

Dr Michael Lutz
CEO / Managing Director
HepaRegeniX
www.heparegenix.com

This article is taken from issue 20 of Europa Health Quarterly. Click on here to get your free subscription today.




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