“EU-PEARL can serve as a reference in the diagnosis, prevention and treatment of NASH”

On occasion of NASH Day, we talk to EU-PEARL specialists on Nonalcoholic fatty liver disease Juan M. Pericás and Jesús M. Rivera (VHIR) to learn more about NASH. We also ask them where we are in the fight against this disease and how EU-PEARL is contributing to improve prospects for NASH patients.

Today is NASH day.  Why do we need to mark a day in our calendars to talk about NASH?

NAFLD (Nonalcoholic fatty liver disease)/NASH (Nonalcoholic Steatohepatitis) is one of the most significant current global health challenges. The impacts caused by the epidemics related to metabolic syndrome, including that of NAFLD, have multiple major implications at the epidemiology, health systems, and clinical levels. We are talking about a disease present in about a third of the world’s population. NAFLD can progress to advanced stages leading to liver cirrhosis and transplant in a significant proportion of patients, thus entailing huge health and economic burdens. Sadly, NAFLD-NASH continues to be a relatively poorly known disease, even amongst healthcare professionals. Moreover, there are currently no treatments available to most of NASH patients. Therefore, initiatives such as NASH day are essential to educating the general population and the scientific community and gathering momentum for global strategies against a worldwide public health problem.

Globally, what is the current scenario on NASH? Who is more at risk and why? What tools do we currently have to fight this disease?

Globally, the foreseen landscape is worrisome and dismal at 10-20 years from now if the roots of the obesity and diabetes epidemics are not steadily tackled. Although there are specific situations according to the geographical setting, we face massive health problems in general terms.  At the public health level, the fact that for the first time in history, over half of the population are overweight or obese has profound implications. It requires a change of paradigm in the way we cope with health education, the design of health policies and interventions. Furthermore, many of these patients have a liver disease associated with their metabolic disorders with NASH often coexisting with other causes such as alcohol.

“Globally, the foreseen landscape is worrisome and dismal at 10-20 years from now if the roots of the obesity and diabetes epidemics are not steadily tackled”

We know that patients with risk factors, such as the presence of metabolic comorbidities (i.e diabetes), expression of some genetic variants (i.e. PNPL3) or microbiome changes are more likely to progress to advanced stages and develop liver cirrhosis, hepatocellular carcinoma and/or death. Although no effective drugs are available despite the vast scientific efforts underway, the early identification of patients at risk for presenting complications and proper and follow up of these patients allows for better metabolic control and early identification of complications, which are a cornerstone of NASH management.

From a scientific standpoint, what is holding us back to make progress on treatment and prevention?

There are three main reasons that could be underpinned: first, the physiopathology of NASH is utterly complex, with many mechanisms involved and remarkably a tight relationship between the liver, the gut and the adipose tissue with large interindividual changes, which requires detailed and systemic knowledge and advanced personalized medicine tools; secondly, from a clinical trials perspective, there has been a lack of collaboration between companies, which for instance has hindered the use of combination therapies until recently; and lastly, the design of clinical trials is still pretty much based on the use of liver biopsy.

How can EU-PEARL contribute to prevent and fight NASH?

EU-PEARL represents an excellent opportunity to redefine the different approaches to the disease and for NASH itself. The conjunction of clinicians, patients associations, researchers, industry and regulators around a unique platform poses a new multidisciplinary dimension of the whole spectrum of the disease. From a diagnostic and prevention perspective, the EU-PEARL platform can serve as a reference for designing and implementing healthcare policies to early identify NASH patients, test new tools, and stratify patients according to the risk of developing an advanced disease. These measures would allow avoiding unnecessary liver biopsies and reducing screening failures rates at therapeutic clinical trials.

On the other hand, drug development in NASH trials faces several obstacles that limit the final release of the compound. EU-PEARL consortium can facilitate regulatory processes, harmonizing and simplifying political and ethical requirements. The IRP platform entails a dynamic and novel approach to clinical trials, with multiple compounds tested simultaneously, selecting and efficiently promoting the most promising drugs.

In summary, EU-PEARL provides a great opportunity to help advancing the field in order to circumvent the three main barriers mentioned earlier: from a scientific perspective, by putting together the talent, resources and discoveries of foremost experts from both the public and private domains; by generating collaborative platforms where the academy and industry collaborate with each other and different companies also align to advance the field of drug development on NASH; and lastly, by implementing innovative trial designs that optimize non-invasive biomarkers and therefore reserve the use of liver biopsy to those cases in which the regulatory agencies still consider is mandatory to approve the use of a certain drug.

What progress has been made so far within the project to advance in this direction?

Networking, interactions and collaborations between the different work packages and integrants of the consortium have led to fruitful results. From a specific NASH perspective, we conducted a thorough review on the use of biomarkers in NASH trials, a consultation with a external advisory board on the most suitable design for a NASH platform trial, and produced a document summarizing the main challenges and advantages of a NASH integrated research platform to conduct platform trials. In addition, we have engaged with NASH patients and their representatives at the global level. The progress made in the last months is expected to be shared through some impactful publications shortly.

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