Vall d'Hebron participates in an international clinical trial that has led to approval of the first drug for advanced fatty liver disease

Metabolic dysfunction–associated liver disease (MASLD) and its more advanced stage with steatohepatitis (MASH, formerly called NASH) is caused by the accumulation of fat in the liver, which can cause the organ to stop functioning properly. Preliminary results from the international Phase III MAESTRO-NASH clinical trial show that the drug resmetirom is able to reduce liver damage in patients with MASH. The study, recently published in The New England Journal of Medicine, involves Vall d'Hebron and the CIBER of Liver and Digestive Diseases (CIBEREHD). These results have led to the approval of this drug for the treatment of MASH by the FDA in the United States, and the process of applying for approval by the European Medicines Agency (EMA) is underway.

MASLD is a disease that affects 25-30% of the European adult population, and 20% of these develop steatohepatitis (MASH), which is characterized by the presence of fat, inflammation, and damage to liver cells. It is the fastest growing cause of advanced liver disease globally. This pathology can lead to liver fibrosis, which is associated with cardiovascular complications (heart attacks and strokes, among others), non-hepatic cancers and progression to cirrhosis.

Over the past 20 years, dozens of clinical trials have been performed at different stages and with multiple molecules to treat MASLD-associated steatohepatitis and liver fibrosis. However, so far none of these has clearly achieved the requirements set by their approval for regulatory agencies (FDA and EMA). "Until now, there was no approved pharmacological treatment for this pathology, beyond interventions to induce weight loss and physical exercise. In any pathology, the fact that there are treatments available in addition to changes in lifestyle habits is associated with an improvement in the overall diagnosis and follow-up, which is also expected in the case of metabolic fatty liver disease. To this end, it is essential to find new drugs that will help us to reverse fibrosis and prevent or improve the most severe cases of MASH", explains Dr. Juan M. Pericàs, member of the Hepatology Service at the Vall d’Hebron University Hospital, principal investigator of the Liver Diseases group at the Vall d’Hebron Research Institute (VHIR), both led by Dr. Joan Genescà, and researcher at CIBEREHD. Dr. Pericàs is the only Spanish lead author in the paper published in NEJM.

Resmetirom shows good results in patients with advanced fatty liver disease

In this context, the MAESTRO-NASH study, promoted by Madrigal Pharmaceuticals, analyzes the safety and efficacy of resmetirom for the treatment of MASH. It is an oral drug that acts on thyroid hormone beta receptors located in liver cells and helps to regulate lipid and glucose metabolism. This Phase III clinical trial involves the collaboration of 245 centers in 15 countries around the world.

The study involved 966 patients, who were divided into three groups: one group received placebo, one received 80 mg of resmetirom and the last group received 100 mg of resmetirom. The patients underwent a liver biopsy at the beginning of the study and a second one a year after starting the treatment, to determine whether the characteristics of MASH and fibrosis in the liver improved.

It was seen that, in patients receiving resmetirom, MASH improved in 26-30% of cases, while it improved in only 9.7% of those taking placebo. A reduction in fibrosis was also observed in 24-26% of patients on the drug and only 14% of those on placebo. In addition, the results show that fat levels, such as LDL cholesterol (a well-validated marker of cardiovascular complications) or triglycerides, were reduced.

The study also showed that the side effects of the treatment are, in most patients, mild to moderate, the most common of which are digestive system disorders.

The trial is scheduled to continue until patients have been on treatment for 4.5 years, to study progression, including possible progression to cirrhosis, the last and most severe stage of MASH. "We know that all the improvements observed so far are associated with a decreased risk of liver disease progression and cardiovascular complications. We therefore hope that these data will translate into a clinical benefit for patients in the medium to long term", says Dr. Pericàs.

In addition to the approval of resmetirom (the brand name of which in the U.S. is Rezdiffra) to treat MASH, this study raises several questions that may revolutionize the field. Among others, the results of non-invasive tests derived from MAESTRO-NASH to evaluate the efficacy of the drug could later lead to a very relevant change in the approval criteria of regulatory agencies, which until now have been based on liver biopsy. On the other hand, the design of new trials in this disease could change, so that resmetirom could be established as the standard of treatment and would replace placebo. Aspects such as combination therapy with several drugs, how patients will be selected as drug candidates, and how the efficacy of the treatment will be monitored in real clinical practice are also being considered.