Editor's Note: On June 8, the European Association for the Study of the Liver (EASL) Annual Meeting concluded successfully in Milan, Italy. This conference brought together top experts and scholars from around the world to discuss the latest technologies and future trends in liver disease treatment. Among the key topics was the development of new drugs for metabolic-associated fatty liver disease (MAFLD). Professor Jian Gao Fan, Director of the Gastroenterology Department at Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, shared insights on the current state and cutting-edge progress in MAFLD drug development.Background and Importance: As the most widespread chronic progressive liver disease globally, MAFLD, formerly known as non-alcoholic fatty liver disease (NAFLD), is gaining increasing attention. The latest research developments in drug development, diagnostic technologies, and basic medical research were among the hottest topics at this year’s EASL Annual Meeting. The conference featured focused academic reports, oral presentations, and poster sessions on the diagnosis and treatment strategies for MAFLD, with particular emphasis on new drug development.
Recent Developments: On March 14, 2024, the world’s first new drug for non-alcoholic steatohepatitis (NASH), now renamed metabolic-associated steatohepatitis (MASH), the selective thyroid hormone receptor β agonist Resmetirom, was approved for market in the United States. It is mainly used to treat NASH patients with clinically significant liver fibrosis. However, as Professor Fan mentioned in a previous interview, despite Resmetirom being the first approved drug, its therapeutic effect is not the best. Current research data shows that its improvement on steatohepatitis and fibrosis is not ideal, with efficacy rates below 30%, only statistically superior to the placebo group. In reality, most patients treated with Resmetirom did not respond effectively.
Promising New Drugs: Fortunately, the latest clinical trial results presented at the conference indicate significant progress in MAFLD drug development. Some new drugs focusing on weight management and metabolic regulation show far better effects in treating NASH than Resmetirom. For example, Eli Lilly’s investigational drug Tirzepatide, a dual GIP and GLP-1 receptor agonist, has already shown excellent performance in weight loss for overweight or obese adult patients in China. This conference presented the results of a Phase II clinical trial of Tirzepatide for NASH. The 52-week data[1] showed that 73.9% of patients receiving the highest dose (15 mg) of Tirzepatide achieved NASH resolution without worsening liver fibrosis, with more than half showing significant improvement in fibrosis by at least one stage, and one-third improving by more than two stages. The drug demonstrated a clear dose-response relationship, with better outcomes for higher doses.
New Perspectives: These results remind us that the root causes of MAFLD/MASH may lie in obesity and metabolic dysfunction. Effective weight loss, improved insulin resistance, and alleviated metabolic disorders might not require as long a treatment duration as previously thought. A relatively short course of treatment could potentially achieve the desired therapeutic outcomes.
Besides drugs targeting “obesity and metabolic dysfunction,” some medications directly target the liver, addressing hepatic fat accumulation and inflammation. These drugs show positive effects in anti-inflammation and anti-fibrosis but still need deeper interventions at the root level. Other new NASH drugs, such as FGF21 analogs[2], also focus on systemic metabolism, showing better results than those targeting only the liver.
Future Directions: NASH drug development needs to achieve at least 50% efficacy, meaning that after one year of treatment, at least half of the patients with fibrotic NASH should see a resolution of steatohepatitis and improvement in fibrosis. This is the benchmark for clinically promotable drugs. The previous goal of a “30% reduction in liver fat content by MRI-PDFF” is no longer sufficient, with a “50% reduction” likely becoming the new target.
Additionally, non-invasive testing indicators and the application of artificial intelligence in drug development are gaining increasing attention. Technologies like MRI-PDFF and transient elastography provide more precise evaluations of changes in liver fat content and stiffness. These new technologies make treatment evaluation more accurate and comprehensive.
Ongoing Research: Professor Fan’s team is conducting a nationwide multi-center NASH drug development trial. The interim results of the Phase IIb clinical trial indicate that the drug’s efficacy seems superior to the approved selective thyroid hormone receptor β agonist. However, whether the final therapeutic effects can meet the ideal goals depends on weight management and other factors, requiring further liver biopsies for clarification.
In conclusion, the development of new drugs for MAFLD/MASH and related liver fibrosis or cirrhosis is in full swing. Despite some controversies over the naming of MAFLD, new drug development provides fresh evidence for MAFLD treatment, and updates to related clinical guidelines are imminent. In May, the Chinese Society of Hepatology organized experts to revise the “Guidelines for the Prevention and Treatment of Non-alcoholic Fatty Liver Disease (2018 Update),” renaming it to the “Guidelines for the Prevention and Treatment of Metabolic (Non-Alcoholic) Fatty Liver Disease (2024 Edition).” These guidelines offer 40 recommendations based on the latest clinical progress for screening, monitoring, diagnosing, evaluating, treating, and following up on MAFLD. The European Association for the Study of the Liver, Diabetes, and Obesity Societies also updated their 2016 NAFLD guidelines on June 7 at the EASL Annual Meeting, recommending conditional use of Resmetirom for patients with biopsy or non-invasively confirmed MASH and F2 or F3 fibrosis. We believe that with the progress in new drug development, MAFLD drug treatment will soon enter a new era of diverse and effective therapies.
References:
- EASL 2024, abstract LBO-001.
- EASL 2024, abstract OS-118.
