Galien week of innovation

Background and Topics for Discussion 

Research to understand the complex biologic and lifestyle factors that contribute to chronic disease is opening new doors for medicines linked to the human condition known as metabolic syndrome. The syndrome underlies or contributes to numerous debilitating diseases which often appear in patients simultaneously, making research, diagnosis and treatment more challenging. 

A prominent example of clinical progress in this area is a new generation of incretin hormones (GLP-1 receptor agonists, dual (GLP-1 and GIP) agonists, and other combinations) medicines originally developed to improve glucose control in diabetes that now show much broader efficacy as pharmacologic approaches to overweight and obesity. The fact that obesity is a foundational condition associated with diverse health risks beyond diabetes (as many as 200, according to some estimates) means these new drug classes – and potentially others on the horizon – will add to our therapeutic armamentarium against metabolic syndrome. Even modest research breakthroughs in this area not only will contribute to improved health for individual patients but have the potential to contribute to improvements in population-wide health outcomes as well as easing the burden metabolic diseases place on scarce health resources.

Today’s panel focuses on a proliferating but still “under the radar” liver disorder, Metabolic Dysfunction-Associated Steatohepatitis (MASH). It’s a new name (replaceing the term NASH) for an existing condition that is both deadly and largely asymptomatic. Patients with MASH experience a progressive metabolically driven build-up of excess fat in the liver, resulting in inflammation and cell death that progresses to fibrosis and scarring that can lead to cirrhosis. Advanced cirrhosis may eventually necessitate a transplant as the only option remaining to prevent death. Today, an estimated 22 million US adults are living with MASH and its related stages and co-morbidities. A large proportion of victims have yet to be formally diagnosed or are not receiving treatment. Awareness of MASH as a mortality risk and public health threat remains low, an unfortunate situation because the disease can often be prevented entirely through lifestyle changes and behaviors before the need for pharmacologic intervention. 

With such statistics in mind, clinicians are working to clarify the nomenclature for diagnosing and managing this disease. In 2023, a joint collaboration between hepatology clinicians and patient groups proposed that the disease’s existing name, Non-Alcoholic Steatohepatitis (NASH) be dropped, on grounds that the “non-alcoholic” label failed to accurately define the disease as the “hepatic manifestation of metabolic syndrome.” MASH (and its accompanying label for less severe forms of the disease, Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) also removes the “stigmatization” linked to the previous label’s indirect reference to excess consumption of alcohol. Likewise, the existing shorthand characterizing a milder version of this disease, Non-Alcoholic “Fatty Liver” Disease (NAFLD) was abandoned for seemingly targeting obese patients to the exclusion of others who might benefit from treatment. 

The new designations mark a turning point in securing greater awareness among patients, clinicians and the public about the many dangers of MASH and the burden it imposes on the health system. MASH is the leading cause of the steep rise in costly liver transplants in the US: more than 10,000 were performed in 2023 alone. More important, seemingly unrelated co-morbidities from MASH ranging from heart disease, type 2 diabetes, solid tumor cancers and even neurocognitive decline also can result in death. In fact, patients with MASH/MASLD are twice as likely to die of cardiovascular diseases (CVD) than from liver failure. 

In recent years, the complexity of MASH as a research target and the challenges of clinical development programs persuaded a number of leading drugmakers to abandon development programs in this disease area, with numerous candidates failing in early development. This situation now is changing as the insights around metabolic signaling derived from the GLP-1 agonist class bear fruit. 

In March, the FDA granted the small biotech Madrigal Pharmaceuticals conditional approval to Rezdiffra (resmetirom), a thyroid hormone beta receptor agonist for adults with noncirrhotic non-alcoholic steatohepatitis characterized by moderate to advanced liver scarring (fibrosis). The first treatment that directly addresses the liver damage that can lead to liver failure and death, Rezdiffra bears a requirement for use only in conjunction with a lifestyle regimen of diet and exercise; clinical benefit must also be reaffirmed on completion of another 54-month clinical trial. Multiple other biotechnology and biopharmaceutical companies including three represented on this panel (Boehringer-Ingelheim, Eli Lilly & Co. and Novo-Nordisk A/S) have MASH candidates in development , all of which build on the potential of their vastly successful GLP-1 weight loss molecules. 

Topics our six-member expert panel may address include: 

• Identify and assess the most promising biologic pathways toward treating and curing MASH/MASLD. Is big pharma and biotech on course to “crack the code” on metabolic syndrome? 
• Define the principal barriers to the approval of novel drug therapies for MASH/MASLD from a discovery, development, regulatory and patient access perspective. Do the potential financial returns justify the investments in R&D? 
• Identify the challenges in providing better diagnostics to screen, identify and track MASH/MASLD. Are current clinical practice guidelines adequate to the task of differentiating among the many facets of this condition?
• What strategies are necessary to build awareness of MASH/MASLD and assure patient behavior changes are introduced early enough to prevent liver failure as the ultimate end point of disease? Is losing weight the single best response to reversing the course of disease?