To build on the momentum in MASH, we—at Madrigal Pharmaceuticals and the industry more widely—must further expand approaches to diagnosis, monitoring and individualized treatment to help more patients.
For decades, metabolic dysfunction-associated steatohepatitis was one of the most challenging areas in drug development. Despite increasing scientific understanding and substantial investment across academia and industry, effective therapies remained elusive.
That changed in 2024 with the field’s first approved medicine, developed and commercialized by Madrigal Pharmaceuticals, where I serve as chief medical officer.
The impact of a first treatment often extends far beyond the medicine itself. It demonstrates that therapeutic intervention is possible and opens the door to a new phase of scientific and clinical discovery.
In diseases ranging from cystic fibrosis to chronic myeloid leukemia, breakthrough therapies have transformed not only treatment options, but also how patients are identified, monitored and studied. New diagnostics, care pathways and endpoints emerge. Treatment expectations shift, and subsequent innovations build upon the original breakthrough.
Metabolic dysfunction-associated steatohepatitis (MASH) is now entering this exciting phase of renewed innovation.
A new era for liver health
MASH is a serious liver disease that is estimated to affect approximately 5% of adults in the United States, with consequences that extend beyond this critical organ. As understanding of the disease continues to grow, researchers are gaining greater insight into the connections between MASH and other aspects of cardiometabolic health, including obesity, type 2 diabetes and cardiovascular disease. For example, MASH has been identified as an independent risk factor for cardiovascular disease, and conversely, cardiovascular disease is the leading cause of mortality among patients with MASH.
This growing understanding is reshaping how researchers think about MASH biology and the therapeutic approaches needed to address it. Instead of looking at MASH through the lens of a single biological pathway, researchers are pursuing approaches that target different drivers of the disease, from the manifestations of metabolic dysfunction and dysregulated energy balance to inflammation, fibrosis and lipid handling.
Potential interventions include incretin-based therapies, FGF21-based approaches and DGAT2 inhibition, among other emerging mechanisms. Like many complex, multifactorial diseases, optimal treatment of MASH will likely involve multiple complementary mechanisms of action. Researchers are also identifying genetic factors that increase the risk of MASH progression, such as mutations in the PNPLA3 gene.
Together, these approaches may reflect a more complete understanding of how liver disease both influences and is influenced by broader cardiometabolic health—and highlight a growing interest in liver health’s effects on other outcomes throughout the body. The expanding range of mechanisms under investigation, along with growing investment across the industry, reflects increasing confidence in the future of MASH drug development.
That confidence is likely to accelerate the pace of innovation. In oncology, cardiovascular disease and diabetes, deeper insights into disease biology have ultimately led to multiple therapeutic classes, combination strategies and increasingly personalized approaches to care. MASH will similarly benefit from continued advances in understanding the disease’s complex biology, further expanding treatment options and supporting more individualized approaches.
Evolving diagnostics and monitoring of MASH
Realizing the full potential of MASH interventions will also depend on identifying and monitoring patients earlier and more effectively. Historically, MASH assessment has relied heavily on liver biopsy to assess disease severity. Advances in noninvasive tests are creating opportunities to assess liver fat and stiffness and other biomarkers of disease activity in a more patient-friendly manner.
This opportunity is particularly important given the substantial gap between the number of people living with MASH and those who have been diagnosed—only about 10% of patients are currently under the care of a specialist who treats the disease. As diagnostic capabilities improve, clinicians may be able to identify patients earlier, monitor treatment response more routinely and intervene before serious liver damage occurs.
The next chapter of MASH will be built on what the first approval makes possible: complementary therapeutic strategies and combinations, genetically targeted approaches informed by disease biology and better tools to identify and monitor patients and run more efficient trials.
The question facing the field is no longer whether progress can be made. It is how far that progress can take us.
