Image Citation: [1]
Written by Matthew Liu ‘26
Edited by Yilin Xie ‘26
For a long time, metabolic dysfunction-associated steatohepatitis (MASH) has been known to be a leading driver of liver failure and the increasing need for liver transplantation. Around 5% of the world’s adults are affected by MASH, representing a high global prevalence [2]. Despite the vast knowledge of the mechanisms behind this disease and the clear need for a cure, while there have been many initially promising drug candidates, they have been abandoned due to modest efficacy combined with safety risks: so far, there has not been a successful treatment for MASH. Recently, the FDA approved Madrigal Pharmaceuticals’s drug resmetirom, which has been shown to reduce scar tissue in the liver and other hallmarks of the disease.
What is MASH?
MASH is an advanced stage of the metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD happens when your liver starts to store fat, which it does not normally do [3]. For most people, this often does not cause issues, but when the fat (steato-) starts to cause inflammation (-hepatitis), then it results in MASLD as the inflammation disrupts cellular activity. Most liver diseases are associated with heavy alcohol use, but MASLD can affect even those with low alcohol use. Researchers are not entirely sure what causes MASLD or why some people seem to have a predisposition, but studies have shown a positive correlation between certain conditions with high blood lipid levels (e.g., obesity, high cholesterol, high blood pressure, diabetes) and demographic factors, such as Hispanic or Asian ethnicity and being over the age of 40 years old [4].
While MASH is not necessarily life-threatening, when it is present alongside with other risk factors, it can increase the risk of end-stage liver disease, which is terminal. It can also cause fibrosis, leading to an unprecedented increase in scar tissue and functional decline of the liver [5]. Additionally, there is an increased risk of other diseases, such as heart attack and stroke, since comorbidities (having more than one disease present) tend to accelerate the progression of inflammation and damage [3]. As a result, there is a clear need for viable medications that can help people with MASH manage their symptoms. Until resmetirom, there had not been any effective candidate that made it past Phase 3 clinical trials, which test the safety and compares the new treatment with a standard treatment.
Enter Resmetirom
Resmetirom works by increasing the liver’s sensitivity to thyroid hormone, which can stimulate the beta-oxidation of fatty acids [4]. Beta-oxidation is the process of metabolizing fatty acids; as a result, this causes more fatty acids to be released and less fat to be stored in adipocytes (special cells that serve as fat reserves), leading to less stress on the liver. In a Phase 3 clinical trial, resmetirom reduced fat build-up by 30% compared to 10% in the placebo and reduced fibrosis by 26% compared to 14% in the placebo [2]. The reduction in fibrosis is especially important because it makes resmetirom the first MASH drug to reduce scar tissue, meaning that it can be useful for those with moderate to severe liver scarring. Furthermore, the drug had only mild side effects, suggesting that resmetirom could be used to improve patients’ wellbeing [3]. It is important to note that the FDA granted accelerated approval, which means that Madrigal Pharmaceuticals would need to be able to provide long-term evidence that resmetirom has any meaningful effects — all the studies to date have been short-term. While it can be sold on the market for now, if there is no statistically significant evidence that the drug improves survival, then pharmaceutical companies will be back to square one in trying to synthesize an effective drug.
Concerns about Long-Term Benefits
In the meantime, there are ongoing studies for other compounds. One study is testing semaglutide, a common weight-loss drug, against MASH since weight loss has been correlated with decreased severity, but further trials will need to be done [5]. At the moment, resmetirom can serve as the best resource for MASH, but there needs to be a clear knowledge about the limited data and that it will work best combined with other methods. Physicians recommend managing blood lipid levels through maintaining a healthy weight, eating a diet that is low in cholesterol, getting exercise, and avoiding carcinogens in addition to taking resmetirom [3]. Another issue that arises is access: many people who need treatment are often part of disadvantaged communities in which obesity and diabetes are prevalent but access to quality health care is not [2]. Moreover, since the clinical trials were solely conducted in the United States, access in other countries will have to wait until their populations are considered and tested. Despite the multiple unknown variables in relation to its future, resmetirom has shown promise and has been given the green light to curb a previously untreatable obesity-linked liver disease that is on the rise globally.
References
[1] Kale DV. What is drug-induced liver disease? [Internet]. Dr. Vikrant Kale. 2023 [cited 2024 Nov 19].
Available from:
[2] Ledford H. First US drug approved for a liver disease surging around the world. Nature [Internet].
2024 Mar 15 [cited 2024 Apr 9]; Available from: https://www.nature.com/articles/d41586-024-00747-9
[3] Cleveland Clinic [Internet]. [cited 2024 Apr 9]. Metabolic Dysfunction-Associated Steatohepatitis:
What It Is, Causes. Available from: https://my.clevelandclinic.org/health/diseases/22988-nonalcoholic-steatohepatitis
[4] Harrison SA, Bedossa P, Guy CD, Schattenberg JM, Loomba R, Taub R, et al. A Phase 3,
Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. N Engl J Med. 2024 Feb 8;390(6):497–509.
[5] Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V, et al. A Placebo-Controlled
Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N Engl J Med. 2021 Mar 25;384(12):1113–24.
Comments