In March 2024, the US Food and Drug Administration approved Rezdiffra (resmetirom) for the treatment of adults with metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced liver scarring (fibrosis), to be used along with diet and exercise. Rezdiffra is the first and only treatment for MASH approved by FDA.  According to materials from Madrigal Pharmaceuticals presented at the 43rd Annual J.P. Morgan Healthcare Conference in January, Resmetirom's full-year 2024 net sales ranges of  $177 million to $180 million. By the end of 2024, over 11,800 patients are on therapy. [1]

In October 2024, semaglutide reported Phase 3 clinical trial results for patients with F2-F3 stage MASH and plans to submit a marketing application in 2025. The analysis demonstrated that the trial met both primary endpoints, with a 2.4 mg dose of semaglutide significantly improving liver fibrosis in MASH patients compared to placebo, without worsening liver inflammation. Additionally, semaglutide promoted the resolution of liver inflammation without aggravating liver fibrosis. [2]

On January 27, 2025, Akero Therapeutics announced that its investigational drug, Efruxifermin, significantly reversed stage 4 MASH-related cirrhosis in the Phase IIb SYMMETRY study. Data showed that among patients with baseline and week 96 biopsies (n=134), 39% of patients treated with 50mg EFX (n=46) (p=0.009) experienced reversal of cirrhosis with no worsening of MASH, compared to 15% for placebo (n=47). To date, no drug has shown a statistically significant effect in reversing MASH-induced cirrhosis. This milestone achievement marks a major breakthrough in the history of MASH drug development.  [3]

Figure 1. Efruxifermin Phase 2b SYMMETRY Study

About MASH

MASH is a chronic liver disease characterized by a buildup of fat in the liver, causing inflammation and potential damage to liver cells, often linked to metabolic conditions like obesity, diabetes, and high cholesterol, and occurring in individuals who do not consume excessive alcohol; essentially, it's a severe form of fatty liver disease with significant inflammation and potential for liver fibrosis (scarring) if left untreated. 

MASH is classified into stages F0 to F4 based on the degree of fibrosis. F0–F1 indicates no or mild fibrosis, F2–F3 represents moderate to advanced fibrosis, and F4 signifies cirrhosis. Stages F2–F3 are the key phases for optimal treatment and new drug development.

Once patients progress to MASH with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis), the risk of adverse liver outcomes increases dramatically. These patients face a 10–17 times higher risk of liver-related mortality compared to those without fibrosis. Progression to cirrhosis increases this risk up to 42 times, highlighting the critical need to treat MASH before cirrhosis-related complications develop.

Potencial Therapies

Currently, over 500 MASH therapies are in development worldwide, with 5 drugs having advanced to Phase 3 clinical trials. These candidates have shown promising results, and several are expected to gain regulatory approval in the coming years.

Table 1. MASH pipelines

The development of MASH therapies primarily focuses on targeting metabolic dysfunction, inflammation, and fibrosis. Key mechanisms involve FGF21, THRβ, and PPAR, which play direct roles in disease modulation. FGF21 and PPAR are broadly expressed across various tissues, effectively enhancing lipid metabolism, reducing inflammation, and slowing the progression of fibrosis. In contrast, THRβ is predominantly active in the liver, exerting metabolic effects mainly through lipid-lowering pathways. Additionally, GLP-1 acts indirectly in the gut, pancreas, and other tissues, helping regulate blood glucose levels, suppress appetite, promote weight loss, and offering hepatoprotective benefits.

Figure 2. Key mechanisms of MASH therpies

References:
[1] https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal-pharmaceuticals-announces-preliminary-fourth-quarter
[2] https://pmc.ncbi.nlm.nih.gov/articles/PMC11784563/
[3] https://ir.akerotx.com/news-releases/news-release-details/akero-therapeutics-reports-preliminary-topline-results-showing