Fat buildup in the liver can escalate into metabolic dysfunction-associated steatohepatitis (MASH), a severe form of metabolic liver disease formerly known as nonalcoholic steatohepatitis (NASH). Characterized by inflammation and fibrosis, MASH heightens the risk of liver failure, yet it remains largely untreated — only one Food and Drug Administration (FDA)-approved therapy currently exists. Now, a Phase 2b trial of denifanstat, an oral fatty acid synthase inhibitor developed by Sagimet Biosciences, offers new hope (1). 

“There’s a very close association between obesity and having liver fat,” said Magda Montgomery, a metabolism researcher at the University of Melbourne who did not participate in this work. Given the global obesity epidemic, fatty liver diseases are expected to become more prevalent. “So, we definitely need new drugs to target MASH; it’s urgent,” she added. 

Fatty acid synthase is one of the major enzymes driving the conversion of carbohydrates to fats. Thus, inhibitors like denifanstat block this enzyme, preventing fat accumulation and potentially reducing subsequent liver damage and inflammation (2). 

We definitely need new drugs to target MASH; it’s urgent.
- Magda Montgomery, University of Melbourne

To gauge denifanstat’s efficacy, the researchers enrolled 168 participants who received either 50 mg of the drug or a placebo daily for up to 52 weeks. The team measured MASH improvement through a liver biopsy where they assessed disease activity and changes in fibrosis, alongside blood-based MASH-related biomarkers to evaluate how well the drug worked. 

Among participants who received at least one dose of denifanstat, 38 percent achieved a meaningful improvement in disease activity — including decreased surface area with abnormal fat infiltration in the liver and/or fewer numbers of ballooned hepatocytes — compared to 16 percent on placebo. Moreover, 26 percent of the denifanstat group achieved MASH resolution — no or very little liver fat present — versus 11 percent on placebo. For people who stayed on the treatment for a minimum of 42 weeks, the results were even stronger: 52 versus 20 percent showed meaningful improvement in disease activity and 36 versus 13 percent achieved MASH resolution. Denifanstat also significantly stopped additional fibrosis from occurring and in some cases healed existing fibrosis, compared to placebo. 

These improvements were quite pronounced, said Montgomery. She cautioned, however, that relying on liver biopsy-based scores as the primary indicator has limitations. “The human liver is huge,” she explained, and liver biopsies only capture a tiny piece of it. “Not every single part of the liver has the same problem; some areas of the liver will have a lot of fibrosis and a lot of fat, and then a different lobe might not.” She noted that this is a common challenge in liver research, and not specific to this trial, as liver biopsy remains the gold standard for MASH diagnosis and monitoring. Of note, patients with MASH treated with denifanstat also showed improvement in other biomarkers associated with the disease such as reduced levels of alanine aminotransferase, an enzyme linked to liver damage, and lower low-density lipoprotein (LDL) cholesterol levels. 

Despite the biopsy limitation, the trial was very impactful, said Montgomery, and she thinks that the results definitely merit a Phase 3 trial. 

Although the drug did not cause serious adverse events, some participants experienced hair thinning as a notable side effect. Half of the patients in the denifanstat group who stopped the treatment did so because of this issue. “We will continue to monitor for this signal,” said coauthor Rohit Loomba, a liver doctor at the University of California, San Diego, who consults for multiple pharmaceutical companies. Loomba and his colleagues are planning to develop a strategy, such as incorporating vitamin supplementation, to support patients experiencing hair thinning due to denifanstat treatment. 

Based on these Phase 2b trial results, Sagimet Biosciences is planning to advance to a Phase 3 trial. 

References

1. Loomba, R. et al.  Denifanstat for the treatment of metabolic dysfunction-associated steatohepatitis: a multicentre, double-blind, randomised, placebo-controlled, phase 2b trial. Lancet Gastroenterol Hepatol  9, 1090-1100 (2024).
2. O’Farrell, M. et al.  FASN inhibition targets multiple drivers of NASH by reducing steatosis, inflammation and fibrosis in preclinical models. Sci Rep  12,15661 (2022).