Resmetirom, an oral thyroid hormone receptor beta-selective agonist, produced significantly higher rates of both metabolic dysfunction-associated steatohepatitis (MASH) resolution and liver fibrosis improvement compared with placebo at 52 weeks, according to a phase 3 trial published in The New England Journal of Medicine. The finding, from the MAESTRO-NASH study of 966 adults with biopsy-confirmed disease and moderate-to-advanced fibrosis, supported the FDA’s accelerated approval of resmetirom (Rezdiffra) in March 2024, making it the first medicine ever approved for MASH.
Why MASH has needed a treatment
Metabolic dysfunction-associated steatohepatitis, previously known as non-alcoholic steatohepatitis (NASH), is the aggressive form of fatty liver disease. It combines fat accumulation in the liver with inflammation and cell damage, and it can progress to fibrosis, cirrhosis, and liver cancer. Around 5% of U.S. adults are estimated to have MASH, and it is now among the leading indications for liver transplantation in the United States. Until 2024, no medicine had ever been approved specifically for MASH; treatment consisted of weight loss, control of diabetes and cardiovascular risk, and management of complications.
How resmetirom works
Resmetirom is an oral, once-daily agonist selectively targeting thyroid hormone receptor beta (THR-β), a receptor found predominantly in the liver. Activating THR-β accelerates hepatic fat metabolism and reduces the lipotoxic accumulation that drives inflammation and fibrosis in MASH. The drug’s liver-selective design distinguishes it from broad thyroid hormone activation, which would produce cardiac and skeletal side effects. In effect, resmetirom mimics part of the metabolic benefit of thyroid stimulation on the liver without engaging the receptor subtypes responsible for systemic thyroid effects.
How the trial was designed
MAESTRO-NASH was an ongoing, multicenter, randomized, double-blind, placebo-controlled phase 3 trial. Investigators enrolled 966 adults with biopsy-confirmed MASH and a fibrosis stage of F1B, F2, or F3 (on a scale where F0 indicates no fibrosis and F4 indicates cirrhosis). Approximately 60% of participants in each arm had F3 fibrosis, representing advanced but not yet cirrhotic disease. Participants had a mean age of 56.6 years and were predominantly white (89.3%). Metabolic risk factors were common: hypertension in 78.1%, dyslipidemia in 71.3%, and type 2 diabetes in 67.0%. Participants were randomized 1:1:1 to receive resmetirom 80 mg, resmetirom 100 mg, or placebo, all once daily.
The trial had two primary endpoints assessed at week 52: MASH resolution with no worsening of fibrosis, defined as a hepatocellular ballooning score of 0, a lobular inflammation score of 0 or 1, and a reduction of at least 2 points in the NAFLD activity score; and improvement in fibrosis by at least one stage with no worsening of the NAFLD activity score.
What the trial found
Both primary endpoints were met at both doses. MASH resolution with no worsening of fibrosis was achieved in 25.9% of patients on the 80 mg dose and 29.9% on the 100 mg dose, compared with 9.7% on placebo (P<0.001 for both comparisons). Fibrosis improvement by at least one stage with no worsening of MASH occurred in 24.2% on the 80 mg dose and 25.9% on the 100 mg dose, compared with 14.2% on placebo (P<0.001 for both). Both endpoints combined, MASH resolution and fibrosis improvement, were achieved in 10.1% and 16.0% of the two treatment arms respectively, compared with 4.9% on placebo.
Secondary endpoints reinforced the primary findings. LDL cholesterol fell by 13.6% on the 80 mg dose and 16.3% on the 100 mg dose at week 24, compared with essentially no change on placebo. Liver enzymes (ALT, AST, GGT), imaging measures of liver fat (MRI-PDFF), and non-invasive markers of fibrosis all improved with resmetirom relative to placebo.
Side effects and tolerability
The most common adverse events were gastrointestinal, particularly diarrhea and nausea, and were more frequent in the 100 mg group than the 80 mg group. Rates of serious adverse events were similar across treatment and placebo groups. Small elevations in liver enzymes occurred in some treated patients but generally resolved. The label carries recommendations for baseline liver function testing and periodic monitoring during treatment.
How the effect size should be read
Both primary endpoints were statistically significant, but the absolute treatment differences were modest. About 26% to 30% of treated patients achieved MASH resolution, compared with about 10% on placebo, meaning three to four patients would need to be treated for a year to produce one additional MASH resolution. The fibrosis improvement effect was similar in magnitude. These endpoints are surrogate markers, defined on liver biopsy. They correlate with long-term liver outcomes, but the trial’s follow-up is not yet long enough to demonstrate whether resmetirom reduces progression to cirrhosis, liver failure, transplantation, or death. Those hard clinical outcomes are the focus of longer-term extension studies.
What the evidence cannot yet answer
MAESTRO-NASH is an ongoing 54-month trial. Whether resmetirom improves clinical outcomes such as progression to cirrhosis, liver-related mortality, and hepatocellular carcinoma is being evaluated in the longer-term primary composite endpoint, and those data will inform full FDA approval. The population enrolled was predominantly white, and effects in more diverse populations remain to be characterized. Resmetirom was not tested in patients with cirrhosis (F4), so its role in more advanced disease is unknown. The FDA’s accelerated approval was granted specifically for non-cirrhotic MASH with moderate-to-advanced fibrosis (F2-F3), and prescribers must confirm this fibrosis stage, typically with liver biopsy or a validated non-invasive equivalent, before initiating treatment.
What the approval settled
Before resmetirom, MASH was a wait-and-see condition. Patients received lifestyle advice, treatment of related conditions such as diabetes and dyslipidemia, and monitoring, but no medicine specifically targeted the disease itself. The March 2024 approval reframes MASH as an actively treatable disease, alters how hepatologists and primary care physicians discuss diagnosis and prognosis with patients, and creates commercial and scientific incentive for the next generation of MASH drugs, several of which are in phase 3 development. The drug remains an addition to, not a substitute for, weight loss, blood sugar control, and cardiovascular risk reduction, which remain the foundational interventions for patients with fatty liver disease.
The trial authors concluded that “both the 80-mg dose and the 100-mg dose of resmetirom were superior to placebo with respect to NASH resolution and improvement in liver fibrosis by at least one stage.” For patients whose disease was previously followed rather than treated, resmetirom offers a specific pharmacological option, and its arrival is likely to change both how MASH is diagnosed and how it is discussed with the patients who have it.
References
- Harrison SA, Bedossa P, Guy CD, et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. New England Journal of Medicine, 2024; 390: 497-509. DOI: 10.1056/NEJMoa2309000