Real-World Resmetirom Gains in MASH: Naim Alkhouri, MD

Real-world data confirm that resmetirom (Rezdiffra; Madrigal Pharmaceuticals) produces clinically meaningful improvements in liver biomarkers within approximately 6 months of treatment in patients with noncirrhotic metabolic dysfunction–associated steatohepatitis (MASH) and moderate-to-advanced fibrosis, which is earlier than the 52-week readout from the pivotal MAESTRO-NASH trial, explained Naim Alkhouri, MD, FAASLD, chief medical officer at Summit Clinical Research and hepatologist at NorthShore Gastroenterology & Endoscopy Centers.

Alkhouri discussed findings from 2 studies he presented at the 2026 European Association for the Study of the Liver (EASL) Congress. In a real-world cohort of 712 resmetirom users followed for a mean of 5.7 months, roughly 40% to 47% of patients met response thresholds across liver stiffness, alanine aminotransferase (ALT), and the FibroScan AST (FAST) composite biomarker.¹ He also reviewed 2-year data from a compensated MASH cirrhosis cohort, where the ANTICIPATE-NASH scoring tool identified patients at highest risk for liver-related events, specifically those with a baseline clinically significant portal hypertension (CSPH) risk above 25% who did not respond to treatment.²

Alkhouri addressed the implications for combination therapy with glucagon-like peptide 1 (GLP-1) receptor agonists, noting that real-world data show added liver benefit when resmetirom is used alongside GLP-1 agents, with no clinically significant drug-drug interactions.

This interview was edited for clarity.

AJMC: Your real-world data showed clinically meaningful improvements in biomarkers after about 6 months of resmetirom, which was earlier than what was seen in the MAESTRO-NASH trial. What do you think explains that difference?

Alkhouri: Resmetirom is a thyroid hormone receptor β agonist that was approved by the FDA³ and the EMA based on the results of the MAESTRO-NASH trial, where we did an interim analysis after 12 months of treatment and showed MASH resolution and fibrosis regression by at least 1 stage at higher rates than placebo. In this real-world analysis, which we presented at the International Liver Congress, we utilized a large cohort of patients treated with resmetirom outside of a clinical trial, and biomarker assessments were available in some of them after only 6 months of treatment. Of course, we did not do invasive liver biopsies here. We looked at noninvasive biomarkers that tell us there is improvement in the liver, including the liver enzyme ALT; VCTE [vibration-controlled transient elastography], which is an imaging biomarker for liver fibrosis; and liver fat reduction.

We've known for some time that resmetirom probably starts impacting the liver in a positive way before the 1-year mark. We've seen this even in the clinical trials, with improvement in liver enzymes after 12 weeks of treatment and improvement in MRI-PDFF [proton density fat fraction], a quantitative measure of liver fat. These findings come as no surprise, but they also emphasize that what we are seeing in the real world reflects what we saw in the clinical trials and that patients are getting that benefit outside of a rigorous clinical trial, just being seen by their gastroenterologists, hepatologists, and treating physicians.

AJMC: You reported that slightly less than half of patients met response thresholds for FAST score, ALT, and liver stiffness. What do those thresholds represent and why is the FAST score a useful composite measure?

Alkhouri: We noticed that around 40% to up to 48% of patients had improvement in at least 1 of these biomarkers: ALT improvement by 17 U/L from baseline, or 20%, which has been associated with histologic improvement in previous studies; reduction in liver stiffness by 25% from baseline, which can also predict fibrosis improvement; and reduction in liver fat. The FAST score is a particularly useful composite because it incorporates liver stiffness for fibrosis, the CAP score for steatosis, and the liver enzyme AST. In that way, it is a combination biomarker that gives a global assessment of disease activity. About 45% of patients had a clinically meaningful reduction in their FAST score of more than 0.22.

AJMC: In the real-world study, GLP-1 co-use didn't dramatically change ALT or AST outcomes, but there were differences in liver stiffness and FIB-4. What's your read on the role of combination therapy going forward?

Alkhouri: Many patients who come to our hepatology clinics are already on a GLP-1 receptor agonist such as semaglutide [Wegovy; Novo Nordisk] or tirzepatide [Mounjaro; Eli Lilly and Company] typically for a different indication: type 2 diabetes or obesity. There are no drug-drug interactions to worry about when adding resmetirom on top of a GLP-1 agent, and we've actually seen added benefit from a liver perspective by combining them.

We've also seen high discontinuation rates of GLP-1 receptor agonists in the real world, so patients who do not tolerate a GLP-1 can be switched to resmetirom, and then a GLP-1 can be added back on top of resmetirom for other indications. For example, if we start resmetirom in someone with MASH and advanced fibrosis who still needs better glycemic control, a GLP-1 can definitely be added.

In some real-world settings, about 20% of patients, and in some cases higher, are already on a GLP-1 when they start resmetirom. We're seeing people switch from a GLP-1 to resmetirom because of tolerability, and we're also seeing the combination used in a growing percentage of patients, especially those with type 2 diabetes.

AJMC: The ANTICIPATE-NASH findings suggest that patients with a baseline CSPH risk above 25% who don't respond to treatment are at the highest risk for liver-related events. How should that shape how clinicians monitor and manage patients with compensated MASH cirrhosis on resmetirom?

Alkhouri: Let me provide some background. Resmetirom is indicated to treat patients with MASH and F2 to F3 fibrosis. We do not yet have an indication for patients with cirrhosis. There is an ongoing phase 3 clinical trial that will provide that answer. But as part of a study called MAESTRO-NAFLD-1 [NCT04197479], we had an open-label extension arm where we treated a cirrhotic cohort. We treated 180 patients with compensated MASH cirrhosis with resmetirom for 1 year; there was a gap period of about 77 days, and then we treated them for another year, so we have patients with cirrhosis treated for a total of 2 years. We started with 180 patients in the first cohort and continued treatment for 2 years in 122 patients.

In patients with cirrhosis, not all have what we call clinically significant portal hypertension [CSPH], and the presence of CSPH indicates higher rates of liver outcomes such as variceal bleeding, encephalopathy, and ascites. We have traditionally used the Baveno criteria to diagnose CSPH in chronic liver disease, and that includes liver stiffness by VCTE as a measure of fibrosis and platelet count. But it does not include BMI [body mass index], and we know BMI affects liver stiffness. That's why we started using the ANTICIPATE-NASH score, which incorporates liver stiffness by VCTE, platelet count, and BMI. The higher the ANTICIPATE-NASH risk score, the more likely the patient will develop outcomes.

We divide patients into 4 risk categories: less than 25%, 25% to 50%, 50% to 75%, and greater than 75%. That highest-risk group has the highest rates of developing outcomes over a 3-year period. What we learned from the open-label cirrhosis cohort is that at baseline, about 44% of patients had an ANTICIPATE-NASH score above 50%, and by the end of year 2, that percentage had decreased to about 25%. We anticipate those patients will develop fewer outcomes because of that reduction.

When we looked at the outcomes that developed in this trial, they only occurred in patients with an ANTICIPATE-NASH score above 25% who did not also decrease their score in response to resmetirom. The totality of the data supports, first, that resmetirom is improving CSPH, and second, that we're now better able to identify which patients should be monitored most closely and predict who is likely to develop outcomes. Platelet count is another important factor—the lower the count, the higher the risk. We've seen some preliminary data suggesting there may also be an increase in platelet count with resmetirom treatment, which is another encouraging finding.

AJMC: The ANTICIPATE-NASH score identified which cirrhosis patients were at risk for liver-related events with strong accuracy. How practical is it to apply in a community gastroenterology or hepatology setting vs an academic or research center?

Alkhouri: Diagnosing CSPH in patients with compensated cirrhosis is very important and has direct clinical consequences. Once we diagnose CSPH, these patients benefit from being on a nonselective beta-blocker—specifically carvedilol, propranolol, or nadolol—because starting these medications can decrease the risk of liver events such as encephalopathy, ascites, and variceal bleeding. So it is very important for the practicing clinician, when they have a patient with cirrhosis, to classify them: do they have CSPH or not? And if they do, they need to start appropriate treatment.

The ANTICIPATE-NASH score is easy to calculate. There is an online calculator. It has added benefit over the Baveno criteria because it incorporates BMI alongside liver stiffness and platelet count, accounting for a factor the Baveno criteria misses. That said, I can tell you that many of my colleagues are not yet familiar with it and are not using it routinely in their clinical practice. There is definitely a knowledge gap and educational work that needs to happen for this to become part of standard of care.

References

1. Alkhouri N, Kim Y, Johnston K, et al. Early real-world effectiveness of resmetirom in adults with metabolic dysfunction associated steatohepatitis and moderate-to-advanced fibrosis. Presented at: EASL Congress 2026; Barcelona, Spain; May 27-30, 2026. Abstract 174.

2. Alkhouri N, Raub R, Lu X, Schattenberg JM, Noureddin M. Baseline ANTICIPATE score and response predicts liver outcome events in an 180 patient MASH cirrhosis cohort treated with resmetirom. Presented at: EASL Congress 2026; Barcelona, Spain; May 27-30, 2026. Abstract 3320.

3. Joszt L. FDA approves resmetirom, first treatment for NASH with liver fibrosis. AJMC®. March 14, 2024. Accessed June 11, 2026. https://www.ajmc.com/view/fda-approves-resmetirom-first-treatment-for-nash-with-liver-fibrosis