Rethinking MASH clinical endpoints: Is liver fibrosis the key predictor of adverse outcomes?

Clinical trials in metabolic dysfunction-associated steatohepatitis (MASH) have traditionally used biopsy-based endpoints, with MASH resolution and fibrosis improvement considered the principal measures of treatment response. However, growing recognition of fibrosis as a key predictor of adverse outcomes, coupled with advances in non-invasive assessment tools, is shaping ongoing debate about the future of endpoint selection in MASH research.

In this Q&A, we spoke with Dr Zobair Younossi (Center for Outcomes Research in Liver Diseases, Washington, DC, USA) about the evolving management of MASH, the growing importance of fibrosis as a predictor of outcomes, and the implications of prioritising fibrosis-focused endpoints in clinical trials and practice.

Abstract: Liver fibrosis is the only predictor of adverse outcomes: time to remove metabolic dysfunction associated steatohepatitis (MASH) resolution as a clinical trial endpoint. EASL 2026, May 27–30, Barcelona, Spain.

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Questions

1. What challenges exist in the management of MASH, and what is the current treatment landscape? (0:41)
2. How does current evidence position liver fibrosis as the key predictor of adverse outcomes in MASH? (3:03)
3. Why is MASH resolution no longer sufficient as a primary clinical trial endpoint? (4:33)
4. How could fibrosis-focused endpoints reshape future MASH trial design? (8:03)
5. What are the clinical implications of prioritising fibrosis over MASH resolution? (9:06)

Transcript

Hi, I’m Zobair Younossi, I’m the Chairman of the Global MASH/NASH Council at the Center for Outcomes Research in Liver Diseases here in Washington, DC. I’m also a Professor of Medicine and Chairman of the Global Center for Liver Outcomes and Policy Research at Georgetown School of Medicine also in Washington, DC. I’m a hepatologist, and I’ve been involved in the field of MASH/MASLD for the past three decades.

What challenges exist in the management of MASH, and what is the current treatment landscape?

One of the biggest challenges that we have currently is that the burden of disease is very high. The prevalence of MASLD is about 30-35%, and the prevalence of the progressive form of MASLD is about 5-7% in the general population, but there is a huge concentration of this disease in patients with type 2 diabetes.

The biggest challenge we have right now is that although we have a large number of patients that may progress to advanced liver disease, awareness about the disease is pretty low in the population as well as in the primary care setting, where a lot of these patients go. In terms of management, the biggest challenge we have is identifying the patients that could potentially be candidates for treatment.

We do have a couple of treatments, resmetirom and semaglutide, available in the United States, which are getting approved across the rest of the world. But the challenge is that although patients will have relatively good responses with these drugs, they aren’t perfect. We need to develop better drugs that will probably combine multiple different drugs that can help patients. I suspect that most patients will not get cured in the same way that patients do from viral hepatitis C or autoimmune liver disease, but at least we could potentially manage their disease in the long term.

So our challenge is to, number one, find the patient that potentially could benefit from treatment. Number two, to find drugs or drug regimens that could have very high efficacy in terms of preventing disease progression to advanced outcomes.

How does current evidence position liver fibrosis as the key predictor of adverse outcomes in MASH?

The most important outcome in any disease, including this one, is liver mortality or development of cirrhosis or liver cancer. Now short of that, we usually develop surrogates. These surrogates are “predictors of this outcome”, and the best predictor in terms of finding out who is going to be at risk of development of adverse outcomes is actually stage of fibrosis.

If patients have a higher stage of fibrosis, especially if fibrosis stage goes from 0 to 4; with 4 being cirrhosis and 0 being no fibrosis. Once patients hit stage 2 or higher, over the long term they tend to develop bad liver disease or risk of of dying from liver disease.

The stage of fibrosis is especially important if the patient has other clinical risk factors. For example, patients with type 2 diabetes or visceral obesity are at a higher risk. Patients who tend to drink, especially if alcohol consumption is episodic or binge drinking, can actually develop more aggressive liver disease.

Why is MASH resolution no longer sufficient as a primary clinical trial endpoint?

Our study was a large dataset of almost 10,000 patients with liver biopsies. Outcomes clearly demonstrated that stage of fibrosis predicts mortality, which was already known. These can either be determined by histology/liver biopsy or increasingly by non-invasive tests, such as transient elastography or enhanced liver fibrosis tests.

Now, the steatohepatitis that we see on the liver biopsy, which tells us the type of disease, is very important in terms of driving fibrosis. In terms of pathogenesis, having steatohepatitis is important, but it really is fibrosis that predicts the outcome.

The second reason is that steatohepatitis itself is diagnozed by biopsy. There is no non-invasive test for steatohepatitis. You have to look at a liver biopsy and see evidence of hepatic steatosis or fatty liver plus some evidence of liver cell damage, what we call ballooning of the hepatocytes or liver cells, which tells us it is steatohepatitis.

There is a lot of variability in the reading of the biopsy among pathologists that makes it very difficult to find patients who can be enrolled in clinical trials. We have had a large number of patients who don’t qualify for clinical trials, because steatohepatitis is a requirement for inclusion. If the purpose of the clinical trials in early phase 2, or even phase 1, is to find a mechanism that drives steatohepatitis, then I think steatohepatitis or MASH is appropriate.

In phase 3 clinical trials, where the ultimate outcome is to improve long-term outcomes like mortality, then use the best predictor of that long-term outcome – in that context, it is the stage of fibrosis or an improvement of fibrosis. Our presentation was that we think that the primary endpoint should be fibrosis improvement, but the secondary endpoint should remain resolution of steatohepatitis, because you may still see that.

I think that should also be a requirement for approval of the drug. Not the only requirement, because some agencies require both fibrosis improvement and also resolution of steatohepatitis, which might not be very reliable in all in cases. The histologic diagnosis of CRF status is done through liver biopsy, which is invasive and requiring that for drug approval, slows down the process.

How could fibrosis-focused endpoints reshape future MASH trial design?

This could make enrollment into clinical trials a little bit easier. We showed in our study that it wasn’t just histologic fibrosis, it was non-invasive surrogate endpoints. Moving away from the requirement of a liver biopsy for enrollment in clinical trials, VCTU or ELF could be used as non-invasive surrogates of fibrosis. Hopefully, that will bring in additional potential companies that will introduce new agents and we will have a more accelerated field, having lots of different agents available for patients.

What are the clinical implications of prioritizing fibrosis over MASH resolution?

Fibrosis is a surrogate of long-term outcomes and especially mortality, while steatohepatitis is a closely tied endpoint to fibrosis which does quite accurately predict the stage of fibrosis, but does not independently predict a long-term outcome.