MASH Cirrhosis Trials Lack Consistent End Points

Clinical trials of therapies for metabolic dysfunction-associated steatohepatitis (MASH) cirrhosis suffer from a lack of consistent end points and a lack of consensus about how to define efficacy.

Those are the key takeaways from a new systematic review of phase 2 and 3 trials of novel MASH cirrhosis therapies. The review was published in the Journal of Clinical Medicine.¹

The search for improved therapies for MASH and metabolic dysfunction-associated fatty liver disease (MASLD) more broadly is important because the latter has an estimated global prevalence of 35%, the authors noted.² Still, current management strategies for MASH are focused on things like diet and exercise and managing comorbidities, they noted. Such measures often fail to achieve long-term disease control, they said.

In recent years, a number of therapies have been developed that could potentially help certain patients with MASH, including the selective thyroid hormone receptor-β agonist resmetirom (Rezdiffra; Madrigal) and the glucagon-like peptide-1 receptor agonist semaglutide (Wegovy; Novo Nordisk).

“Despite these therapeutic advances, no pharmacological therapy has yet been approved specifically for adults with MASH-related cirrhosis (stage F4) and treatment options in this population remain limited,” the authors wrote.

Part of the issue, the authors said, is that as scientists have gained a better understanding of the pathophysiology of the disease, they have developed a wide range of potential therapeutic targets, including metabolic modulators, antifibrotic therapies, bile acid pathway modulators, and apoptosis and inflammation inhibitors. Yet, the diversity of those targets has also sparked a diversity of potential end points. That diversity of end points, in turn, makes it hard for regulators to compare and interpret results across trials.

“The aim of the present study was to systematically identify, categorize, and critically assess the end points reported in phase 2 and 3 clinical trials of new therapies for MASH cirrhosis, with particular focus on their consistency across studies,” the authors wrote.

The investigators searched three scientific databases seeking phase 2 and 3 trials of novel MASH cirrhosis therapies. To be included in the review, trials needed to involve adult patients with biopsy-confirmed MASH cirrhosis. The trials utilized a range of outcomes, including clinical, histological, hemodynamic, imaging, and laboratory outcomes.

The authors found a total of 9 trials that met their inclusion criteria, all but one of which was a phase 2 trial. Three of the trials studied the pan-caspase inhibitor emricasan, one studied semaglutide, and the 5 other trials targeted various pathways.

The primary end points of the trials differed largely based on the intended mechanism of action, the authors found. Studies of antifibrotic strategies tended to focus on histological outcomes assessed via liver biopsy, they said. The most frequently used of those end points was improvement of liver fibrosis by at least one stage without worsening of steatohepatitis.

Studies assessing portal hypertension and the risk of clinical decompensation and hemodynamic assessment of portal pressure tended to be the primary outcome. This was generally achieved by measuring hepatic venous pressure gradient. Still, the authors said it was notable that hemodynamic parameters were not more common, given that they have established prognostic value.

The authors also found that biochemical metrics and imaging-based markers were often used as secondary or exploratory end points. Patient-centered outcomes were “notably underrepresented,” the authors said, and were generally used as exploratory outcomes when included in trials.

The authors concluded that the lack of consistency in which end points were used and how they were measured in these clinical trials points to a larger problem that may be holding back meaningful therapeutic advances in MASH cirrhosis.

“Our findings support the need for a more standardized and transparent end point framework, with clear distinction between primary, secondary, and exploratory outcomes,” they said.

They said future studies should consider composite strategies incorporating non-invasive biomarkers, hemodynamic assessment, and clinically meaningful outcomes, along with patient-reported measures.

“Consensus-driven efforts—particularly through multi-society collaborations—will be essential to define core outcome sets suitable for cirrhosis-stage disease,” they said.

References

1. Żurakowski G, Wiela-Hojeńska A, Petryszyn P. Primary, secondary and exploratory endpoints in phase 2 and 3 clinical trials with novel therapies in MASH cirrhosis: a systematic review. J Clin Med. 2026;15(7):2621. Published 2026 Mar 30. doi:10.3390/jcm15072621

2. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73-84. doi:10.1002/hep.28431