Biopsy-free MASH trials need longer runs

A letter published in Alimentary Pharmacology & Therapeutics on 10 June 2026 argues that biopsy-free MASH trials need longer follow-up periods and composite non-invasive test (NIT) endpoints to produce clinically meaningful results^[1]. The reply, authored by Veeral Ajmera and Rohit Loomba of UC San Diego, responds to questions about the design of the SAMARA trial, a 52-week study that tested semaglutide against placebo using NIT-based assessments rather than liver biopsy.

What the SAMARA trial showed

SAMARA was a multicentre, randomised, placebo-controlled trial of 55 participants with MASH identified through non-invasive tests rather than biopsy. After 52 weeks, semaglutide produced a greater reduction in FAST score (a composite of liver stiffness, AST, and controlled attenuation parameter) than placebo: -0.28 versus -0.12 (p = 0.002). Sixty percent of semaglutide-treated patients achieved a 30% or greater reduction in liver fat measured by MRI-PDFF, compared with 17% on placebo^[2].

Weight loss was also markedly different between groups: 64% of semaglutide-treated patients lost 5% or more of body weight, versus 8.3% on placebo. Liver enzymes, HbA1c, and LDL cholesterol all improved in the semaglutide arm^[2]. Gastrointestinal side effects (nausea, diarrhoea, constipation) were the most common adverse events, consistent with the known side-effect profile of GLP-1 receptor agonists.

The trial was the first to enrol patients using NITs alone and to track treatment response without requiring a single liver biopsy. That design choice was deliberate: conventional MASH trials lose 70-80% of screened patients at biopsy because the tissue sample fails to confirm the disease^[3]. By eliminating that step, SAMARA aimed to show that NIT-based trials are feasible.

Why the authors say feasibility is not enough

In their reply, Ajmera and Loomba acknowledge that SAMARA demonstrated feasibility but argue the field must now move beyond it^[1]. They make two specific points. First, 52 weeks is too short to capture fibrosis regression, which is the endpoint regulators care about most. The ESSENCE trial, which led to semaglutide's FDA approval for MASH with fibrosis in August 2025, required 72 weeks to show that 37% of patients achieved fibrosis improvement of at least one stage without worsening of steatohepatitis^[4]. ESSENCE is continuing to 240 weeks to track liver-related clinical events.

Second, the authors call for composite NIT endpoints that combine multiple biomarkers rather than relying on any single test. A separate analysis of 17 NITs in a semaglutide phase 2b trial found that all showed significant reductions versus placebo by week 72, but no individual test perfectly predicted histological outcomes^[5]. Fibrosis-related NITs such as FIB-4, liver stiffness measurement, and the enhanced liver fibrosis (ELF) test correlated with biopsy-confirmed fibrosis stage at baseline, yet their ability to track change over time varied. A composite that draws on multiple signals could reduce the noise inherent in any single marker.

The regulatory backdrop

The push for biopsy-free endpoints has regulatory momentum. In September 2025, the FDA accepted a letter of intent from Echosens to qualify liver stiffness measurement by vibration-controlled transient elastography (FibroScan) as the first non-invasive surrogate endpoint in MASH drug trials. That process, backed by Eli Lilly, Boehringer Ingelheim, and Novo Nordisk, is still underway but signals that regulators are open to alternatives to biopsy^[2].

Meanwhile, the phase 3 trial of retatrutide and tirzepatide in MASH, registered in September 2025, dropped biopsy entirely, using ELF and VCTE for both enrolment and secondary outcomes at 104 weeks. If that trial succeeds, it would be one of the first large-scale biopsy-free MASH registration studies.

What this does not tell us

The Ajmera-Loomba letter is a reply to editorial correspondence, not a new study. It does not present new data or a specific composite endpoint design. The SAMARA trial itself enrolled only 55 patients, far too few to validate any NIT against hard clinical outcomes such as cirrhosis progression or liver-related death^[2].

No NIT has yet been formally qualified by the FDA as a surrogate endpoint for MASH. The FibroScan qualification process accepted in September 2025 is still at the letter-of-intent stage, meaning full qualification could take years. A NIT must satisfy three conditions before the FDA will accept it as a reasonably likely surrogate: biological plausibility, epidemiological evidence linking it to patient outcomes, and proof that changes in the NIT correspond to clinically meaningful risk reductions. Until a NIT or composite clears that bar, liver biopsy remains the reference standard for confirmatory trials.

MASH is a condition that requires diagnosis and monitoring by a hepatologist or gastroenterologist. Semaglutide is approved for MASH with moderate-to-advanced fibrosis only under medical supervision. If you have concerns about fatty liver disease, consult a healthcare provider for appropriate evaluation.