Non-Invasive Tests Show Promise for Tracking Treatment Response in Semaglutide MASH Trial

Blood-based biomarkers and imaging measures may eventually serve as practical tools for monitoring disease activity in patients with metabolic dysfunction-associated steatohepatitis (MASH), according to a new analysis.1

The retrospective phase 2b study, which explored the use of various non-invasive tests (NITs) to assess response to semaglutide, adds to growing evidence that the drug not only improves metabolic parameters but may also produce early and measurable liver benefits detectable through blood-based and imaging biomarkers.

The results support the concept that noninvasive tests may serve as meaningful indicators of treatment response and fibrosis improvement in MASH. | Image credit: luchschenF - stock.adobe.com

If these NITs prove useful in further research, write the researchers, they could reduce reliance on repeated liver biopsies, which remain the current standard despite their limitations.

Although biopsy-confirmed histology is required for clinical trials, repeated biopsies are burdensome for patients and challenging for trial execution. As drug development accelerates, there is increasing pressure to validate NITs, such as liver stiffness measurement, fibrosis scores, or circulating biomarkers, as surrogate indicators of treatment response.

This new study, published in Alimentary Pharmacology & Therapeutics, assessed 268 patients with biopsy-confirmed MASH and fibrosis stages F1–F3 who completed 72 weeks of treatment and had both baseline and end-of-treatment biopsy and NIT measurements. Patients had been randomized to receive one of 3 semaglutide doses or a placebo. For this exploratory analysis, all semaglutide doses were pooled to increase statistical power.

The investigators examined 17 unique NITs, including liver enzymes (ALT, AST), CK18 fragments, FibroScan-based metrics (controlled attenuation parameter and liver stiffness measure [LSM]), composite fibrosis scores (FIB-4, ELF, ADAPT), and proprietary biomarker panels such as NIS-4, MASEF, and several SomaSignal tests.

Across the pooled semaglutide group, nearly all NITs showed meaningful reductions from baseline to week 72, with improvements emerging as early as week 28. Measures tied to inflammation, steatosis, or fibrosis demonstrated consistent downward trends. In contrast, the placebo group showed little change, reinforcing that the improvements were treatment related. These findings aligned with biopsy-based assessments from the original study, which showed higher rates of MASH improvement and lower rates of fibrosis progression among semaglutide recipients.

To quantify whether NITs could serve as treatment-response markers, investigators defined “responders” as those achieving a ≥20% improvement in a given NIT (or ≥0.5-unit reduction for ELF based on prior clinical significance criteria). By this definition, semaglutide recipients had significantly more responders across nearly all NITs compared with placebo. For example, large proportions of semaglutide-treated patients demonstrated improved liver stiffness, fibrosis scores, steatosis markers, and inflammatory signatures. These NIT improvements frequently corresponded with histological improvement, supporting their potential utility as surrogate end points.

The study also explored whether baseline NIT levels predicted spontaneous fibrosis improvement or progression in placebo recipients. In this prognostic assessment, lower baseline fibrosis-related NIT scores, such as FIB-4, ELF, PRO-C3, and the SomaSignal fibrosis score, were associated with greater likelihood of improvement. Conversely, higher baseline FIB-4 values were linked to fibrosis progression. These findings suggest that some NITs may capture disease trajectory independent of treatment, though larger validation studies are needed.

Another evaluation focused on whether patients moved across clinically meaningful risk categories after treatment. In subgroups with elevated baseline risk, such as those with liver stiffness ≥8 kPa or ELF ≥9.8, a substantially higher proportion of semaglutide-treated individuals shifted into lower-risk categories compared with placebo. More than half of patients receiving semaglutide with elevated liver stiffness dropped below the 8-kPa threshold by week 72, compared with only 21% of placebo recipients. Similar patterns were observed for higher thresholds (12 kPa) and for ELF-based risk assessments.

“LSM is of considerable interest given that it is already in use clinically to detect fibrosis in hepatic disease as part of risk stratification,” explained the researchers. Moreover, LSM is recommended in MASLD guidelines because of its convenience and low cost.”

Collectively, these results support the concept that NITs may serve as meaningful indicators of treatment response and fibrosis improvement in MASH. However, the authors caution that this analysis was exploratory and not powered for regulatory validation. With no correction for multiple comparisons and the absence of long-term clinical outcomes, additional research, including the ongoing ESSENCE phase 3 trial of semaglutide treatment in patients with MASH,2 is needed before NITs can be adopted as formal surrogate end points.

References

1. Nitze LM, Ratziu V, Sanyal AJ, et al. Exploration of multiple non-invasive tests for assessing response to treatment in a semaglutide phase 2b trial in patients with MASH. Aliment Pharmacol Ther. Published online September 23, 2025. doi:10.1111/apt.70376

2. Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 trial of semaglutide in metabolic dysfunction–associated steatohepatitis. N Engl J Med. 2025;392(21):2089-2099. doi:10.1056/NEJMoa2413258