Abbreviations
- MASH
metabolic dysfunction‐associated steatohepatitis
- NIT
non‐invasive test
- NMA
network meta‐analysis
- RCT
randomised controlled trial
We appreciate the constructive commentary by Soni and Díaz on our network meta‐analysis (NMA) evaluating pharmacological therapies for compensated metabolic dysfunction‐associated steatohepatitis (MASH) cirrhosis [1, 2]. In this synthesis, we found that efruxifermin was the only intervention significantly superior to placebo for ≥ 1‐stage fibrosis improvement without worsening of MASH, whereas efruxifermin, semaglutide + cilofexor + firsocostat and semaglutide were significantly superior to placebo for MASH resolution [2], complementing our previous investigation [3]. The points raised by Soni and Díaz provide a timely contextualisation of our findings within the challenging landscape of therapeutic development in MASH cirrhosis [1]. Herein, we would like to extend this discussion by emphasising the potential role of non‐invasive tests (NITs) in refining the design of MASH randomised controlled trials (RCTs).
We agree that early identification and longitudinal monitoring are critical needs in the care of patients with MASH cirrhosis, especially in trial settings. This concept has recently been further explored through NIT‐based approaches. As noted in the commentary, the SAMARA trial illustrates the feasibility of NIT‐based eligibility criteria, investigating semaglutide in NIT‐assessed at‐risk MASH patients [4]. This strategy may improve patient enrichment and reduce the operational burden associated with biopsy‐based screening, potentially lowering screen failure rates [5, 6]. Beyond risk stratification, however, the field is also moving towards dynamic assessment of treatment response, with increasing interest in NIT‐based changes [7, 8]. For example, recent data suggest that MRI‐proton density fat fraction (PDFF) super‐response (defined as a 50% relative reduction) may predict fibrosis regression in patients with biopsy‐proven MASH and F2‐F3 fibrosis [8]. Although validation in compensated MASH cirrhosis remains necessary, particularly given its phenotypic heterogeneity, architectural distortion and lower hepatic fat content, these findings support further evaluation of NITs as tools for therapeutic monitoring in future RCTs [9].
Treatment duration is another central consideration, as Soni and Díaz note [1]. Fibrosis regression in cirrhosis is biologically slow and relatively short follow‐up may underestimate the antifibrotic potential of some investigated therapies. The SYMMETRY trial [10] is informative in this context, highlighting the importance of longer follow‐up to better capture histological response. This consideration also has important implications for the interpretation of our NMA [2]. As acknowledged in our study, the network was based predominantly on indirect comparisons; therefore, treatment rankings should be interpreted with caution until confirmed in adequately powered phase 3 and/or head‐to‐head RCTs.
Finally, we agree that the clinical heterogeneity of compensated MASH cirrhosis supports refined phenotyping and well‐designed combination strategies [9]. Future RCTs should aim to align therapeutic mechanisms with patient phenotype, considering cardiometabolic risk factors, portal hypertension and background therapies, all of which may influence treatment response and safety.
The authors' declarations of personal and financial interests are unchanged from those in the original article [2].
Author Contributions
Matheus Souza: writing – original draft, writing – review and editing. Daniel Q. Huang: writing – review and editing, supervision. Rohit Loomba: writing – review and editing, supervision.
Funding
D.Q.H. receives funding support from the Singapore Ministry of Health's National Medical Research Council (Grants MOH‐001370 and MOH‐001566) and the NUHS Clinician Scientist Programme (Grant NCSP2.0/2023/NUHS/DH). R.L. receives funding support from NCATS (Grant 5UL1TR001442), NIDDK (Grants U01DK061734, U01DK130190, R01DK106419, R01DK121378, R01DK124318 and P30DK120515), NHLBI (Grant P01HL147835) and John C Martin Foundation (Grant RP128).
Conflicts of Interest
D.Q.H. has served as an advisory board member for Gilead and Roche. R.L. serves as a consultant for Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol‐Myer Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc., Madrigal, Metacrine Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, Terns Pharmaceuticals and Viking Therapeutics. In addition, his institutions received research grants from Arrowhead Pharmaceuticals, Astrazeneca, Boehringer‐Ingelheim, Bristol‐Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Merck, Pfizer, Sonic Incytes and Terns Pharmaceuticals. He is also a co‐founder of LipoNexus Inc.
Linked Articles
This article is linked to Souza et al. papers. To view these articles, visit https://doi.org/10.1111/apt.70824 and https://doi.org/10.1111/apt.70565.
Souza M., Huang D. Q., and Loomba R., “Letter on ‘Network Meta‐Analysis: Comparison of Pharmacological Therapies in Compensated MASH Cirrhosis for Fibrosis Regression and MASH Resolution’. Authors' Reply,” Alimentary Pharmacology & Therapeutics 64, no. 4 (2026): 560–561, 10.1111/apt.70827.
Handling Editor: Grace Wong
Contributor Information
Daniel Q. Huang, Email: daniel_huang@nus.edu.sg.
Rohit Loomba, Email: roloomba@health.ucsd.edu.
Data Availability Statement
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.