Expert Delphi Consensus on Surrogate Endpoints for Treatment Assessment in Metabolic Dysfunction-associated Steatohepatitis

Arun J Sanyal; Atsushi Nakajima; Elisabetta Bugianesi; Giada Sebastiani; Jörn M Schattenberg; Leon A Adams; Mazen Noureddin; Masato Yoneda; Pierre Bedossa; Zobair M Younossi; Assim A Alfadda; Andreas Geier; Frank Tacke; Giulio Marchesini; Giovanni Targher; Hussain Abdulrahman Al-Omar; Hannes Hagström; Juan G Abraldes; Jerome Boursier; Kento Imajo; Kwabena Opuni; Luis Calzadilla Bertot; Naim Alkhouri; Nobuharu Tamaki; Rohit Loomba; Riku Ota; Raluca Pais; Scott L Friedman; Saumya Jayakumar; Salvatore Petta; Vlad Ratziu; Vincent Wai-Sun Wong

doi:10.1016/j.cgh.2025.12.001

Expert Delphi Consensus on Surrogate Endpoints for Treatment Assessment in Metabolic Dysfunction-associated Steatohepatitis

Clin Gastroenterol Hepatol. 2025 Dec 6:S1542-3565(25)01014-6. doi: 10.1016/j.cgh.2025.12.001. Online ahead of print.

Authors

Arun J Sanyal¹, Atsushi Nakajima², Elisabetta Bugianesi³, Giada Sebastiani⁴, Jörn M Schattenberg⁵, Leon A Adams⁶, Mazen Noureddin⁷, Masato Yoneda², Pierre Bedossa⁸, Zobair M Younossi⁹, Assim A Alfadda¹⁰, Andreas Geier¹¹, Frank Tacke¹², Giulio Marchesini¹³, Giovanni Targher¹⁴, Hussain Abdulrahman Al-Omar¹⁵, Hannes Hagström¹⁶, Juan G Abraldes¹⁷, Jerome Boursier¹⁸, Kento Imajo², Kwabena Opuni¹⁹, Luis Calzadilla Bertot²⁰, Naim Alkhouri²¹, Nobuharu Tamaki²², Rohit Loomba²³, Riku Ota¹⁹, Raluca Pais²⁴, Scott L Friedman²⁵, Saumya Jayakumar²⁶, Salvatore Petta²⁷, Vlad Ratziu²⁴, Vincent Wai-Sun Wong²⁸

Affiliations

¹ Virginia Commonwealth University, Richmond, Virginia. Electronic address: arun.sanyal@vcuhealth.org.
² Yokohama City University, Yokohama, Japan.
³ Department of Medical Sciences, University of Turin, Turin, Italy.
⁴ McGill University Health Centre, Montreal, Quebec, Canada.
⁵ Department of Internal Medicine II, Saarland University Medical Center, Homburg, and Saarland University, Saarbrücken, Germany.
⁶ Department of Hepatology, Medical School, The University of Western Australia, Sir Charles Gairdner Hospital, Perth, Australia.
⁷ Houston Methodist/Weill Cornell Medical College, 8 Houston Research Institutes, Houston, Texas.
⁸ Groupe Hospitalier Paris Nord, Hôpital Beaujon, Paris, France.
⁹ The Global NASH/MASH Council (GNC), Washington, District of Columbia.
¹⁰ Obesity Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia; Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
¹¹ Division of Hepatology, Department of Medicine II, University Hospital Wuerzburg, Wuerzburg, Wuerzburg, Germany.
¹² Charité - Universitätsmedizin Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany.
¹³ University of Bologna, Bologna, Italy.
¹⁴ University of Verona, Verona, Italy.
¹⁵ Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
¹⁶ Department of Medicine, Huddinge, Karolinska Institute, Stockholm, Sweden & Division of Hepatology, Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden.
¹⁷ Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Alberta, Canada.
¹⁸ Centre Hospitalier Universitaire d'Angers, HIFIH Laboratory, SFR ICAT 4208, Angers University France, Angers, France.
¹⁹ Novo Nordisk A/S, Bagsværd, Denmark.
²⁰ Department of Hepatology, Medical School, The University of Western Australia, Sir Charles Gairdner Hospital, Perth, Australia; CIBER Liver and Digestive diseases (CIBEREHD), Seville, Spain.
²¹ Summit Clinical Research, San Antonio, Texas.
²² Musashino Red Cross Hospital, Tokyo, Japan.
²³ MASLD Research Center, University of California at San Diego, La Jolla, California.
²⁴ Sorbonne Université /Hôpital Pitié-Salpêtrière/ICAN (Institute of Cardiometabolism and Nutrition), Paris, France.
²⁵ Icahn School of Medicine at Mount Sinai, New York, New York.
²⁶ University of Alberta, Edmonton, Alberta, Canada.
²⁷ Section of Gastroenterology, PROMISE Department, University of Palermo, Palermo, Italy.
²⁸ State Key Laboratory of Digestive Disease, Department of Medicine and Therapeutics, Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong, China.

PMID: 41360159
DOI: 10.1016/j.cgh.2025.12.001

Abstract

Background & aims: The growing burden of metabolic dysfunction-associated steatohepatitis (MASH) and the urgency for effective therapies have driven the adoption of surrogate endpoints for treatment evaluation. Consensus on the most appropriate measures for regulatory approval, clinical practice, or reimbursement remains limited. This study aimed to establish expert consensus on appropriate surrogate endpoints and potential surrogate outcome measures in MASH.

Methods: A modified Delphi process was conducted with 23 international experts across hepatology, gastroenterology, and others. A targeted literature review informed 2 structured survey rounds. Round 1 addressed measures relevant to establishing efficacy/effectiveness for reimbursement; Round 2 explored their application for monitoring treatment effectiveness in clinical practice. Consensus was defined as ≥75% agreement, and strong consensus as ≥95%. The process was conducted and reported in accordance with established frameworks, including Conducting and REporting DElphi Studies (CREDES).

Results: Histological endpoints-specifically, ≥1-stage fibrosis improvement without MASH worsening, and MASH resolution without fibrosis worsening-were considered appropriate for regulatory/reimbursement settings, mostly owing to current regulatory guidelines. In clinical practice, noninvasive tests (NITs) were preferred. There was consensus that a ≥30% reduction in liver stiffness measurement (LSM) assessed via vibration-controlled transient elastography (VCTE) or magnetic resonance elastography (MRE) is a meaningful indicator of treatment response and reasonably likely translates to improved long-term outcome benefit. Consensus also supported replacing liver biopsy with NITs in practice.

Conclusions: This international Delphi study highlights histological and NIT-based measures as key for MASH treatment evaluation. It also supports a shift toward NITs-particularly LSM by VCTE or MRE-for disease monitoring in routine practice, with implications for trial design, reimbursement, and clinical guidelines.

Keywords: Delphi Consensus; MASH; Noninvasive Tests; Surrogate Endpoints; Treatment Efficacy.