Poster Presentation Australian and New Zealand Obesity Society Annual Scientific Conference 2024

Glucagon and GLP-1 receptor dual agonist survodutide improved liver histology in people with MASH and fibrosis: Results from a randomized, double-blind, placebo-controlled phase 2 trial (#250)

Morag Nelson 1 , Arun J Sanyal 2 , Pierre Bedossa 3 , Mandy Fraessdorf 4 , Guy W Neff 5 , Eric Lawitz 6 , Elisabetta Bugianesi 7 , Quentin M Anstee 8 , Samina Ajaz Hussain 4 , Philip N Newsome 9 , Vlad Ratziu 10 , Azadeh Hosseini-Tabatabaei 11 , Joern M Schattenberg 12 , Mazen Noureddin 13 , Naim Alkhouri 14 , Ramy Younes 4
  1. Boehringer Ingelheim, North Ryde, NSW, Australia
  2. Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
  3. Liverpat and University of Paris, Paris, France
  4. Boehringer Ingelheim, Ingelheim, Germany
  5. Covenant Metabolic Specialists, LLC , Sarasota & Ft Myers, FL, USA
  6. Texas Liver Institute, University of Texas Health San Antonio, San Antonio, TX, USA
  7. Department of Medical Sciences, Division of Gastroenterology, University of Turin, Turin, Italy
  8. Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
  9. National Institute for Health Research Biomedical Research Centre and the Centre for Liver and Gastrointestinal Research, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
  10. The Institute of Cardiometabolism and Nutrition, Sorbonne Université, Hôpital Pitié–Salpêtrière, Assistance Publique–Hôpitaux de Paris, INSERM Unité Mixte de Recherche Scientifique 1138 Centre de Recherche des Cordeliers, Paris, France
  11. Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
  12. Department of Internal Medicine II, Saarland University Medical Center, Homburg, Germany
  13. Houston Methodist Hospital and Houston Research Institute, Houston, TX, USA
  14. The Texas Liver Institute, University of Texas Health San Antonio, San Antonio, TX, USA

Aims: We report the findings of glucagon receptor/glucagon-like peptide-1 receptor dual agonist survodutide, in metabolic dysfunction-associated steatohepatitis (MASH).

 

Methods: In this phase 2 trial (NCT04771273), 295 people (18–80 years) with biopsy-proven MASH (Non-alcoholic fatty liver disease Activity Score [NAS] ≥4), fibrosis stage F1–F3, and BMI ≥25 kg/m2 were randomised to once-weekly subcutaneous injections of placebo or survodutide 2.4/4.8/6.0 mg (escalated over ≤24 weeks). Primary endpoint was histological improvement of MASH (≥2 point decrease in NAS with ≥1 point decrease in lobular inflammation or ballooning sub-scores) without worsening of fibrosis after 48 weeks’ actual treatment (dose received at start of maintenance phase) in patients with baseline and end-of-treatment biopsies (paired biopsies; n=219).

 

Results: Baseline characteristics were similar across groups. At Week 48, the primary endpoint was reached in 64.3% receiving 2.4 mg survodutide, 83.0% receiving 4.8 mg, and 65.9% receiving 6.0 mg vs 18.2% receiving placebo (p<0.001, all doses). When treated with 6.0 mg survodutide, 50.0% of participants had ≥1 stage improvement in fibrosis without worsening of MASH vs 21.2% with placebo (p<0.001). Mean reduction in alanine aminotransferase from baseline was 37.5–38.0 U/L (baseline: 54.6–59.1 U/L) with survodutide and 6.2 U/L (baseline: 57.8 U/L) with placebo; mean reduction in aspartate aminotransferase from baseline was 28.1–30.9 U/L (baseline: 43.2–48.0 U/L) and 2.9 U/L (baseline: 51.3 U/L), respectively. Adverse events (AE) occurred in 95.0% of participants across all survodutide groups and 91.9% in the placebo group (most commonly gastrointestinal). AEs leading to discontinuation for survodutide and placebo groups were 20.1% and 2.7%, respectively. No unexpected safety issues were reported.

 

Conclusions: Survodutide substantially improved histological activity of MASH without worsening of fibrosis and demonstrated improved fibrosis without worsening of MASH in people with MASH and fibrosis. Survodutide was generally well tolerated and showed benefit in fibrosis management.