Lee M. Kaplan, Elena Startseva, Carel W. le Roux, Sean Wharton, Biykem Bozkurt, Daniel F. Mazo, J. von Schlippenbach, Sandra González Maldonado, Samina Ajaz Hussain, Guy W. Neff, Yaneicy Gonzalez Rojas, Charles Smith, Ramy Younes, Arun J. Sanyal, on behalf of the SYNCHRONIZE-MASLD Investigators, Antonio O. Martin, Mark Leibowitz, Douglas Denham, Kevin Korenblat, Michael Herman, Shekhar Challa, Rasha Youssef, Masi Khaja, Apinya Vutikullird, Humberto Aguilar, Naga Chalasani, James Maher, Ronald Surowitz, Cassandra Steimle, Yaneicy G. Rojas, Antonio Sanchez, Ruth E. Kavcioglu, Julio Vijil, Robert Perry, Guy Neff, Martha G. Navarro, Omer Khalid, Rizwana Mohseni, Julie Vu, Gregg Lucksinger, Satish Iduru, Dmitry Shuster, Bruce Segal, Paul Hellstern
Abstract Survodutide is a glucagon receptor/glucagon-like peptide-1 receptor dual agonist under investigation for treating obesity and related diseases. The SYNCHRONIZE-MASLD phase 3, randomized, double-blind, placebo-controlled trial included 216 adults (131 female and 85 male) with obesity (defined as a body mass index ≥30 kg m − 2 or ≥27 kg m − 2 with at least one obesity complication) and at-risk metabolic dysfunction-associated steatotic liver disease (MASLD), defined by MASLD with evidence of liver inflammation and/or fibrosis by noninvasive tests (NITs) or biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH). Participants were randomized (2:1) and treated with once-weekly subcutaneous injections of survodutide 6.0 mg ( n = 146) or placebo ( n = 70). The co-primary endpoints, ≥30% reduction in magnetic resonance imaging-proton density fat fraction (MRI-PDFF)-assessed liver fat content (LFC) and percentage change in body weight (both baseline to week 48), were met. In total, 84.2% of survodutide-treated patients versus 24.3% of placebo-treated patients had ≥30% reduction in LFC using the efficacy estimand ( P < 0.0001; treatment regimen estimand: 68.5% versus 28.6%, respectively; P < 0.0001). Mean percentage change in body weight was −12.2% with survodutide and −1.0% with placebo using the efficacy estimand ( P < 0.0001; treatment regimen estimand: −8.7% versus −1.4%, respectively; P < 0.0001). The most frequently reported adverse events with survodutide were gastrointestinal, commonly occurring during dose escalation, and were generally of mild-to-moderate severity. In adults with obesity and at-risk MASLD, survodutide treatment was statistically and clinically superior to placebo for reductions in MRI-PDFF-assessed LFC and body weight. Limitations included short trial duration (48 weeks) and limited global reach (participants recruited in the United States and Spain).