1700-P: Durable Cardiometabolic Effects of Utreglutide in Metabolic Dysfunction–Associated Steatotic Liver Disease Patients with Nondiabetic and Prediabetic Status

Introduction and Objective: Utreglutide (UTG, GL0034) is a potent GLP-1RA. This phase 1b/2a trial evaluated its safety and efficacy in subjects with obesity and MASLD. Methods: The study enrolled 48 subjects (BMI≥30 kg/m2, liver fat content≥10% by MRI-PDFF), randomized (3:1) to once-weekly s.c. UTG with dose titration (0.4 to 1.6 mg over 10 weeks) followed by a fixed dose of 2.4 mg for 3 weeks, or placebo for 13 weeks. The biomarkers presented are BMI, body weight (BW), HbA1c, glucose, insulin, C-peptide, systolic BP, MRI-PDFF and leptin. Results: UTG (total dose, 17.6 mg) was well tolerated, with GI events typical of the incretin class. In subjects with HbA1c5.7%, changes in each of BMI and BW were -7.2% and -5.7% at Weeks (W) 14 and 17 respectively; HbA1c reduction was significant (P0.05) at W17. In subjects with HbA1c≥5.7%, lasting changes in BMI and BW observed were -6.8% and -7.1% each, and ≥5% BW loss improved from W14 to W17. Reductions in HbA1c (P0.001) and leptin (P0.05) were significant and sustained. SBP decreased by 10.5 mm of Hg at W14 (P0.001), with concurrent changes in insulin, C-peptide, and glucose. Significant reduction (P0.001) in relative liver fat content of 26% (table). Conclusion: In individuals with obesity and MASLD, 13 weeks of once-weekly UTG dosing resulted in clinically meaningful improvements in cardio-metabolic biomarkers. The data is indicative of potential for monthly dosing in T2D patients. Disclosure R. Thennati: Employee; Current; Sun Pharmaceutical Industries Ltd. V. Burade: Employee; Current; Sun Pharmaceutical Industries Ltd. M. Natarajan: None. P. Shahi: None. R. Nagaraja: None. B. Thorens: Advisory Panel; Current; Sun Pharmaceutical Industries Ltd. R. Pratley: Consultant; Current; Lilly USA LLC. Research Support; Current; National Institutes of Health, Novo Nordisk. Speaker's Bureau; Current; Novo Nordisk. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Current; Novo Nordisk. Consultant; Current; Pfizer Inc., Recordati Rare Diseases Inc., Regeneron Pharmaceuticals Inc., Response Pharmaceuticals, Rona Therapeutics Ltd. Research Support; Current; Sanofi. Consultant; Current; Scholar Rock Inc. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Current; Sun Pharmaceutical Industries Ltd. Consultant; Current; Third Rock Ventures, Verdiva Bio Dev Limited. Research Support; Current; AstraZeneca AB, Boehringer Ingelheim International GmbH, Abbott Laboratories. Consultant; Current; Abbott Laboratories, AbbVie Inc. Other - Consulting; stock options; Current; Altanine, Inc. Consultant; Current; Amgen Inc., AstraZeneca Pharmaceuticals LP. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Current; Bayer AG, Bayer HealthCare Pharmaceuticals Inc. Research Support; Current; Biomea Fusion. Consultant; Current; Boehringer Ingelheim Pharmaceuticals Inc., Carmot Therapeutics, Inc., Corcept Therapeutics. Research Support; Current; Dompé, Eli Lilly and Company. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Current; Eli Lilly and Company. Research Support; Current; Endogenex Inc. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Current; Endogenex Inc. Consultant; Current; F. Hoffmann-La Roche Ltd. Research Support; Current; Fractyl Health, Inc. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Ended; Gasherbrum Bio Inc., Genprex. Consultant; Current; Hanmi Pharm. Co., Ltd. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Ended; Intas Pharmaceuticals Ltd. Research Support; Current; Lexicon Pharmaceuticals, Inc. Consultant; Current; Lexicon Pharmaceuticals, Inc. Speaker's Bureau; Current; Lilly USA LLC. J. Olynyk: None. R. Loomba: Consultant; Current; Aardvark Therapeutics, Altimmune, Arrowhead Pharmaceuticals, AstraZeneca, Cascade Pharmaceuticals, Eli Lilly, Gilead, Glympse bio, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc., Lipidio, Madrig. Stock/Shareholder; Current; Sagimet biosciences. Research Support; Current; Arrowhead Pharmaceuticals, Astrazeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceu. Other - Co-founder of LipoNexus Inc.; Current; Co-founder of LipoNexus Inc.