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 HbA1c<5.7%, changes in each of BMI and BW were -7.2% and -5.7% at Weeks (W) 14 and 17 respectively; HbA1c reduction was significant (P<0.05) 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 (P<0.001) and leptin (P<0.05) were significant and sustained. SBP decreased by 10.5 mm of Hg at W14 (P<0.001), with concurrent changes in insulin, C-peptide, and glucose. Significant reduction (P<0.001) 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.