2813-LB: CT-388, a cAMP Signal-Biased GLP-1/GIP Receptor Agonist, Achieves Clinically Meaningful Weight Loss in People With Overweight/Obesity: A 48-Week Phase 2 Study

Introduction and Objective: This trial (NCT06525935) evaluated the efficacy, safety, and dose-response of CT-388 in participants (pts) with overweight/obesity without T2D. Methods: This was a double-blind, placebo-controlled, multicenter trial which enrolled pts with BMI ≥30 kg/m² or BMI ≥27kg/m² with ≥1 obesity-related conditions, of whom 467 were randomized (1:1:1:1:1:1) to treatment with once-weekly subcutaneous CT-388 (target doses: 4, 8, 12, 16, or 24 mg) or volume-matched placebo (Pbo) for 48 weeks. Primary endpoint was % WL from baseline (BL) to Week (W) 48, analyzed using a mixed model for repeated measures based on an ‘efficacy’ estimand. Results: Pts in the study had a mean (SD) age of 49 (13.1) years, BMI of 38 (6.9) kg/m²; 71% were White, 68% women and ~50% had prediabetes (per ADA). Figure shows WL (%) effect of CT-388 vs Pbo. With CT-388 (24 mg) at W48: no WL plateau was observed, 95.7% of pts achieved ≥5% WL, 87.0% ≥10% WL, 47.8% ≥20% WL, and 26.1% ≥30% WL. Among pts with prediabetes at BL, 73% of CT-388 24 mg achieved normoglycemia (vs 7.5% on Pbo). The rate of treatment discontinuations from adverse events were low. GI events were the most frequent. Conclusion: CT-388 demonstrated clinically meaningful, statistically significant dose-dependent WL of up to 22.7% (W48) and safety/tolerability profile consistent with the incretin class. Disclosure I. Lingvay: Consultant; Current; Aadvarak Therapeutics, Abbvie, Alveus Therapeutics, Amgen, Antag Therapeutics, Arrowhead Pharmaceuticals, Astra Zeneca, Baim Institute, Bain Capital, Bayer, Betagenon AB, Bioio Inc., Biomea, Boehringe. Research Support; Current; Novo Nordisk A/S, Dexcom, Inc., Boehringer Ingelheim International GmbH. Consultant; Current; Eli Lilly, Genentech, Janssen/J Current; Amgen, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Rhythm Pharmaceuticals. Other - scientific advisory board; Current; Amgen, AstraZeneca, Boehringer Ingelheim, Biohaven, Eli Lilly, Metsera, Novo Nordisk, Pfizer, Regeneron, Roche/Genentech, Scholar Rock, Structure Therapeutics, Syntis Bio, WW International, Zealand Ph. Other - academic co-founder; Current; State 4 Therapeutics. D. Lender: None. H.E. Bays: Research Support; Current; 89bio, Inc., Alon Medtech/Epitomee, Altimmune, Amgen Inc., AstraZeneca, Bioage, Boehringer Ingelheim International GmbH, Carmot Therapeutics, Inc., Eli Lilly and Company, Graviton, Merck Current; 89bio, Inc., Altimmune, Amgen Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Regeneron Pharmaceuticals Inc., Rivus, Zomagen, zyversa. Research Support; Current; Kailera. Advisory Panel; Current; Merck Current; Genentech, Inc. C. le Roux: Advisory Panel; Current; Novo Nordisk, Lilly, Amgen Inc., Boehringer Ingelheim International GmbH, Pfizer Inc., AstraZeneca, Roche Pharmaceuticals, Herbalife International of America, Inc., Arrowhead Pharmaceuticals, Inc., Medtronic. E. Shearer-Kang: Employee; Current; Genentech, Inc. G. Palermo: Employee; Current; Roche Pharmaceuticals. J. Willis: Employee; Current; Genentech, Inc. A. Steinberg: Employee; Current; Genentech, Inc. Employee; Ended; Carmot Therapeutics, Inc. S.C. Sharp: None. S.B. Bollepalli: None. K.T. Kim: Research Support; Current; Genentech, Inc., Amgen Inc., Eli Lilly and Company, GlaxoSmithKline plc., Sanofi, AstraZeneca, Teva Pharmaceutical Industries Ltd., Regeneron Pharmaceuticals Inc. Funding F. Hoffmann-La Roche, Ltd