Abstract Disclosure: C.W. Le Roux: Consulting Fee; Self; Boehringer Ingelheim, Novo Nordisk, GI Dynamics, Herbalife, Johnson & Johnson, Eli Lilly, Keyron. O. Steen: Consulting Fee; Self; Eli Lilly & Company, Novo Nordisk, Sanofi. Grant Recipient; Self; Alnylam, Anji, AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Janssen, Genzyme Corporation, Medacorp, Novo Nordisk, Medicago, Moderna, Novavax, Pfizer, Sanofi, Zucara Therapeutics, Gilead, ViaCyte, CRISPR Therapeutics, Kowa. Speaker; Self; Amgen Inc, AstraZeneca, Bausch Health, Janssen, LMC, Novo Nordisk. K.J. Lucas: None. E. Startseva: Employee; Self; Boehringer Ingelheim. A. Unseld: Employee; Self; Boehringer Ingelheim. A.M. Hennige: Employee; Self; Boehringer Ingelheim. Aim: To explore the effect of gender and BMI on weight loss and adverse events with survodutide in people living with overweight/obesity. Methods: In this double-blind, placebo (PBO)-controlled Phase II trial (NCT04667377), 387 adults with BMI ≥27 kg/m2 without diabetes were randomized 1:1:1:1:1 to weekly subcutaneous survodutide (0.6, 2.4, 3.6, 4.8 mg) or PBO over 46 weeks. Percentage change in body weight (primary endpoint), absolute change in body weight and waist circumference (secondary endpoints), and adverse events (AEs) were assessed in subgroups based on gender and BMI at baseline (BL). Data were analyzed descriptively for all participants who received ≥1 dose of study drug and had data for ≥1 efficacy endpoint (full analysis set [FAS]; planned treatment: n=384). Results: Of 384 participants, 68.2% (262) were female. At BL, 9.9% (38), 30.5% (117), 31.8% (122), and 27.9% (107) had a BMI of <30, 30-<35, 35-<40, and ≥40 kg/m2, respectively. Demographics and clinical characteristics at BL were similar between males and females and across BMI subgroups. At Week 46, mean percentage change in body weight from BL with survodutide 4.8 mg vs PBO was -11.9% vs -3.3% in males and -17.0% vs -3.2% in females, and -19.1% vs -1.7%, -15.8% vs -3.1%, -15.4% vs -5.8%, and -13.4% vs -0.8% across BL BMI categories. Mean absolute body weight loss from BL (survodutide 4.8 mg vs PBO) was -15.9 vs -4.2 kg in males and -22.0 vs -3.0 kg in females. Reductions in absolute body weight with survodutide 4.8 mg vs PBO were similar across BMI subgroups: -21.3 vs 1.4 kg, -16.2 vs -3.3 kg, -22.2 vs -7.5 kg, and -19.9 vs -1.6 kg. Mean absolute change in waist circumference from BL (survodutide 4.8 mg vs PBO) was -12.8 vs -1.7 cm in males and -17.9 vs -4.9 cm in females, and -8.4 vs -2.6 cm, -14.3 vs -6.4 cm, -17.5 vs -5.0 cm, and -17.2 vs 3.3 cm across BL BMI categories. A higher proportion of participants lost ≥15% of BL body weight with survodutide 4.8 mg vs PBO: 31.8% vs 9.5% in males and 66.7% vs 3.0% in females, and 75.0% vs 14.3%, 57.9% vs 4.5%, 52.0% vs 6.7%, and 50.0% vs 0.0% across BL BMI categories; respectively. All survodutide doses (pooled) were tolerated as expected across gender and BL BMI subgroups. In males vs females, respectively, rates of any AE (87.9% vs 92.4%), serious AEs (4.0% vs 4.3%), and discontinuations due to AEs (25.3% and 24.3%) were comparable. Gastrointestinal (GI) AEs with all survodutide doses were experienced by fewer males (65.7%) than females (79.5%); mild to moderate nausea was the most frequently reported GI AE in both subgroups. Conclusion: After 46 weeks of survodutide treatment, females appeared to lose more body weight and waist circumference than males. Participants with a lower vs higher BL BMI generally lost more proportional body weight, with an opposite trend observed for waist circumference. Presentation: 6/2/2024