105-OR: an Exploratory Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Effect of Cotadutide on Energy Balance in Overweight and Obese Subjects with Type 2 Diabetes Mellitus

Background: Cotadutide is a GLP1/glucagon receptor dual agonist under development for the treatment of nonalcoholic steatohepatitis and type 2 diabetes (T2D) with diabetic kidney disease. Early-phase clinical studies show that cotadutide achieves clinically significant weight loss. We aimed to establish mechanistically to what extent this effect is mediated via changes in energy intake (EI) or energy expenditure (EE). Methods: We conducted a phase 2a single-center randomized double-blind placebo-controlled trial in overweight/obese adults (BMI 27-40 kg/m2) with T2D (HbA1c 6.5-8%). Participants underwent a 16-day single-blind placebo run-in and were randomized to double-blind 42-day cotadutide or placebo. Cotadutide was given subcutaneously, up to 300 µg daily. Primary outcome: % weight change from day 17 to day 59. Secondary outcomes: % and absolute changes in EI (ad libitum lunch), and EE (indirect calorimetry). Results: A total of 19 (63%) cotadutide and 9 (78%) placebo participants completed the study. Least-squares (LS) mean weight change was -3.98% (90% CI -4.85%, -3.10%) and -1.40% (90% CI -2.66%, -0.13%) for cotadutide and placebo, respectively, p= 0.011 between groups. The cotadutide group had a striking 35% lower EI vs. placebo: LS mean -35.0% (90% CI -61.8%, -8.2%), p=0.037. Total EE (kJ/kg lean mass) after cotadutide treatment decreased vs. placebo: -6.0% vs. 0.3%, p<0.001. Significant reductions in absolute resting and activity EE were noted with cotadutide after 42 days, but there was no change in resting EE (8.5%; cotadutide vs. placebo 1.2%, p=0.177) after 16 days of therapy despite a reduction in body weight. No additional safety concerns were raised. Conclusions: Weight loss caused by cotadutide is predominantly due to reduced EI rather than increased EE. Transient preservation of EE in the early phases of cotadutide treatment may reflect glucagon receptor engagement. Disclosure R. Golubic: None. M. Evans: Advisory Panel; Self; Pila Pharma, Zucara Therapeutics Inc., Other Relationship; Self; Abbott Diabetes, Medtronic, Novo Nordisk, Research Support; Self; AstraZeneca, Imcyse. J. Kennet: None. V. E. Parker: Employee; Self; AstraZeneca, Stock/Shareholder; Self; AstraZeneca. D. Robertson: Employee; Self; AstraZeneca, Employee; Spouse/Partner; GlaxoSmithKline plc., Stock/Shareholder; Self; AstraZeneca. D. Luo: None. L. Hansen: Employee; Self; AstraZeneca. L. Jermutus: Employee; Self; AstraZeneca, Stock/Shareholder; Self; AstraZeneca. P. Ambery: Employee; Self; AstraZeneca. A. Park: Other Relationship; Self; Novo Nordisk.