1782-P: Phase 1b Study of AMPK/Mitochondrial Activator ATX-304 in Prediabetic Obese Participants

Introduction and Objective: ATX-304 (ATX) is a novel small molecule dual AMP-activated protein kinase (AMPK) and mitochondrial activator that improved glucose and lipid metabolism, increased energy expenditure and reduced body weight in animal models of obesity without decrease in food consumption. In combination with incretins, ATX increased weight loss and prevented weight regain after incretin withdrawal, without change in lean tissue mass. This Phase 1b study investigated translation of metabolic effects in humans. Methods: Safety, pharmacokinetics and pharmacodynamics (PD) of ATX were studied in 23 obese prediabetic subjects (defined by HbA1c range and abnormal fasting glucose or OGTT) randomized 2:1 to once daily oral treatment with 400 mg ATX or placebo for 8 weeks with an optional open label extension to 16 weeks. Results: ATX was safe and well tolerated. Compared to baseline, ATX significantly increased total adiponectin in plasma and reduced liver and visceral fat assessed by MRI in a time-dependent manner. Resting metabolic rate assessed by indirect calorimetry increased up to 33% compared to baseline. Conclusion: ATX is the first safe dual AMPK and mitochondrial activator. Clinical investigations in larger Phase 2 studies are planned to assess the utility of ATX as a weight loss drug with an orthogonal mechanism of action to incretins. Disclosure R.I. Thieroff-Ekerdt: Employee; Current; Cambrian Biopharma. D. Jacobs: Employee; Current; Cambrian Biopharma. J. Hall: None. E.J. Schneider: Employee; Current; Cambrian BioPharma, Amplifier Therapeutics AB. J. Ainscough: Employee; Current; Cambrian Biopharma. J. Peyer: Board Member; Current; Cambrian Biopharma. T. Heise: Research Support; Ended; Afon Technology. Research Support; Current; Betagenon AB, Civica, Corteria Pharmaceuticals. Research Support; Ended; Cytoki Pharma. Research Support; Current; DioGenX, ENYO Pharma, Gan Current; Gan Current; Nanexa, Neodyne Biosciences, Sam Chun Dang. Research Support; Ended; Liom. Research Support; Current; Sun Pharmaceutical Industries Ltd., Zealand Pharma A/S. Other - Travel Grants; Current; Zealand Pharma A/S. Research Support; Current; AstraZeneca, Biocon, Eli Lilly and Company. Speaker's Bureau; Current; Eli Lilly and Company. Research Support; Current; Novo Nordisk, Roche Diagnostics. Consultant; Current; i2o Therapeutics. Speaker's Bureau; Current; Novo Nordisk.