1883-LB: ATR-258 Is a Precision Modulator of ß2-AR Signaling That Improves Glucose Homeostasis and Is Safe in Humans

Abstract

Introduction & Objective: Stimulation of β2-adrenergic receptors (β2-AR) in skeletal muscle improves glucose uptake capacity and is a promising avenue in the treatment of type 2 diabetes (T2D). To circumvent common β2-AR-associated cardiovascular side-effects through cAMP activation, we have developed a novel β2-AR agonist, ATR-258, with low cAMP induction but improved glucose tolerance and insulin sensitivity in preclinical models. Here we present preclinical efficacy data and phase 1 safety data for our candidate drug ATR-258. Methods: We have used various in vitro models to analyze the functional characteristics of ATR-258. These include receptor selectivity, downstream signaling profiles, cAMP induction and glucose uptake. We assessed the in vivo effects of ATR-258 on glucose tolerance and insulin sensitivity in diet-induced obese C57BL/6 mice and diabetic Goto-Kakizaki rats. To test safety in humans, we performed single and multiple ascending dose studies in a total of 46 healthy male volunteers. In a third cohort, 23 male patients with T2D received either placebo (n = 8) or 2.5 mg ATR-258 (n = 15) once daily for 28 days. Safety profiles, PK, and PD variables such as HbA1c and glucose tolerance were measured. Results: ATR-258 displayed limited cAMP induction and no promotion of β-arrestin recruitment or receptor desensitization, but a maintained ability to induce glucose uptake compared to classical β2-AR agonists in vitro. ATR-258 improved glucose tolerance and insulin sensitivity in a dose-dependent manner in mouse and rat models of obesity and diabetes. Our first-in-human phase 1 data showed that ATR-258 is safe and well-tolerated in healthy volunteers and T2D patients. Conclusion: ATR-258 is a β2-AR agonist with a preferential signaling and safety profile resulting in beneficial effects on glucose homeostasis in preclinical models and a promising safety profile in humans. ATR-258 could lead the way of a new class of adrenergic agonists to treat T2D. A. Kalinovich: Employee; Atrogi AB. Stock/Shareholder; Atrogi AB. E. Waara: Employee; Atrogi. J.M.A. de Jong: Employee; Atrogi AB. B. Pelcman: Consultant; Atrogi AB. T. Bengtsson: Stock/Shareholder; Atrogi, Sigrid therapeutics.