2865-LB: ATR-258, a GRK2-Biased ß2AR Modulator, Mitigates Worsening of Insulin Resistance in Type 2 Diabetes after Metformin Withdrawal

Introduction and Objective: Skeletal muscle insulin resistance is a hallmark of type 2 diabetes (T2D) inadequately addressed by current therapies. ATR-258 is a first-in-class oral GRK2-biased β2AR partial agonist that drives insulin-independent glucose uptake in skeletal muscle via mTORC2-GLUT4 signaling. This study aimed to evaluate the safety and tolerability of ATR-258, and its exploratory pharmacodynamic effects on insulin sensitivity, in persons with T2D following metformin withdrawal. Methods: In a randomized, double-blind, placebo-controlled Phase 1b trial (ATTRACTIVE-1, NCT05409924), persons with T2D underwent metformin washout and received ATR-258 2.5 mg once daily (N=17; n=15 completers) or placebo (N=8) for 28 days. oGTTs were performed at baseline (day -7) and day 28. Primary endpoints were safety and tolerability. Exploratory pharmacodynamic endpoints derived from oGTT included total and incremental insulin AUC (iAUC), glucose AUC, and the insulin-to-glucose AUC ratio. Results: ATR-258 was safe and well tolerated with low incidence of class-specific Treatment-Emergent Adverse Events (TEAEs). Following metformin withdrawal, placebo became more insulin resistant: mean insulin AUC increased from baseline (+35.2 ± 39.7 h·mU/L) whereas it decreased with ATR-258 (-10.7 ± 32.6 h·mU/L). Incremental insulin AUC (iAUC) rose in the placebo group but remained unchanged with ATR-258. The insulin AUC:glucose AUC ratio similarly increased in placebo but decreased with ATR-258, indicating ATR-258 mitigated the expected deterioration in insulin sensitivity. Conclusion: ATR-258 mitigated worsening of insulin resistance after metformin withdrawal in persons with T2D, as shown by divergent changes in insulin AUC, iAUC, and insulin:glucose ratio versus placebo. These findings support GRK2-biased β2AR modulation as a novel muscle-targeted approach to T2D warranting Phase 2 evaluation. Disclosure M. Bokhari: Employee; Current; Atrogi. E. Rollman Waara: Employee; Current; Atrogi AB. J. de Jong: Employee; Ended; Atrogi. A. Kalinovich: Employee; Current; Atrogi AB. N. Dehvari: Employee; Current; Atrogi AB. T. Bengtsson: Other - Founder; Current; Atrogi AB, Sigrid Therapeutics AB. Consultant; Current; Insulife AS. Other - Founder; Current; TBRC research and Development AB. Funding Swedish Research Council (grant agreement numbers 2019-01508 and 2024-02446), Eurostar project SYNSTAR (grant agreement number E114421), Diabetes Wellness Sverige