Design and characterization of a surfactant‐conjugated, long‐acting, balanced GLP‐1/glucagon receptor dual agonist

Abstract

AbstractExisting candidates for treating non‐alcoholic steatohepatitis (NASH), including glucagon‐like peptide‐1 (GLP‐1) analogs and previous GLP‐1/glucagon receptor (GLP‐1R/GCGR) dual agonists, do not address the need for substantial weight loss adequately. We sought a more effective, evenly balanced GLP‐1/GCGR dual agonist suitable for weekly administration. We studied a new class of covalent modifiers, glycolipid surfactants, to prolong the duration of action of candidate peptides. Variation of the hydrophobic tail of such surfactant modifications resulted in a wide and tunable range of physical properties and t1/2 values. We selected compound 17, which demonstrated high, evenly balanced potency for activation of human GLP‐1R and GCGRs, return of diet induced obese (DIO) rodents to lean body/liver weight and prolonged duration correlated with high serum albumin binding. We observed a prolonged pharmacodynamic (PD) profile in rodents and pharmacokinetics (PK) in mini‐pigs (t1/2 = 52 hours, mean residence time, MRT = 86 hours), suggesting suitability for weekly dosing. Accordingly, 17 (ALT‐801) was selected for clinical development.