Existing 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. View publication

The authors have characterized a set of cannabinoid CB2 receptor ligands, including triaryl bis sulfone inverse agonists, in a cell-based receptor/β-arrestin interaction assay (DiscoveRx PathHunter™). The results were compared with results using a competitive ligand binding assay, and with effects on forskolin-stimulated cAMP levels (PerkinElmer LANCE™). The authors show good correlation between the 3 assay systems tested, with the β-arrestin protein complementation assay exhibiting a more robust signal than the cAMP assay for cannabinoid CB2 agonists. Further assay validation shows that DiscoveRx PathHunter™ HEK293 CB2 β-arrestin assay can be carried out from cryopreserved cell suspensions, eliminating variations caused by the need for multiple cell pools during live cell screening campaigns. View publication

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) regulate glucose and energy homeostasis. Targeting both pathways with GIP receptor (GIPR) antagonist antibody (GIPR-Ab) and GLP-1 receptor (GLP-1R) agonist, by generating GIPR-Ab/GLP-1 bispecific molecules, is an approach for treating obesity and its comorbidities. In mice and monkeys, these molecules reduce body weight (BW) and improve many metabolic parameters. BW loss is greater with GIPR-Ab/GLP-1 than with GIPR-Ab or a control antibody conjugate, suggesting synergistic effects. GIPR-Ab/GLP-1 also reduces the respiratory exchange ratio in DIO mice. Simultaneous receptor binding and rapid receptor internalization by GIPR-Ab/GLP-1 amplify endosomal cAMP production in recombinant cells expressing both receptors. This may explain the efficacy of the bispecific molecules. Overall, our GIPR-Ab/GLP-1 molecules promote BW loss, and they may be used for treating obesity. View publication