Monoagonist combinations for the treatment of obesity and diabetes, and the impact of biased signalling

Abstract

GLP-1 analogues (GLP-1RAS) are leading therapeutics for diabetes and obesity; however, their glucose control and weight loss potential are dose-limited by side effects. Glucagon receptor co-agonism, which increases energy expenditure (EE), may enhance their therapeutic utility; as may biased signalling – the ability of a given ligand to preferentially stimulate one pathway over others – at the GLP-1R. Consequently, numerous unimolecular multi-agonists have been explored; however, their success has been limited due to the inherent challenge of optimising several ligand-receptor interactions within one molecule. Thus, this thesis proposes an alternative approach: the combined administration of a GCGRA (G6067) and a biased GLP-1RA (G7097), intentionally designed for co-formulation. The effects of glucagon on EE, however, are not well understood. Hence, this work first investigated the phenotypic response of rodents to acute and chronic glucagon administration. Although a series of behavioural studies could not link the EE effect of glucagon to spontaneous movement, it was confirmed through transgenic models to be initiated by the hepatic GCGR. For the first time, this effect was also linked to the reduction of plasma amino acids. Subsequent chronic feeding studies in the rat using G6067+G7097 treatment, however, indicated that this reduction was minimal at therapeutically relevant doses. In addition to this, the benefits of bias at the GLP-1R were explored. Through in vitro and in vivo characterisation of three pharmacologically distinct agents (G7097, G7124 and semaglutide), it was demonstrated that biased GLP-1RAs exhibit prolonged anti-hyperglycaemic effects and superior inhibition of glucagon-induced hyperglycaemia compared to non-biased agents. Thus, biased GLP-1RAs may offer superior glucose control in the context of GLP-1R/GCGR co-agonism. Lastly, this project validated the drugability of G6067+G7097. Both were determined to be suitable for once-weekly administration in humans by a small, painless injection, likely via a cold-stored multi-use syringe. Additionally, chronic rat feeding studies established their co-administration as a safe, robust competitor to the market leaders, and provided guidance for dose-ratio translation for first-in-human studies.