A novel peptide agonist with pharmacological activity at GLP-1 and GLP-2 receptors was designed to explore the hypothesis that peptides with dual pharmacology provide benefits on nutrient absorption and intestinal function. The design strategy focused on modifications aimed to achieve pharmacological and pharmacokinetic differentiation from the clinical agent, teduglutide (Revestive, Gattex). Teduglutide is a selective GLP-2 receptor agonist approved for the treatment of short bowel syndrome. It was hypothesised that dual acting peptide agonists may enhance intestinal function by allowing greater nutrient absorption and additionally improve glucose control in patients on parenteral nutrition.<br/>HTL0030023 was identified as a molecule demonstrating potent activity at both GLP-2 and GLP-1 receptors (pEC50 10.9 and 10.5, respectively). The molecule has excellent PK properties, displaying a longer pharmacokinetic half-life in preclinical species compared to teduglutide. When compared to teduglutide, HTL0030023 promotes superior intestinal growth and additionally displays robust efficacy in the oral glucose tolerance assay, highlighting opportunity for differentiation from GLP-2 selective analogues.<br/>Based on the unique pharmacological profile, the molecule was further progressed into two further in vivo models to explore its therapeutic potential in metabolic diseases. HTL0030023 demonstrated encouraging efficacy in a mouse model of non-alcoholic steatohepatitis (NASH), as well as diet induced obesity (DIO), highlighting promising opportunities across multiple indications including non-alcoholic fatty liver disease (NAFLD) and NASH.<br/>HTL0030023 has completed rodent and non-rodent dose range finding (DRF) safety studies where it was shown to be well tolerated.<br/>Disclosure of the chemical structure of HTL0030023, a summary of the design process and the preclinical profile of the candidate will be presented in this poster.

Identification and characterisation of a dual GLP-1/GLP-2 agonist peptide, HTL0030023 using structure based drug design

ACS Spring 2022

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