Hypoglycaemia as a result of excessive insulin secretion from the pancreatic β-cell (hyperinsulinemic hypoglycaemia, HI) is a rare but serious condition that if left untreated can result in cognitive impairment, loss of consciousness, seizures and in infants the risk of permanent brain damage. HI is the hallmark of a number of rare disorders including congenital hyperinsulinism (CHI) and post-bariatric hypoglycaemia (PBSH). Despite significant progress in diagnosing and management of these conditions there have been no new medications approved in the last 20 years. Recently the specific GLP-1 receptor antagonist, Ex9-39, has been demonstrated to represent a promising treatment for HI through its specific actions to block excessive pancreatic insulin production. However Ex9-39 exhibits a short plasma half-life (mouse CL 15ml/min/kg and t1/2 0.1hr) and modest potency at the GLP-1 receptor (pKi 7.6 at hGLP-1). Using a structural understanding of the GLP-1 peptide binding pocket we designed a highly selective GLP-1 antagonist peptide (HTL0033097), which demonstrated a significantly improved pre-clinical pharmacokinetic (mouse CL 2.5ml/min/kg and t1/2 6hr) and in vitro pharmacology profile (hGLP-1 pKi 9.7) with a significantly improved clinical human dose predictions profile compared to Ex9-39. In vivo administration of HTL0033097 reversed GLP-1 agonist stimulated insulin secretion and increased plasma glucose in both rodents and non-human primates consistent with the proposed mechanism of action. Based on these encouraging data HTL0033097 has progressed into pre-clinical development where it was shown to be well tolerated in rodent and non-rodent dose range finding safety studies. Disclosure of the chemical structure of HTL0033097, a summary of the design process and the supporting pre-clinical pharmacokinetic and pharmacodynamic profile will be presented.

Identification and characterisation of a novel GLP-1 receptor antagonist peptide HTL0033097

ACS Spring 2022

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