A subtype selective somatostatin SST5 receptor agonist has been designed to explore the hypothesis that such an agent might give effective hypoglycaemic control and a better side effect profile compared with non-selective somatostatin agonists used off-label in clinical practice for hypoglycaemic disorders such as congenital hyperinsulinism (CHI) and post-bariatric surgery hypoglycaemia (PBSH). By virtue of activation of only SST5 it was proposed that inhibition of GH secretion would be minimised, as this effect is thought to be primarily driven through SST2. The non-selective drug pasireotide, a cyclic hexapeptide, was the start-point to introduce SST5 selectivity (vs SST2). The design process was driven by use of computer aided drug design (CADD), generating models of peptides bound to optimized homology models of SST5 and SST2. An additional objective was to identify a peptide with improved preclinical pharmacokinetics compared with pasireotide to give confidence of its utility in human clinical trials. After a focused program of work a clinical candidate HTL0030310 was identified. The absorption, distribution, metabolism and excretion of HTL0030310 were investigated in non-clinical species and the data supported its potential for once daily SC dosing in man. HTL0030310 was demonstrated to have low clearance with a moderate to low volume of distribution (similar to intracellular or extracellular fluid volume) and well-characterised half-life (4-15 hours) in the rat, dog and cynomolgus monkey. Extensive in vitro pharmacological profiling, in vivo efficacy studies and in vitro and in vivo safety studies have been completed, establishing that HTL0030310 is a highly functionally selective agonist of SST5 over SST2 and otherwise has a very similar SST agonist signature to pasireotide, has no significant off-target pharmacology and no overt adverse safety concerns in vivo. This full preclinical data package supported initiation of human clinical trials and the peptide has been manufactured and formulated for clinical use by subcut injection. HTL0030310 has completed a Phase 1 clinical study and the findings support its further investigation in hypoglycaemic conditions with the potential for differentiation from standard of care. Disclosure of the chemical structure of HTL0030310, a summary of the design process and the preclinical profile of the clinical candidate will be presented in this poster.

Identification of subtype selective SST5 agonist peptide HTL0030310 using structure-based drug design

ACS Spring 2022

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