A CGRP receptor antagonist peptide formulated for nasal administration to treat migraine.

Bengt Von Mentzer,Andrew F Russo,Zhongming Zhang,Gillian A Hutcheon,Patrick M Killoran,Adisa Kuburas,Vicky Capel,David A Kendall,Laura Nizic,Christopher R Coxon,Vera D’Aloisio

doi:10.1111/jphp.13317

Abstract

ObjectivesTo investigate the formulation of the peptide-based antagonist (34Pro,35Phe)CGRP27–37, of the human calcitonin gene-related peptide (CGRP) receptor as a potential nasally delivered migraine treatment.MethodsPeptide sequences were prepared using automated methods and purified by preparative HPLC. Their structure and stability were determined by LC-MS. Antagonist potency was assessed by measuring CGRP-stimulated cAMP accumulation in SK-N-MC, cells and in CHO cells overexpressing the human CGRP receptor. In vivo activity was tested in plasma protein extravasation (PPE) studies using Evans blue dye accumulation. Peptide-containing chitosan microparticles were prepared by spray drying.Key findings(34Pro,35Phe)CGRP27–37 exhibited a 10-fold increased affinity compared to αCGRP27–37. Administration of (34Pro,35Phe)CGRP27–37 to mice led to a significant decrease in CGRP-induced PPE confirming antagonistic properties in vivo. There was no degradation of (34Pro,35Phe)CGRP27–37 and no loss of antagonist potency during formulation and release from chitosan microparticles.Conclusions(34Pro,35Phe)CGRP27–37 is a potent CGRP receptor antagonist both in vitro and in vivo, and it can be formulated as a dry powder with no loss of activity indicating its potential as a nasally formulated anti-migraine medicine.

Highlights

Migraine is a common, frequently chronic, neurovascular disorder of the brain characterised by recurrent, severe attacks of headache often associated with nausea and sensory hypersensitivity rendering suffers unable to function at work or at home.[1]
We show that (34Pro,35Phe) CGRP27–37 is a potent calcitonin gene-related peptide (CGRP) receptor antagonist both aCGRP27–37 (34Pro,35Phe) aCGRP1–37 A Ca in vitro and, for the first time, in vivo and demonstrate how it can be formulated for dry powder nasal delivery without loss of potency
This investigation evaluated (34Pro,35Phe)CGRP27–37, a modified analogue of aCGRP (Table 1), as a potent CGRP receptor antagonist in vitro and in vivo to demonstrate its potential as a new nasal migraine medicine

Summary

Introduction

Frequently chronic, neurovascular disorder of the brain characterised by recurrent, severe attacks of headache often associated with nausea and sensory hypersensitivity rendering suffers unable to function at work or at home.[1]. Most importantly from a drug development perspective, a number of ‘gepants’, small molecule CGRP receptor antagonists,

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