Clinical Report: MEDI0618, a PAR2 Antibody, Shows Efficacy in Preclinical Migraine Models
Overview
MEDI0618, a fully humanized monoclonal antibody targeting protease activated receptor 2 (PAR2), demonstrated potent inhibition of migraine-like pain in multiple preclinical rodent models. It effectively prevented cutaneous allodynia induced by various migraine triggers, including CGRP-independent mechanisms, but showed no efficacy in a post-traumatic headache model.
Background
Migraine remains a significant unmet medical need despite advances in CGRP-targeted therapies, which are ineffective in a substantial subset of patients. PAR2, a G-protein coupled receptor activated by mast cell proteases such as tryptase, is implicated in migraine pathophysiology through neuronal sensitization. MEDI0618 is a novel, pH-sensitive monoclonal antibody engineered for enhanced recycling and specificity to PAR2, currently under clinical development for migraine prevention.
Data Highlights
Model
Trigger
Effect of MEDI0618
Effect of Olcegepant (CGRP-R antagonist)
Systemic nitroglycerin
Systemic NTG
Prevention of cutaneous allodynia
Not reported
Compound 48/80 (mast cell degranulator)
Systemic and supradural
Prevention of cutaneous allodynia and restored rearing behavior
Not reported
Inflammatory mediator (IM) cocktail
Supradural
Prevention of cutaneous allodynia regardless of olcegepant pretreatment
Failed to reduce IM-induced allodynia
Umbellulone (TRPA1 agonist)
Inhalational with restraint stress
Prevention of cutaneous allodynia
Not reported
Post-traumatic headache
Mild traumatic brain injury
No prevention of headache measures
Not reported
Key Findings
MEDI0618 binds specifically and with high affinity to human PAR2, blocking protease-induced calcium signaling in human cells.
In vivo, MEDI0618 prevented migraine-like cutaneous allodynia induced by nitroglycerin, mast cell degranulation, and inflammatory mediators in mice.
MEDI0618 efficacy was observed in CGRP receptor antagonist-resistant migraine models, indicating activity against CGRP-independent pathways.
MEDI0618 prevented behavioral signs of headache pain such as decreased rearing induced by mast cell degranulation.
MEDI0618 did not show efficacy in a mild traumatic brain injury model of post-traumatic headache.
The antibody’s pH-sensitive design allows enhanced FcRn recycling, supporting its pharmacokinetic profile for clinical development.
Clinical Implications
MEDI0618 represents a promising novel therapeutic approach for migraine prevention, particularly for patients who do not respond to CGRP-targeted therapies. Its ability to inhibit PAR2-mediated pathways suggests potential efficacy in both CGRP-dependent and independent migraine attacks. However, its lack of effect in post-traumatic headache models indicates the need for alternative strategies in that patient population.
Conclusion
MEDI0618 is a potent and selective PAR2 monoclonal antibody that effectively prevents migraine-like pain in multiple preclinical models, including those resistant to CGRP receptor antagonism. These findings support further clinical development of MEDI0618 as a novel migraine preventive therapy.
References
Original Article -- Assessment of MEDI0618, a pH-sensitive monoclonal antibody aimed at PAR2, in preclinical migraine models
by Caroline M Kopruszinski, John E Linley, Peter Thornton, Alison S Walker, Philip Newton, Sadhana Podichetty, Radhey Hemendra Ruparel, Luiz Henrique Moreira de Souza, Edita Navratilova, Guy Meno-Tetang, Ian Gurrell, David W Dodick, Claire Dobson, Tharani Chessell, Frank Porreca, Iain Chessell
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