CGRP pathway monoclonal antibodies for cluster headache

ABSTRACT

Introduction

The involvement of the calcitonin gene-related peptide (CGRP) pathway in primary headache disorders, especially migraine, had led to recent success in the development of new migraine therapies. The CGRP pathway also plays a role in the pathophysiology of cluster headache, so CGRP pathway monoclonal antibodies have been studied in the prevention of cluster headache attacks.

Areas covered

This review will outline the trials of fremanezumab and galcanezumab, the two CGRP pathway monoclonal antibodies that have undergone trials in cluster headache prevention. This review will highlight key efficacy and safety outcomes from the trials.

Expert opinion

Galcanezumab was shown to be efficacious, reducing the frequency of attacks in episodic cluster headache, while fremanezumab failed its primary endpoint in episodic cluster headache. Both fremanezumab and galcanezumab trials in chronic cluster headache were terminated after futility analysis predicting the failure of both trials to fulfil their primary endpoint. The role of CGRP in cluster headache supports ongoing trials of the remaining CGRP pathway monoclonal antibodies and gepants for preventive and acute treatment.

A broad view would include targeting neuropeptides involved in parasympathetic signaling in cluster headache, such as pituitary adenylate cyclase-activating peptide (PACAP); such targets warrant exploration in the search of new treatments.

KEYWORDS:

• Cluster headache
• calcitonin gene related peptide
• fremanezumab
• galcanezumab
• monoclonal antibody
• pituitary adenylate cyclase-activating peptide

Article highlights

• Galcanezumab has been approved for use in the prevention of attacks in episodic cluster headache by the US FDA after a phase three trial demonstrating efficacy and safety.

• The trial involving fremanezumab for the prevention of attacks in episodic cluster headache was not completed. An interim analysis indicated a significant attack reduction would be unlikely and the trial was terminated.

• The fremanezumab and galcanezumab trials for the prevention of attacks in chronic cluster headache were negative. At the time of writing, a calcitonin gene-related peptide (CGRP) pathway monoclonal antibody has yet to demonstrate efficacy in the prevention of chronic cluster headache.

• The established significance of the CGRP pathway in cluster headache pathophysiology supports ongoing trails with other CGRP pathway monoclonal antibodies as well as CGRP receptor antagonists, otherwise known as ‘gepants,’ as acute and preventive treatments.

This box summarizes the key points contained in the article.

Declarations of interests

C Chan has received travel grants from Guarantors of Brain and honoraria from New England Journal of Medicine Journal Watch and MedLink Neurology. PJ Goadsby reports, over the last 36 months, grants, and personal fees from Amgen and Eli-Lilly and Company, and personal fees from Alder Biopharmaceuticals, Allergan, Autonomic Technologies Inc., Biohaven Pharmaceuticals Inc., Celgene, Clexio, Electrocore LLC, eNeura, Epalex, Impel Neuropharma, MundiPharma, Novartis, Teva Pharmaceuticals, Trigemina Inc., WL Gore, and personal fees from MedicoLegal work, Massachusetts Medical Society, Up-to-Date, Oxford University Press, and Wolters Kluwer; and a patent magnetic stimulation for headache assigned to eNeura without a fee. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

One of the reviewers of this paper has participated in Eli Lilly and TEVA advisory boards for migraine and cluster headache products. Two additional peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper represents independent research funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care