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The efficacy of anti-CGRP therapies (CGRP mAbs and gepants) in migraine is well established. However, the precise mechanisms of action are unclear and the question of whether a central or peripheral mechanism is responsible for their efficacy remains unresolved. Dr Kuan-Po Peng, from the Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Germany, reviews the latest evidence.

The recognition that a migraine starts neurobiologically, electrophysiologically, and symptomatically, hours to days before the headache, has provided insights into the mechanisms of attack initiation and migraine pathogenesis. Neurologist, Dr Nazia Karsan, who works as a postdoctoral researcher in the Headache Group at King’s College London, UK, discusses recent progress in mechanism research and opportunities for early attack treatment with the aim of preventing headache and reducing attack-related disability.

Multiple randomised controlled trials support the safety and efficacy of CGRP mAbs as the first target-driven treatment for migraine prevention, and a growing body of real world evidence supports these findings and provides key information about the use of CGRP mAbs in a more heterogeneous population. However, as Dr Alicia Alpuente from Vall d’Hebron University Hospital, Barcelona, Spain, explains, the variability of patient response to CGRP mAbs and cost considerations make it important to optimise the use of these agents in clinical practice by studying predictors of response.

Despite being one of the top 10 causes of global disability-adjusted life-years in adolescents and second only to road injuries in those aged 10-24 years, childhood headache is under-evaluated around the world. Paediatric migraine is not just a ‘small version of adult migraine’, and it requires careful diagnosis and management strategies to meet the expectations not only of children and adolescents but also of their families, explains Dr Aynur Özge Professor of Neurology, Algology and Clinical Neurophysiology, Mersin University School of Medicine, Mersin, Turkey.

Since the US approval of the first gepant for the acute treatment of migraine in December 2019, clinicians have been reporting their experiences of combining these agents with CGRP monoclonal antibodies (mAbs) in some patients. Richard Lipton, Edwin S Lowe Professor of Neurology at the Albert Einstein College of Medicine, New York, USA, discusses the …

With trials underway of anti-CGRP therapies in post-traumatic headache (PTH), Henrik Winther Schytz, Associate Professor of Neurology at the Danish Headache Center, University of Copenhagen, Denmark, discusses the links between PTH and migraine and the implications for treatments that target CGRP.  Post-traumatic headache (PTH) is by far the most frequent symptom after traumatic brain injury, …

CGRP-based therapy is not expected to be approved in Japan until 2021, but clinical trial data have been reported on three agents and there is a high level of expectation amongst Japanese clinicians – as Mamoru Shibata, Associate Professor in the Department of Neurology at Keio University School of Medicine, Tokyo, Japan, explains. Globally, monoclonal …

In September 2019, Emgality (galcanezumab) became the first anti-CGRP therapy to be approved for migraine prevention in adults in Korea – a country with a migraine prevalence of 6.1% which is similar to other countries in Asia.1 Clinical trials of Aimovig (erenumab) and Ajovy (fremanezumab) are nearing completion, with approvals expected in 2021. Byung-Kun Kim, …

Following the approval of the first CGRP inhibitors for migraine prevention in adults, clinical trials are currently assessing their safety and efficacy for migraine prophylaxis in children and adolescents. Dr Ana Recober, Assistant Professor of Neurology, at the University of Pennsylvania, Philadelphia, USA, provides practical advice and tips for clinicians who are considering prescribing these …

In Canada, Aimovig (erenumab) is currently the only approved CGRP antibody but Emgality (galcanezumab) and Ajovy (fremanezumab) are being considered by Health Canada and are expected to be available at the end of 2019 or early 2020. As Canadian physicians start using anti-CGRP therapies, Dr Elizabeth Leroux, Headache Neurologist in Montreal, Quebec, and President of …

With anti-CGRP therapy rapidly becoming available to clinicians, it’s a good time to consider where it fits within our therapeutic options for migraine, says Professor David Dodick, from the Mayo Clinic, Scottsdale, Phoenix, Arizona, USA. In the USA, erenumab, fremanezumab and galcanezumab are approved for the preventive treatment of migraine in adults, while the EU licence …

Migraine is not only a common disease but also one of the most disabling brain disorders, explains Mamoru Shibata, MD, PhD Department of Neurology, Keio University School of Medicine, Tokyo, Japan. According to the Global Burden of Disease Study 2015, migraine is the second largest contributor of disability-adjusted life-years (DALYs) in neurological diseases1. Migraine affects chiefly …

There are four mAbs currently in development; three are humanized mAbs targeting the CGRP ligand and one is a fully human mAb against the CGRP receptor. They have a rapid onset of efficacy (roughly one week) following a single dose administration. All are thought to work peripherally. Therapeutic mAbs are designed to achieve high target …

Recent studies reported by Dr Greg Dussor (University of Texas, Dallas) at the 2017 American Headache Society meeting in Boston, USA, have opened up an exciting new perspective on CGRP actions. Dr Dussor’s unexpected finding is that CGRP can directly stimulate the dura of female, but not male, rodents to cause periorbital hypersensitivity. First a …

No biomarker or imaging technique is currently available to quantify migraine. To this day, the outcomes of therapeutic interventions are still based on headache diaries. Multiple techniques have been used to analyse results, but the mean decrease in headache days (including headache, migraine, probable migraine and moderate/severe days) and the 50% response rate have been …

We should not forget the potential off-target metabolic effects of CGRP inhibitors, say Christopher S Walker and Debbie L Hay of the School of Biological Sciences, The University of Auckland, New Zealand The major concern when considering the possible off-target effects of blocking CGRP activity in migraine with small molecule antagonists or antibodies, appears to be …

Novel CGRP-targeted small molecule antagonists and monoclonal antibodies are making giant strides in clinical trials, but to date there has been little insight into the basic mechanisms of CGRP.  Dr Philip R Holland, Lecturer in Neuroscience at King’s College, London discusses a new stable CGRP analogue that offers the possibility of exploring underlyIng and central …

As a novel migraine therapeutic approach, monoclonal antibodies against CGRP or its receptor are currently in clinical trials for migraine prophylaxis. The key question then is: Does it make a difference whether we choose the CGRP receptor or CGRP itself as a therapeutic target? This is hard to answer. Intuitively, blocking the receptor is likely …

Headache is a highly complex condition and thus cannot be explained by a single mechanism. There are no biomarkers for headache, and no effective diagnostic tests which are universally applicable. For instance, the International Classification of Headache Disorders (ICHD) criteria for conditions such as chronic migraine (CM), hemicrania continua (HC) and Tolosa‐Hunt syndrome (THS) require …

The risk of migraine increases in people who are overweight or obese. Now, there is emerging evidence that CGRP may mediate this link. Professor B. Lee Peterlin discusses this issue.