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Migraine Matters: Exciting Development of CGRP-targeted Drugs

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Published: 14 Aug 2019
By Fulye Argunhan, Aisah Aubdool

What is migraine? 

Migraine is a neurological disorder, often described as a moderate to severe throbbing-like headache, associated with increased sensitivity to light or sound. Headaches are typically unilateral, aggravated by physical activity and linked with nausea. It is estimated that 15% of the population suffer from migraine, it is more common in women than men and costs the NHS £150 million annually in the United Kingdom. 

The pathophysiology of migraine is multi-faceted and complex, it comprises the vasculature, inflammation and the central and peripheral pain signalling pathways. Genetic and environmental factors are involved in the root cause of the disease and it is now understood that there is generally a sequence of events which trigger a migraine headache, rather than a threshold-dependent ‘yes’ or ‘no’ occurrence. Migraineurs are stratified into two groups; Group 1 are patients who experience migraine events for 1-14 days, known as 'episodic migraine' whilst Group 2 consists of patients with migraine attacks for more than 15 days a month, referred to as 'chronic migraine'. Importantly, the majority of migraineurs suffer from episodic migraine but those who suffer with chronic migraine experience a substantially greater impact on their daily activities as some episodes of headaches can last 4-72 hours. The World Health Organization has classified severe migraine attacks as among the most disabling illnesses. Furthermore from an economical aspect, a survey carried out across 8 EU countries (55% of the EU adult population) for The Eurolight Project found that the total annual cost of migraine to the EU is a staggering €111 billion. Given the wealth of information on cost and prevalence of migraines, there remains an unmet need to develop new therapies aimed to prevent and treat migraines.   

As there are no cures for migraine, numerous lifestyle changes and treatments are often recommended to migraineurs to manage their symptoms. Lifestyle changes include regular exercise and sleeping pattern, stress management involving relaxation techniques and a healthy diet. Most migraineurs rely solely on over-the-counter medications (analgesics, NSAIDs, anti-emetics, ergotamines) to reduce their symptoms, but these painkillers are mostly effective if taken early in the onset of an attack. Serotonin (5-HT) agonists known as triptans are also widely used. However, due to their lack of tolerability and associated cardiovascular side effects, their therapeutic benefits have been limited. Other drug classes for migraine prevention include anti-hypertensive, anti-epileptic and anti-depressant medications but they are related to many adverse effects, leading to poor compliance and adherence of patients. Clinical trials over the past few decades have demonstrated that migraine involves an increased sensitivity to the neuropeptide calcitonin gene-related peptide (CGRP).  
 

The Majestic Peptide CGRP and its receptors 

CGRP, a 37 amino acid neuropeptide released from sensory neurons (C and A (𝛿) fibres), is a potent vasodilator, especially in the microvasculature. In 1982, there was confounding evidence showing that alternate messenger ribosomal nucleic acid (mRNA) processing of the calcitonin gene produces CGRP in nerve tissues. CGRP was first identified in the 1980s and exists in two isoforms; α and β which are synthesised from two distinct genes at different sites on chromosome 11 in humans and share >90% homology with similar biological activities. CGRP is released after trigeminal ganglion stimulation and during severe migraine attacks. Circulating CGRP levels are elevated in women with a medical history of migraine and CGRP infusion can trigger delayed migraine-like headaches in most migraineurs. Triptans can normalise the levels of CGRP.   

Historically, migraine was considered a vascular disorder but increasing studies have challenged the vascular concept, with a focus on neuro-centric theories. How does it work then? The consensus now is that CGRP is released from trigeminal nerves to initiate pain and other effects involving neurogenic inflammation (as yet not totally clear) in the meninges (connective tissue between bone and nerve tissues around the brain and spinal cord). CGRP also binds to its receptors on vascular smooth muscle cells within vessel walls, increasing blood flow in cerebral vessels. Professor Brain identified CGRP as a potent microvascular vasodilator, as local administration of the native peptide into the skin caused a long-lasting increase in blood flow (Figure 1). Finally, CGRP is also involved in pain transmission whereby post-junctional cell receptors enhance CGRP-induced trigeminal nerve pain signals.


Figure-1-CGRP-Human-Responses-in-the-forearm-01.png
Figure 1 - Calcitonin gene-related peptide (CGRP) induced erythema in Caucasian human skin. The image shows reponses to increasing doese of CGRP in the human forearm.

The CGRP receptor is an intricate complex composed of a seven domain G protein-coupled receptor (GPCR) called calcitonin receptor-like receptor (CLR), and a single transmembrane-spanning domain named receptor activity-modulating protein (RAMP1). RAMP1 is involved in trafficking CLR to the cell surface membrane to produce efficacy, when active as a complex. Lastly, a peripheral membrane accessory protein termed CGRP-receptor component (RCP) couples to CLR /RAMP1 to amplify the cell signalling pathway (Figure 2). The mechanisms underlying CGRP-induced responses are tissue-specific. CGRP receptors are located in the intracranial blood vessel walls, trigeminal ganglion, and dorsal root ganglion. Indeed, the role of CGRP and the vasculature is very important in migraine.  


Figure-2-CGRP-Receptor-01.png
Figure 2 - Model for functional CGRP signalling. The CGRP receptor complex consists of CLR, a small single transmembrane protein RAMP1 for trafficking and pharmacology and an accessory protein RCP for coupling to cellular transduction pathways.
 

More than 20 years after our team at GSK first identified the RAMP protein complex that forms the CGRP receptor, followed by the work done by the team at MSD to discover small molecule antagonists, it is exciting to see a range of different therapeutics finally being approved that will bring benefit to patients for this very distressing disorder - Professor Fiona Marshall (MSD Research Laboratories, UK)

The role of CGRP in migraine has been extensively studied, using various pre-clinical models including the photophobia studies characterised by the Russo group. CGRP treatment causes light aversion, decreased movement, spontaneous pain (grimace) and evokes pain (mechanical allodynia) in mice. Sensitisation to CGRP by overexpressing the receptor subunit human RAMP1 (hRAMP1) in neural sites enhances light sensitiveness following central administration of CGRP. However, CGRP can induce its action in the periphery, altering the microenvironment of the trigeminovascular system. The wide distribution of CGRP receptors in the cranial area was favourable to researchers wishing to target the CGRP receptor complex using antagonists to block the actions of CGRP in migraine and hence, use as a therapeutic agent (Figure 3).

Figure-3-The-development-of-CGRP-Receptor-Antagonists-01.png
Figure 3 - The development of CGRP receptor antagonists
 

Having worked on the pharmacology of the CGRP family of receptors for many years, it is very gratifying that this peptide-receptor family has again yielded effective drugs, this time for migraine and cluster headache. I look forward to further developments in the future - Professor Debbie Hay (University of Auckland, New Zealand) 

Olcegepant (BIBN-4096BS) was the first potent CGRP receptor antagonist studied in an international, multi-centre, double-blinded and randomised clinical trial and showed effectiveness in treating acute migraine attacks in animals and humans. There was a significant increase in the response rate to olcegepant in comparison to placebo, with significant improvements in secondary end-points. However, as a result of its low bioavailability, olcegepant had to be administered intravenously in the clinic. It emerged as proof of concept for the mechanisms, which was ground-breaking for the CGRP field, but was not practical for the acute treatment of migraine. Adverse side effects of olcegepant were limited to higher doses and were mainly mild paresthesias. Merck & Co. further identified and optimised a similar potent molecule called telcagepant, which was the first orally available CGRP receptor antagonist to show triptan-like efficacy in acute treatment of migraine in clinical trials. After optimisation, telcagepant met the primary end-points in two Phase III trials to treat migraine and was generally well-tolerated with an adverse event rate similar to the placebo group. A second large Phase III clinical trial was conducted to confirm the efficacy of telcagepant. In this study, telcagepant (300 and 150mg) was more effective than placebo on all primary (pain freedom, pain relief, and absence of photophobia, phonophobia and nausea at 2h post-dosing) and the key secondary end-point of 2–24h of sustained pain freedom. In a study to assess the long-term safety and tolerability for the intermittent treatment of acute migraine, telcagepant was used by 640 patients to treat up to eight migraine attacks per month for up to 18 months. In these studies, telcagepant was generally well-tolerated and there were fewer of the adverse events commonly associated with triptans such as asthenia, chest pain, chest tightness and paraesthesia. However, in 2009 Merck & Co., Inc. announced that they were delaying the filing of the U.S. application for telcagepant as some patients had elevated liver transaminases based on a Phase II exploratory migraine prophylaxis study where patients were treated twice daily with telcagepant (140 or 280mg) for 3 months.  
 

The trendy CGRP-based therapies  

The recent development of CGRP-targeted therapeutic antibodies and small molecular receptor antagonists for migraine highlights the importance of CGRP as a multifunctional peptide. Several monoclonal antibodies have been approved by the Food and Drug Administration (FDA) for chronic migraine, being long-lasting and aiming to reduce the frequency of injections needed by patients. Erenumab (Aimovig, Amgen/Novartis) which blocks the CGRP receptor and fremanezumab (AJOVY, Teva Pharmaceuticals), galcanezumab (Emgality, Eli Lilly) and eptinezumab (Alder Biopharmaceuticals) which block the CGRP ligand, are the four antibodies that have been developed. Erenumab, the only antibody targeting the CGRP receptor, has also been approved by the European Medicines Agency (EMA) to prevent episodic migraine, in addition to chronic migraine. Erenumab, fremanezumab and galcanezumab are administered monthly via subcutaneous injection, whereas eptinezumab is delivered intravenously every 3 months (the application for the FDA approval is in review as of 22nd February 2019). If eptinezumab is to be granted FDA approval, it will be launched in the first quarter of 2020. Thus far, it is especially encouraging as all the therapies are effective for at least 15 months and well-tolerated with minimal side effects limited to pain at the injection site. Notably, the monoclonal antibodies do not cross the blood-brain barrier, presumably because of their large size and this further highlights the possible involvement of CGRP action at the peripheral sites in migraine.  

My research over the years has focused on the regulation of CGRP and its actions in the context of trigeminal-mediated disorders. A focus of the lab is a CGRP-sensitised transgenic mouse model we generated based on clinical reports that injection of CGRP is able to induce a migraine in migraineurs, but not in people who do not suffer from migraine. An exciting development is the recent FDA approval of the first in an emerging class of CGRP-targeted drugs designed to prevent migraine. We can now expect advances on several fronts that may help the development of centrally acting antagonists, combinatorial treatments that integrate other therapies, and development of drugs that target other neuropeptides. This is truly an exciting time for CGRP and the migraine field with many more discoveries on the horizon - Dr Andrew F Russo (University of Iowa, USA)

This begs the question, when will they be available in the UK? In January 2019, the UK National Institute for Health and Care Excellence (NICE) stated that it would not recommend using erenumab (the only EMA approved CGRP-related antibody) and that anti-CGRP therapies will unlikely be available to NHS patients at this time. Why? NICE currently recommends botulinum A toxin (botox) for chronic migraine patients who have failed with oral preventive medicines, as it has a good safety profile. However, there are operational issues associated with the running of clinics for botox administration. Importantly, NICE will reconsider the availability of erenumab to chronic migraine patients who do not respond to botox. 

Although all the CGRP-based therapies are efficacious with an excellent safety profile, with up to 32% of patients being completely relieved of symptoms, there are concerns about possible cardiovascular complications of blocking CGRP activity, especially given the prominent cardioprotective functions of CGRP both in humans and in preclinical studies. On the other hand, there is no evidence at this timepoint of worrying cardiovascular side effects in humans.  Although it is an exciting time for migraineurs and researchers in the migraine and CGRP field, the development of CGRP-based drugs is at a relative early stage as there is the need to understand more about where and how CGRP and other neuropeptides act.  

It has been exciting to be involved in discovering and coming to understand the relevance of CGRP, since our discovery of its vasodilator activity. It has not been easy to reach the current state with CGRP antibodies being used as effective anti-migraine agents and it is exciting to consider that the orally active small molecule CGRP antagonists are not too far behind in their journey to the migraine clinic. Perhaps the important point to remember is that the discovery of CGRP to the use of beneficial CGRP-targeted drugs in the clinic has taken over 30 years; emphasising that the discovery of new drugs is not easy. Excitingly, this may not be the end of the CGRP story, as basic science labs such as ours also show that in other circumstances, for example heart failure, CGRP can be protective. So it is very much ‘watch this space! - Professor Susan Brain (Kings College London, UK)

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Published: 14 Aug 2019
By Fulye Argunhan, Aisah Aubdool

About the author

Aisah Aubdool 



Aisah graduated with a BSc (Hons) in Pharmacology before gaining her PhD in 2014 from King’s College London, under the mentorship of Professor Susan Brain. Aisah moved to William Harvey Research Institute in 2016, as a postdoctoral research fellow in the lab of Professor Adrian Hobbs. Aisah’s research focuses on studying the role of C-type natriuretic peptide in vascular remodelling and aortic aneurysms.  

Aisah joined the British Pharmacological Society in 2010 and is currently the regional Ambassador coordinator for London. She is also the Vice Chair of the IUPHAR Young Investigator Committee, as well as a member of the Pharmacology Matters Editorial Board and the Public Engagement and Policy Committee at the British Pharmacological Society.

Fulye Argunhan  

Fulye is a MRC-funded PhD student in Professor Susan Brain’s Lab at King’s College London. She is currently investigating the mechanisms underlying αCGRP-induced vasodilation in hypertension. Fulye has been a member of the British Pharmacological Society since 2015.

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