Updates & Features
CGRP Antibodies for the Treatment of Migraine
October 2018
Can the first migraine-specific therapeutics change the treatment landscape?
PainSolve Editorial Team
State of the art in migraine
Migraine is one of the most prevalent and disabling disorders in the world, yet, until recently, no preventive treatments in clinical use were developed specifically for migraine. In May 2018, the FDA approved the first in a new class of drugs designed for the preventive treatment of migraine in adults.1 Erenumab, administered as a once-monthly self-injection, acts by blocking the activity of calcitonin gene-related peptide (CGRP), a molecule that spikes during migraine attacks.1,2 Three other CGRP-targeted monoclonal antibodies are also under investigation for their potential in the treatment of migraine: galcanezumab, eptinezumab and fremanezumab.3
The pathophysiology of migraine
Migraine is a neurological disorder characterised by debilitating headache accompanied by sensory alterations.4 The trigeminovascular system is intricately involved in the pathophysiology of migraine; it is thought that migraine headache is a manifestation of altered brain excitability activating the trigeminovascular system in genetically susceptible individuals.4,5 The system is centred around the trigeminal nerve, the efferent projections of which synapse with second-order neurons in the trigeminal nucleus caudalis (TNC) of the brainstem.4 These neurons project to the thalamus, where ascending input is integrated and relayed to higher cortical areas.4 Activation of the trigeminovascular system most likely involves peripheral mechanisms, such as inflammatory mediators and agents released during neurogenic inflammation and cortical spreading depression (CSD).4 The most abundant neuropeptide in the trigeminal nerve is CGRP, which is expressed in 35–50% of neurons in the trigeminal ganglia.4
CGRP and its role in migraine
CGRP is a 37-amino acid discovered over 30 years ago that is widely distributed throughout the central and peripheral nervous systems.6 It has been implicated in the pathophysiology of migraine and evidence suggests it also plays a role in other headache and facial pain disorders.6,7 CGRP exists in 2 isoforms: α-CGRP (found in both the central and peripheral nervous systems and preferentially expressed in sensory neurons) and β-CGRP (preferentially expressed in enteric nerves and the pituitary gland).8 α-CGRP is more abundantly expressed than β-CGRP and has a 3- to 6-fold higher concentration.8
CGRP acts on an unusual receptor family that consist of calcitonin receptor-like receptor (CLR) linked to an essential receptor activity modifying protein (RAMP).3,8 The CGRP receptor is expressed throughout the nervous system and is also found throughout the arterial system in the smooth muscle cell layer, including the cardiovascular and cerebrovascular systems, in addition to the adrenal glands, kidneys, and pancreas.3 During a migraine, CGRP is released from trigeminal afferent nerve fibres, causing vasodilatation and neurogenic inflammation. CGRP-targeted antibodies are believed to work by blocking the activity of CGRP, reducing migraine symptoms.6
The evidence for CGRP antibodies in migraine
The use of monoclonal antibodies for the treatment of neurological disorders has increased in recent years, partly due to their highly specific activity and long half-life, making them suitable for conditions such as migraine and allowing for less frequent dosing (i.e. once or twice monthly).3 There are 4 CGRP-targeted monoclonal antibodies currently under investigation for migraine prevention (see table below).9,10 Erenumab is the only antibody that targets the CGRP receptor and has recently been approved by the FDA; the other drugs (galcanezumab, eptinezumab and fremanezumab) target CGRP itself and have received approval from regulatory authorities.1–3
| Drug name | Target | Half-life | Key phase 3 trials |
| Erenumab (AMG-334) |
CGRP receptor with a human antibody | 21 days | STRIVE (completed in EM) ARISE (completed in EM) LIBERTY (ongoing in refractory EM) EMPOwER (ongoing in EM) |
| Galcanezumab (LY2951742) |
CGRP with a humanised antibody | 28 days | EVOLVE-1 and EVOLVE-2 (ongoing
trials in EM) REGAIN (ongoing in CM) |
| Eptinezumab (ALD403) |
CGRP with a humanised antibody | 31 days | PROMISE 1 (ongoing in frequent
EM) PROMISE 2 (ongoing in CM) |
| Fremanezumab (TEV-48215) |
CGRP with a fully humanised antibody | 40–48 days | HALO (ongoing long-term safety) FOCUS (ongoing in refractory EM or CM) |
CM: Chronic migraine; EM: Episodic migraine
Evidence for these innovative treatments in migraine have been positive; phase 2 and phase 3 trials versus placebo treatments indicate efficacy from approximately 4 weeks (current preventative treatments typically take up to 8 weeks), although these results should be interpreted with caution.3 Statistical analyses suggest that these therapies are associated with significantly fewer days with migraine.3,10 Safety and tolerability data appear promising with no major safety signals identified.3,10
The future of migraine therapies
The CGRP-targeted monoclonal antibodies represent the first class of therapeutics targeted at a migraine-specific mechanism and may well shape the future of migraine prevention. The recent FDA approval of erenumab paves the way for more widespread adoption of CGRP antibodies and will allow for the collection of real-world data to better analyse the impact on patients, as well as potential expansions into other indications such as cluster headache.
References
- FDA. Available at: https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm608120.htm
- Science. Available at: http://www.sciencemag.org/news/2018/05/will-antibodies-finally-put-end-migraines
- Tso AR & Goadsby PJ. Curr Treat Options Neurol. 2017; 19(8): 27.
- Russo AF. Annu Rev Pharmacol Toxicol. 2015; 55: 533–552.
- Noseda R & Burstein R. Pain. 2013 Dec; 154 Suppl 1: 10.1016/j.pain.2013.07.021.
- Russell FA et al. Physiol Rev. 2014 Oct;94(4):1099-142. doi: 10.1152/physrev.00034.2013.
- Schuster NM & Rapoport AM. Clin Neuropharmacol. 2017 Jul/Aug;40(4):169-174. doi: 10.1097/WNF.0000000000000227.
- Durham PL. Headache. 2008 Sep; 48(8): 1269–1275.
- Bigal ME et al. Br J Clin Pharmacol. 2015 Jun; 79(6): 886–895.
- Edvinsson L. Headache. 2018 May;58 Suppl 1:33-47. doi: 10.1111/head.13305.