Migraine is an under-recognised and undertreated neurological condition that imposes a considerable health and economic burden worldwide.1 In the 2015 Global Burden of Disease Study, migraine was the seventh leading cause of disability and the leading neurological cause of disability, accounting for over half of the years lost to disability among all neurological disorders.2 Prophylaxis remains the best treatment option for migraine; however, most preventative therapies in current use are designed to treat high blood pressure, epilepsy and depression.3 They lack efficacy in migraine, are not well tolerated and have slow onset of action and high discontinuation rates; a 2013 survey found that less than 50% of people with episodic and chronic migraine were using preventative medicine.4 Recent advances in our understanding of migraine pathophysiology may help address this unmet need. In particular, a new class of biological drugs has emerged that act directly on the brain circuits responsible for migraine. These are humanised monoclonal antibodies that selectively bind to and inhibit calcitonin gene-related peptide (CGRP) or its receptor, which are crucial components in migraine activation.5 Their long duration of action allows for infrequent dosing, at monthly or even quarterly intervals.
Four monoclonal antibodies are currently in development for migraine prevention: three that act directly on CGRP (fremanezumab, galcanezumab and eptinezumab) and one that acts on the CGRP receptor (erenumab). Erenumab (Novartis) has been studied in over 3,000 patients, including an ongoing open-label extension up to five years in duration, and was the first investigational therapy targeting the CGRP pathway to have received Food and Drug Administration (FDA) and European Medicines Agency (EMA) regulatory filing acceptance. In the STRIVE phase III study, erenumab administered subcutaneously at a monthly dose of 70 mg or 140 mg significantly reduced migraine frequency, the effects of migraines on daily activities, and the use of acute migraine-specific medication over a period of 6 months.6 Recently announced data from the phase IIIb LIBERTY study showed that, in patients with episodic migraine who had failed 2–4 prior preventive treatments for migraine, a significant percentage of patients on erenumab achieved at least a 50% reduction of migraine days compared with placebo.7 Erenumab has also demonstrated efficacy in a phase II study of patients with chronic migraine.8
Fremanezumab (Teva Pharmaceuticals) is also administered subcutaneously. In the phase III HALO studies, which have involved more than 2,000 patients, fremanezumab as a preventive treatment for both chronic and episodic migraine resulted in a lower reduction in monthly migraine days compared with placebo over 12 weeks when administered monthly or quarterly. In addition, both dose regimens significantly improved migraine frequency in subjects taking stable doses of other preventative medications.9,10
Galcanezumab (Eli Lilly), is administered subcutaneously once monthly, and has demonstrated efficacy and safety in 2,901 patients in separate phase III studies: EVOLVE-1 and EVOLVE-2 in episodic migraine11 and REGAIN in chronic migraine.12 In all studies, the mean number of migraine headache days was significantly lower in the galcanezumab group compared with the placebo group.
A third CGRP antagonist, eptinezumab (Alder BioPharmaceuticals), is administered quarterly via intravenous infusion to achieve rapid physiological effect and has been administered to over 1,600 patients in clinical trials. In the recent phase III PROMISE studies, eptinezumab demonstrated efficacy and safety, with prevention benefit being reported on day 1 following infusion.13
Safety and tolerability data from all phase II and III clinical trials is excellent for all the anti-CGRP monoclonal antibodies, although long-term safety data is lacking. Injection-site reactions to the drug were commonly reported.14 These drugs are likely to be reviewed by the FDA in the next few months, with one or more potentially becoming commercially available in 2018. They will be expensive, so it will be important to identify patients most likely to benefit. Nevertheless, the anti-CGRP antibodies represent the most important advance in migraine prevention for decades.
While CGRP receptor antagonists have generated a great deal of media attention, they are not the only emerging novel therapeutic targets in migraine. Pituitary adenylate cyclase-activating polypeptides (PACAP), which are found in sensory nerves in the brain, have also emerged as important signalling molecules in migraine and cluster headache, and a number of options for blocking PACAP signalling are being investigated in early-stage clinical studies.15,16 Anandamide and palmitoylethanolamide, which are components of the endocannabinoid system (ECS), have shown promise for migraine prevention.17
The past year has also seen the first significant advances in the acute treatment of migraine for more than two decades. Lasmiditan, a first-in-class agent that selectively targets 5-HT1F receptors expressed in the trigeminal pathway, met its primary and secondary endpoints in the phase III SPARTAN study without the vasoconstrictor activity associated with some migraine therapies.18 Eli Lilly are expected to submit a new drug application for lasmiditan to the FDA in the second half of 2018. In addition, an orally-administered CGRP receptor antagonist has been developed for acute migraine treatment. In the recent ACHIEVE phase III study, ubrogepant 50 mg and 100 mg showed a statistically significant greater percentage of ubrogepant-treated patients achieving pain freedom at 2 hours after the initial dose as compared with placebo patients.19
In summary, a new era of migraine prevention and treatment is emerging, offering hope for both clinicians and patients.
1. World Health Organisation (WHO). Headache disorders. Available at: http://www.who.int/mediacentre/factsheets/fs277/en/ (accessed 6 February 2018).
2. GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388:1545–602.
3. Goadsby PJ, Sprenger T. Current practice and future directions in the prevention and acute management of migraine. Lancet Neurol. 2010;9:285–98.
4. Blumenfeld AM, Bloudek LM, Becker WJ, et al. Patterns of use and reasons for discontinuation of prophylactic medications for episodic migraine and chronic migraine: results from the second international burden of migraine study (IBMS-II). Headache. 2013;53:644–55.
5. Russo AF. Calcitonin gene-related peptide (CGRP): a new target for migraine. Annu Rev Pharmacol Toxicol. 2015;55:533–52.
6. Goadsby PJ, Reuter U, Hallström Y, et al. A controlled trial of erenumab for episodic migraine. N Engl J Med. 2017;377:2123–32.
7. Novartis. Novartis reports erenumab met all primary and secondary endpoints in unique Phase IIIb study in episodic migraine patients who have failed multiple prior preventive treatments. Available at: https://www.novartis.com/news/media-releases/novartis-reports-erenumab-met-all-primary-and-secondary-endpoints-unique-phase-iiib-study-episodic-migraine-patients-who-have-failed-multiple-prior-preventive (accessed 6 February 2018).
8. Tepper S, Ashina M, Reuter U, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2017;16:425–34.
9. Silberstein SD, Dodick DW, Bigal ME, et al. Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med. 2017;377:2113–22.
10. Teva. Teva’s fremanezumab meets all primary & secondary endpoints across both monthly and quarterly dosing regimens in phase III study in episodic migraine prevention. Available at: Tevapharm (accessed 6 February 2018).
11. Skljarevski V, Stauffer VL, Zhang Q, et al. PO-01-197 Phase 3 studies (EVOLVE-1 & EVOLVE-2) of galcanezumab in episodic migraine: results of 6-month treatment phase. Cephalalgia. 2017;37 Suppl. 339–40.
12. Detke HC, Wang S, Skljarevski V, et al. PO-01-195 A phase 3 placebo-controlled study of galcanezumab in patients with chronic migraine: results from the 3-month double-blind treatment phase of the REGAIN study. Cephalalgia. 2017;37 Suppl. 338.
13. Saper J, Lipton R, Kudrow D, et al. A phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of eptinezumab in frequent episodic migraine prevention: primary results of the PROMISE I (PRevention Of Migraine via Intravenous eptinezumab Safety and Efficacy I) trial, Cephalalgia. 2017;37 Suppl. 337.
14. Tso AR, Goadsby PJ. Anti-CGRP monoclonal antibodies: the next era of migraine prevention? Curr Treat Options Neurol. 2017;19:27.
15. Sundrum T, Walker CS. Pituitary adenylate cyclase-activating polypeptide receptors in the trigeminovascular system: implications for migraine. Br J Pharmacol. 2017; doi: 10.1111/bph.14053 [Epub ahead of print].
16. Vollesen ALH, Ashina M. PACAP38: emerging drug target in migraine and cluster headache. Headache. 2017;57 Suppl. 2:56–63.
17. Chirchiglia D, Della Torre A, Chirchiglia P. Focus on the endogenous cannabinoid system in medicine. EMJ Neurol. 2017;5:88–91.
18. Wietecha LA, Kuca B, Case MG, et al. PO-02-180 Phase 3 study (SPARTAN) of lasmiditan compared to placebo for acute treatment of migraine. Cephalalgia. 2017;37 Suppl. 367–8.
19. Allergan. Allergan announces positive top line phase 3 results for ubrogepant – an oral CGRP receptor antagonist for the acute treatment of migraine. Available at: www.prnewswire.com/news-releases/allergan-announces-positive-top-line-phase-3-results-for-ubrogepant–an-oral-cgrp-receptor-antagonist-for-the-acute-treatment-of-migraine-300593912.html (accessed 20 February 2018).