Migraine prophylaxis – finally, something that works

22nd April 2021, Dr Chee L Khoo


We know migraines as recurrent episodes of headache, associated with symptoms such as nausea, photophobia and phonophobia. While we have agents that can treat acute migraine pretty effectively, many patients with migraines have frequent episodes. These patients with frequent migraines should be offered migraine prophylaxis. Unfortunately, amongst patients with frequent migraines, only 3–13% receive migraine preventive treatment [1,2]. Further, among patients who receive preventive treatment, discontinuation rates are up to 68%, mostly because of tolerability issues or lack of efficacy [3-5]. We explored the new agents for migraine prevention about a year ago. One of them is almost here on the PBS. We better get prepared for the launch.

We know the mechanisms that triggers off the symptoms of migraines. Calcitonin gene-related peptide (CGRP) is 37 amino acid neuro-peptide, located both in the central and the peripheral nervous system, especially in the dorsal root and trigeminal ganglions. It acts as a sensory neurotransmitter, vasodilator, and mediator of neurogenic inflammation [6]. CGRP was found to be significantly elevated during migraine attacks, while intravenous infusion of CGRP to individuals with a history of migraine could trigger migraine attacks.

To reduce acute migraine episodes, migraine specific agents could either block the CGRP or CGRP receptor on the post synaptic neuron – See Figure 2. Current agents like triptans, 5-HT1B/D receptor agonists (e.g. ergotamine), and other migraine-specific treatments have been shown to reduce CGRP plasma levels in migraine patients. But what about migraine prevention?

Anti-CGRP Agents

Until recently, preventive treatment was neither disease-specific nor mechanism-based but rather repurposed anti-hypertensive, antiepileptic, and antidepressant agents, therefore, causing a great number of adverse events. It’s kind of hit and missed or prescribe and hope it works over the next three months. The new agents directly act on the CGRP or the receptors. galcanezumab,  fremanezumab, and eptinezumab, which target the ligand, and erenumab, which blocks the receptor. Mechanistically, they should all work in treating acute migraine episodes. But how do they prevent episodes? What if we can have a long acting CGRP antagonist that chronically reduce CGRP action? That should prevent migraine attacks.

Galcanezumab is a humanised monoclonal antibody (mAb) that binds CGRP and prevents its biological activity without blocking the CGRP receptor. It is administered once a month via a prefilled syringe or an autoinjector dosed at 120 mg. Subcutaneous galcanezumab is approved in many countries, including the USA and EU countries, for the prevention of episodic and chronic migraine.

There are 3 clinical scenarios we need to treat – episodic, chronic and treatment resistant migraines. The role of galcanezeumab in each one of those scenarios are examined in 4 randomised, double-blind, placebo-controlled, phase III, multi-centre, clinical trials:

Episodic migraine

This clinical scenario was explored in EVOLVE-1 [7] & EVOLVE-2 [8]. These are patients who were experiencing 4–14 migraine headache days (MHDs) per month, and had ≥ 2 migraine attacks per month during the baseline period. EVOLVE-1 included 858 subjects across 90 sites in North America and EVOLVE-2 studied 915 subjects at 109 study sites around the world, including sites in North America, Europe, the Middle East, and Asia. Most (60-65%) of patients have received prior preventive treatment. Many (4-15%) have failed at least two prior preventive treatment. Both 120mg and 240mg monthly injections of galcanezumab significantly reduce more MHDs compared with placebo (-4.3 and -4.2 vs -2.3). Galcanezeumab had a fairly rapid onset as patient reported reduction of MHD within one week of injection. patients who received galcanezumab reported fewer days of missed work or school, reduced productivity at work or school, missed household work, reduced productivity in household work, and missed family or social activities than placebo recipients.

Chronic migraine

This clinical scenario was explored in the REGAIN [9] trial. Patients had chronic migraine (≥15 headache days per month, of which _8 were MHDs), aged 18–65 years. Both doses of galcanezumab achieved a reduction of 4.8 and 4.6 monthly MHDs, respectively, compared to 2.7 achieved by placebo (p < 0.001).

Treatment-resistant episodic or chronic migraine

This clinical scenario was explored in the CONQUER [10] trial. These are patients who had to have failed to respond to two to four standard-of-care migraine preventive treatments due to poor efficacy or/and poor tolerance (safety reasons). Medication included antihypertensive, antiepileptic, and antidepressant agents such as propranolol, topiramate, and amitriptyline. Galcanezumab was found to be superior to placebo in reducing monthly MHDs (-4.1 vs. -1.0, p < 0.0001).


In the trials galcanezumab had a favourable safety profile and was well-tolerated, as most common treatment-emergent adverse events were transient and of mild to moderate severity. These included injection-related AEs, such as injection site reaction, injection site pruritus, injection site pain and erythema,  nasopharyngitis, and upper respiratory tract infection.

An important side effect worth considering is adverse cardiovascular events. Many of our antimigraine medications are vasospastic agents and may be associated with increased stroke risk. CGRP, is involved in regulation of blood pressure via vasodilation, mostly during hypertensive states rather than under normal circumstances [11]. CGRP also protect against ischemia by increasing cerebral blood flow [12], while it appears to be able to reduce post-stroke brain injury as well [13]. If you block CGRP, will there be a problem?

Although none of the trials reported an increased risk of developing cardiovascular adverse events following galcanezumab administration, in the EVOLVE-2 trial, two patients in the galcanezumab 240 mg group reported acute myocardial infarction and transient ischemic attack (TIA) while hypertension was observed in five patients. Thus, larger, long-term trials need to be conducted to confirm galcanezumab’s safety, especially regarding cardiovascular risk.

All of the anti-CGRP mabs are large peptides, have high target specificity with minimal potential for off-target toxicity, are degraded and cleared within the reticuloendothelial system, do not undergo hepatic metabolism or renal clearance, and do not compete for binding sites. Therefore, there is a minimal likelihood of drug interactions [14].

The development of anti-CGRP monoclonal antibodies represents a very promising emerging option in the prevention of episodic and chronic migraine. Existing migraine prophylactic agents were

not specifically developed for migraine, thus resulting in a noticeable number of TEAEs and poor treatment adherence. On the other hand, anti-CGRP monoclonal antibodies have a greater half-life time compared to conventional oral agents, which allows monthly administration instead of daily intake, making treatment more convenient for migraine patients and potentially improving adherence, thus efficacy.

Galcanezumab is approved by the TGA and is poised to be listed on the PBS anytime soon pending price negotiations.


  1. Lipton, R.B.; Bigal, M.E.; Diamond, M.; Freitag, F.; Reed, M.L.; Stewart, W.F. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology 2007, 68, 343–349.
  2. Blumenfeld, A.M.; Bloudek, L.M.; Becker,W.J.; Buse, D.C.; Varon, S.F.; Maglinte, G.A.;Wilcox, T.K.; Kawata, A.K.; Lipton, R.B. 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, 644–655
  3. Berger, A.; Bloudek, L.M.; Varon, S.F. Adherence with migraine prophylaxis in clinical practice. Pain Pract. 2012, 12, 541–549
  4. Diamond, S.; Bigal, M.E.; Silberstein, S.; Oster, G. Patterns of diagnosis and acute and preventive treatment for migraine in the United States: Results from the American Migraine Prevalence and Prevention study. Headache 2007, 47, 355–363
  5. Loder, E.W.; Rizzoli, P. Tolerance and loss of beneficial effect during migraine prophylaxis: Clinical considerations. Headache 2011, 51, 1336–1345
  6. Ho, T.W.; Edvinsson, L.; Goadsby, P.J. CGRP and its receptors provide new insights into migraine pathophysiology. Nat. Rev. Neurol. 2010, 6, 573–582.
  7. Staufer, V.L.; Dodick, D.W.; Zhang, Q.; Carter, J.N.; Ailani, J.; Conley, R.R. Evaluation of galcanezumab for the prevention of episodic migraine: The EVOLVE-1 randomized clinical trial. JAMA Neurol. 2018, 75, 1080–1088
  8. Skljarevski, V.; Matharu, M.; Millen, B.A.; Ossipov, M.H.; Kim, B.K.; Yang, J.Y. Efficacy and safety of galcanezumab for the prevention of episodic migraine: Results of the EVOLVE-2 Phase 3 randomized controlled clinical trial. Cephalalgia 2018, 38, 1442–1454
  9. Detke, H.C.; Goadsby, P.J.;Wang, S.; Friedman, D.I.; Selzler, K.J.; Aurora, S.K. Galcanezumab in chronic migraine: The randomized, double-blind, placebo-controlled REGAIN study. Neurology 2018, 91, e2211–e2221
  10. Mulleners, W.M.; Kim, B.; Lainez, M.J.; Lanteri-Minet, M.; Pozo-Rosich, P.; Wang, S.; Tockhorn-Heidenreich, A.; Aurora, S.K.; Nichols, R.M.; Yunes-Medina, L.; et al. A randomized, placebo-controlled study of galcanezumab in patients with treatmentresistant migraine: Double-blind results from the CONQUER Study (162). Neurology 2020, 94, 162.
  11. Smillie, S.J.; King, R.; Kodji, X.; Pozsgai, G.; Fernandes, E.;Marshall, N.; deWinter, P.; Heads, R.J.; Dessapt-Baradez, C.; Gnudi, L.; et al. An ongoing role of _-calcitonin gene-related peptide as part of a protective network against hypertension, vascular hypertrophy, and oxidative stress. Hypertension 2014, 63, 1056–1062.
  12. Zhang, J.Y.; Yan, G.T.; Liao, J.; Deng, Z.H.; Xue, H.; Wang, L.H.; Zhang, K. Leptin attenuates cerebral ischemia/reperfusion injury partially by CGRP expression. Eur. J. Pharmacol. 2011, 671, 61–69
  13. Aradi, S.; Kaiser, E.; Cucchiara, B. Ischemic stroke associated with calcitonin gene-related peptide inhibitor therapy for migraine: A case report. J. Stroke Cerebrovasc. Dis. 2019, 28, 104286.
  14. Bigal, M.E.; Walter, S.; Rapoport, A.M. Therapeutic antibodies against CGRP or its receptor. Br. J. Clin. Pharmacol. 2015, 79, 886–895.