Targeted therapies herald new hope for migraine prevention


15 Jun 2020

As calcitonin gene-related peptide inhibitors continue to prove their value as important options in migraine prevention, there’s been a lot of anticipation about the promise for significantly better quality of life outcomes for patients with migraine. What can clinicians expect from this new class of monoclonal antibodies?

Here, the limbic talks to leading migraine specialist Dr Nicole Limberg, neurologist and Director of Migraine Specialist in Brisbane, about the anti-CGRP monoclonal antibodies and why neurologists are excited about using the agents.

Stepwise treatment with triptans

The current treatment landscape for migraine is complex, explains Dr Limberg who recommends stepwise treatment with triptans, usually tried after paracetamol and NSAIDs along with an antiemetic, for acute management of mild to severe migraine.

“We would advocate very early therapy, when migraine onset symptoms are very mild, which is more likely to terminate the migraine and treat more effectively,” said Dr Limberg.

For patients with severe migraine that don’t respond to NSAIDs migraine-specific 5-HT1 agonists, the triptans, are the standard acute treatment1.

Introduced in the 1990s, triptans stop migraine by stimulating receptors for the neurotransmitter serotonin, which reduces inflammation and constricts blood vessels. Use of the 5-HT1 agonists in acute migraine treatment is well established, says Dr Limberg, but they don’t work for everyone.

While triptans might help reduce pain and inflammation the drugs are contraindicated in people with uncontrolled or severe hypertension, ischaemic heart disease, previous myocardial infarction, stroke or coronary vasospasm due to their vasoconstrictive effect, notes Dr Limberg.

Meanwhile, side effects like numbness, dizziness and drowsiness can make them difficult to take2. Taken too often – more than three times a week – can risk triggering medication overuse headache, or rebound headache3.

Consider preventative therapies early on in frequent migraine

For patients with frequent migraine Dr Limberg says minimising regular use of acute treatments and pursuing preventative therapies early on is key.

For decades, the only medications available to prevent migraines were initially developed for other illnesses – seizure medications such as topiramate, amitriptyline, an antidepressant; and propranolol, a blood pressure medication are among an array of drugs borrowed from other disease treatments.

For some migraine patients these drugs come with ‘unbearable’ side effects says Dr Limberg adding that there has to be a ‘justification’ for pursuing such therapies.

“Four migraines per month is the line in the sand we would use to offer a patient a preventative therapy. We need an idea of their burden of disease because that’s when you make the call to say this is affecting you to such a degree that an oral medication every day is justified and of course the tablets have a myriad of unfortunate side effects so it has to be a justification for us to take that next step. We don’t want to over burden the patient with medication either.”

But while around 38% of patients with migraine should be offered preventive treatment4, it’s estimated that between 3-13%5 receive such therapy.

What’s more, among patients receiving preventive treatment, discontinuation rates are high, largely owing to a lack of efficacy or poor tolerability.6

As a result, >50% of patients who receive a prescription for oral migraine-preventive medication discontinue its use.7,8,9

“It’s dismal, the statistics are not good,” says Dr Limberg who adds that patients may also stop taking their therapy because they don’t understand why they’ve been prescribed an anti-seizure drug or an anti-depressant, for instance, as a prevention for migraine, especially if there is no feeling of some immediate benefit.”

According to Dr Limberg, it’s important to have an ‘upfront’ discussion with patients about the types of drugs they will be exposed to once a migraine prevention strategy is initiated, and the investment of time that will be required to get the drug therapy right.

“There is a lot of time spent going back through a patient’s medical history, making sure there are no allergies or medical conditions so that we’re not tripping on any issues there in terms of exacerbating any co-morbidities.

“We might have to try a few different therapies before we get a result and that involves frequent interactions with the patient, dose adjustments, dose escalations often cessation of the drug if side effects were to be developed so you’ve really got to have a very open conversation with the patient about engaging in a process that could go on over a number of months before we get the one that is just right for them – it’s incredibly individual in that regard.”

Nevertheless, if oral preventative therapy fails clinicians now have the option to move on to injection therapy, says Dr Limberg.

CGRP-targeted monoclonal antibodies in migraine prevention

Clinicians are now turning their attention to a new class of drug – a monoclonal antibody that targets either the calcitonin gene-related peptide (CGRP) or its receptors.10

They’re the first class of monoclonal antibody drugs designed specifically to prevent migraines and reduce their frequency, intensity, and duration.10

By blocking CGRP activity the medicine effectively short circuits a chemical process that is thought to be one of the leading causes of migraines, explains Dr Limberg.

The TGA has approved three CGRP-targeted monoclonal antibodies for migraine prevention in adults one of which is galcanezumab (EmgalityTM), which targets the peptide itself rather than the receptor.11

Though these drugs are a new addition to neurologists’ migraine treatment armoury Dr Limberg explains that CGRPs essential involvement in migraine has been known for some time.

In studies of people with migraine, CGRP was detected in the external jugular vein and was significantly elevated during migraine attacks12,13 while infusion of CGRP to individuals with a history of migraine was shown to trigger migraine attacks.14,15,16

“We have been working on CGRP’s role in migraine for 30 years now. Essentially, it’s a peptide that’s involved in inflammatory and vasodilation type functions. In the past vascular theories about migraine drove our research priorities but now evidence suggests there are inflammatory pathways involved and CGRP appears to be implicated in those factors.”

Quality of life improvements with galcanezumab (Emgality): The evidence

The EVOLVE-117 and EVOLVE-218 trials included over 1700 participants with episodic migraine, characterised by those who have between 4-14 migraine headache days (MHDs) per month, who were randomised for six months to monthly subcutaneous injections of galcanezumab (120mg/month, loading dose 240mg) or galcanezumab (240mg/Month) or placebo.

In Australia only the 120mg dose is TGA approved points out Dr Limberg.

“In Australian clinical practice a 240mg loading dose, given as two consecutive subcutaneous injections of 120 mg each, is recommended followed by 120mg dosing per month. These studies are reassuring in that there wasn’t a statistically significant difference between the two doses and in fact the 240mg actually got a bit more injection site reactions.”

In Evolve 1, galcanezumab demonstrated higher ≥50%, ≥ 75% and 100% response rates in the reduction in MHDs in any given month, on average versus placebo.  In total, 62.3% of those on the 120-mg dose achieved ≥50% reduction, versus 38.6% for placebo (P <.001).17

Meanwhile, a ≥75% reduction was achieved by 38.8% of those in the 120-mg dose group compared to 19.3% for placebo (P <.001).17

What’s more, in a smaller number of patients receiving the 120mg dose there was a total prevention of migraine attacks over the trial period with 15.6% of participants experiencing a 100% reduction in MHDs versus 6.2% for placebo (P <.001).17 Similar results were seen in the EVOLVE-2 trial.18

These response rates were separated from placebo within the first month, for both EVOLVE-1 and EVOLVE-2, 17,18 a finding that does not occur with current oral therapies that ‘often do not produce results for two to three months’, Dr Limberg points out.

Commenting on the clinical implications of the two EVOLVE trials, Dr Limberg said: “The researchers reported that over a 12-month period treatment equates to eight weeks of migraine freedom for responders – that’s incredible.”

For many of Dr Limberg’s patients those numbers are life changing.

“Our more severe migraine patients tell us they’d be happy with just one migraine free day here or there – I can’t tell you how many times I hear that – so this is ecstatic news for them. Its not a cure, no migraine drug thus far is, but it’s eight weeks migraine free a year. That’s a massive deal. ”

She also noted the significant change from baseline Migraine Disability Assessment (MIDAS) scores, the questionnaire used to assess how migraine influences a person’s everyday life, for patients treated with galcanezumab17.

“The treated group’s disability inventory [in EVOLVE-1] went from an average of 34.5 – indicating severe disability down to 15 – a moderately limiting disability, which is essentially half their disability and a considerable improvement on patients’ quality of life.”

Daily functioning scores (all domains of MSQ) were also increased by galcanezumab by a range of 4.7 to 8.3 points compared with placebo reflecting a functional improvement.17

Furthermore Evolve-1 and Evolve-2 demonstrated galcanezumab significantly reduced the MHDs that required acute medication use compared to placebo (p<0.001) 17,18 suggesting, that when migraine attacks did occur, their severity might have been reduced.

“Severity is difficult to measure, it’s very subjective which is why trials like these use migraine days [as a measure of efficacy] but people often do not use medication if their headache is mild and acute medicine use among the galcanezumab treated group did drop and that’s a good sign.”

Galcanezumab has also demonstrated clinical benefit and improved function in patients with chronic migraine – a condition where migraine sufferers report more than 15 headache days per month, eight or more of which are migraine.

REGAIN,19 a three-month, double-blind, placebo-controlled study, included over 1100 adult participants with chronic migraine randomised to receive once-monthly galcanezumab 120 mg after an initial loading dose of 240 mg, or galcanezumab 240 mg, or placebo.

The primary endpoint was overall mean change from baseline in the number of monthly MHDs over months one to three.

Baseline MHDs for galcanezumab was 19.4 and placebo was 19.6. Participants given galcanezumab 120mg reported 4.8 fewer monthly headache days compared to 2.7 days for placebo (p<0.001). Results showed at least a 50% reduction in MHDs in any given month of 28% for galcanezumab 120 mg compared to 15% for placebo (p<0.001).

Dr Limberg said findings from all three studies indicate both episodic and chronic migraine patients who have failed several migraine therapies are good candidates for galcanezumab.

“I would say any patient with more than four migraines per month, whose migraines are affecting quality of life – they’re missing days from work or school, they’re saying no to social events or they’ve used up all their sick days for instance – as well as patients whose acute treatments are failing can be considered for this treatment.”

Managing side effects

In both Evolve 1 and Evolve 2 injection-site erythema, injection-site pruritus, and injection site reaction were the most frequently reported treatment emergent adverse events (TEAEs) related to galcanezumab compared with placebo, but most events were mild to moderate in severity and discontinuations owing to AEs of galcanezumab-treated patients were low (3.8%17 and 1.7%18), the study investigators report.

Dr Limberg noted that outside of local injection reactions and constipation in a CGRP receptor blocker, CGRP-targeted monoclonal antibodies had generally been well tolerated.

“It’s relatively early days and there are theoretical concerns in terms of patients with cardiac event history or significant cardiovascular risk factors – these patients were excluded from the trial because of the potential interaction on the cardiovascular bed and that’s something that were continuing to monitor,” she said.

For Dr Limberg the safety and tolerability profile of the monthly treatment, means potentially improved adherence and, ultimately, quality of life for people with migraine.

“These treatments have far more data associated with them [compared to current migraine prevention therapies] and a far more pleasant side effect profile.

We haven’t seen significant adverse events from the medication at this stage – it’s a very well tolerated drug. In the studies it was a very small percentage who discontinued treatment because of injection site reactions they were transient and classed as mild and any more significant events that occurred didn’t occur in more than one patients and were not thought to be related to the preparation.”

Like other B1 category drugs, the safety of the drug class in pregnancy is not yet known cautions Dr Limberg who says clinicians should discuss this with patients of childbearing age.

“Because of their half life the patient are not to try to conceive for five or six months after they’ve been used so every patient on this drug needs to have a very clear understanding of where they are in terms of their childbearing decisions.”



  1. National Institute for Health and Care Excellence (NICE). Headaches. Diagnosis and management of headaches in young people and adults. NICE, 2012
  2. Dodick, D., & Martin, V. (2004). Triptans and CNS Side-Effects: pharmacokinetic and metabolic mechanisms. Cephalalgia24(6), 417–424.
  3. Lipton RB, Silberstein SD. Headache. 2015;55(Suppl. 2):103-122.
  4. Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF; AMPP Advisory Group. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68(5):343-349
  5. Rizzoli P. Preventive pharmacotherapy in migraine. Headache. 2014;54(2):364-369.
  6. Blumenfeld AM, Bloudek LM, BeckerWJ, 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(4):644-655.
  7. Diamond S, Bigal ME, Silberstein S, Loder E, Reed M, Lipton RB. 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(3):355-363.
  8. Loder EW, Rizzoli P. Tolerance and loss of beneficial effect during migraine prophylaxis: clinical considerations. Headache. 2011;51(8):1336- 1345.
  9. Berger A, Bloudek LM, Varon SF, Oster G. Adherence with migraine prophylaxis in clinical practice. Pain Pract. 2012;12(7):541-549.
  10. Tiseo, C., Ornello, R., Pistoia, F. et al.How to integrate monoclonal antibodies targeting the calcitonin gene-related peptide or its receptor in daily clinical practice. J Headache Pain 20,49 (2019).
  12. Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990;28(2):183-187.
  13. Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol. 1993;33(1):48-56.
  14. Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J. CGRP may play a causative role in migraine. Cephalalgia. 2002;22(1):54-61.
  15. Lassen LH, Jacobsen VB, Pedersen PA, Sperling B, Iversen H, Olesen J. Human calcitonin gene related peptide (hCGRP)-induced headache in migraineurs. Eur J Neurol. 1998;5(suppl 3):S63.
  16. Dodick DW, Goadsby PJ, Spierings ELH, Scherer JC, Sweeney SP, Grayzel DS. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2014;13 (9):885-892.
  17. Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR. Evaluation of Galcanezumab for the Prevention of Episodic Migraine: The EVOLVE-1 Randomized Clinical Trial. JAMA Neurol.2018;75(9):1080–1088. doi:10.1001/jamaneurol.2018.1212
  18. Skljarevski, V., Matharu, M., Millen, B. A., Ossipov, M. H., Kim, B.-K., & Yang, J. Y. (2018). Efficacy and safety of galcanezumab for the prevention of episodic migraine: Results of the EVOLVE-2 Phase 3 randomized controlled clinical trial. Cephalalgia,38(8), 1442–1454.
  19. Holland C. Detke, Peter J. Goadsby, Shufang Wang, Deborah I.Friedman, Katherine J. Selzler, Sheena K. Aurora Galcanezumab in chronic migraine The randomized, double-blind, placebo-controlled REGAIN study. Neurology Dec 2018, 91 (24) e2211-e2221
  20. Deen, M., Correnti, E., Kamm, K. et al.Blocking CGRP in migraine patients – a review of pros and cons. J Headache Pain 1896 (2017).

Already a member?

Login to keep reading.

Email me a login link