What do physicians in Canada need to know about anti-CGRP therapies?

In Canada, Aimovig (erenumab) is currently the only approved CGRP antibody but Emgality (galcanezumab) and Ajovy (fremanezumab) are being considered by Health Canada and are expected to be available at the end of 2019 or early 2020. As Canadian physicians start using anti-CGRP therapies, Dr Elizabeth Leroux, Headache Neurologist in Montreal, Quebec, and President of the Canadian Headache Society, addresses some common issues related to prescribing and access.

  1. Which patients should be considered for anti-CGRP treatment?

CGRP monoclonal antibodies (MABs) have been studied in patients with four migraine days or more per month though, in practice, factors other than migraine frequency must be taken into account. We need to consider the disability associated with attacks, the medical background and contra-indications to other drugs, and the preferences of the patient.

Coverage is a key factor, especially for a costly drug. At present, public and private insurers in Canada are evaluating erenumab reimbursement. Criteria for access include eight days or more of migraine per month and previous failure of two other preventives recognised in the Canadian guidelines. Once decisions are made, physicians will need to include this information in their clinical recommendations, as a patient could be an excellent candidate medically but, if coverage is denied, access would be limited.

  1. What dosing schedule is most appropriate?

In the studies on erenumab, both the 70 mg and 140 mg doses were shown to be effective, and there does not seem to be a significant dose-efficacy relationship. In refractory patients though, a sub-analysis showed that the 140 mg dose had a better odds ratio for success. Regarding side effects, once again the two doses did not differ significantly, but clinicians are used to associating a lower dose with better tolerability. This approach of ‘start low-go slow’, well known for oral preventives, may not be appropriate for MABs.

At present, clinicians might choose to start with erenumab 140 mg for refractory patients, and 70 mg for other patients, with the option to increase the dose in this second group according to the response. We are all on the learning curve and hopefully Phase IV studies will be published to guide practice in more detail.

  1. What do patients need to know when starting treatment?

Patients should be aware of the expected response rate and the potential side effects. Expectations should be reasonable as the response rates vary between 50% for some patients and 30% for more refractory patients, who are also the ones most likely to try MABs. MABs have virtually no interactions with other medications, which is a big advantage. Patients should be taught how to inject the product safely and if needed, should have access to resources to help with the first injection. Most patients can manage auto-injectors well, but a bit of help at the beginning is often required.

Regarding side effects, they seem to be more frequently reported in real life than in the studies, and this should not be surprising. This phenomenon has been seen with other medications in the past. This being said, we can wonder about the impact of social media in increasing the expectations of side effects. Forums discussing dramatic side effects may increase anxiety and favour a nocebo effect. Our responsibility is to carefully observe and record side effects to be able to inform our patients fairly. Rare adverse events should be recorded to document long term safety. We already have reassuring data on up to three years of erenumab but as the number of patients exposed grows, we’ll have access to more data.

  1. What does a good response look like?

Looking at the results from the trials, it comes as no surprise that some patients respond better than others. It may be that the underlying pathophysiology of their migraine is more CGRP-related. These ‘super responders’ can improve by 75% on frequency and also show improvements in pain intensity and associated symptoms. These are the patients who talk about a miracle effect. In studies, the 75% response rate was observed in 10 to 20% of patients. Some patients may exhibit a more modest 30% response. In chronic migraine, such an improvement may be clinically significant, and lead to an improvement in daily function.

  1. How do you decide that a patient isn't responding and should stop treatment?

Evaluating the response to a therapy can be obvious in the case of a 75% response, but a headache diary is always helpful. If a patient is not reporting any significant improvement in frequency and/or intensity after three months, studies suggest that it is unlikely that there will be a response. This being said, clinicians working with refractory patients (who were excluded from studies) may prolong the trial period as we do not know if a longer trial could lead to success in this severely affected population. Discussions with colleagues suggest that some patients may improve after three months. This is an important topic for Phase IV studies.

  1. What ongoing research is needed into anti-CGRP therapies?

Dozens of ideas are discussed in the scientific community. There is so much we have to learn. As we use these new therapies in the clinic, research questions become evident. We can list a few: the use of MABs in combination with Botox, the effectiveness in special populations (elderly, paediatric, treated with opioids, with vascular disease) or patients suffering from particular headache subtypes (hemiplegic migraine, vestibular migraine, new daily persistent headache, post-traumatic headache). A lot of work ahead!

  1. Are there any studies underway of anti-CGRP therapies that involve Canadian centres?

A phase IV trial named MAGIC, involving erenumab therapy for patients who have failed two to five preventives, will be initiated soon.

  1. How easy is it to get anti-CGRP therapies paid for in Canada?

Health care is managed provincially in Canada. A majority of Canadians are insured by private payers in association with their employers. Public coverage is available but varies. Some provinces, such as Quebec, have mandatory public coverage. It can be bewildering for physicians to be aware of which drug plan will cover MABs for which patient.

At present, the jury is still out. Private insurers seem to be open to the reimbursement of MABs, at least partially. Public coverage is still undetermined. The Canadian Agency for Drugs and Technology in Health (CADTH) evaluates the cost-effectiveness of therapies and makes recommendations on coverage for public insurers. Erenumab is currently being evaluated, and it is very probable that galcanezumab and fremanezumab will be too. Decisions may take two years and, of course, we hope for a favourable decision.

The co-prescription and coverage of Botox will be a major issue, as many chronic migraine patients get a partial relief with Botox therapy but then get even more relief from the combination with a MAB. This may seem like a costly treatment, but polytherapy is a common approach for multiple other chronic disorders and optimal quality of life should remain our goal for migraine patients. Once again, we are waiting for the insurers’ decisions.

CGRP MABs are a revolution in headache care. We have a lot to learn, but more to offer to our patients. The migraine community should be better organised to advocate for equitable access to optimal care.



Responders and super-responders in migraine prophylaxis trials: definition, distribution and consequences for practice

No biomarker or imaging technique is currently available to quantify migraine. To this day, the outcomes of therapeutic interventions are still based on headache diaries. Multiple techniques have been used to analyse results, but the mean decrease in headache days (including headache, migraine, probable migraine and moderate/severe days) and the 50% response rate have been the most widely chosen and recommended.

Now that CGRP antibodies are being studied, a new wave of methodological questions hits the headache community. Should we use different outcomes, and what would be the consequences of using such outcomes not only on our practice but also on drug coverage policies?

Results of the phase 2 trials for 75% and 100% response rates

50% responder rates have been used in the majority of randomised controlled trials (RCTs) of oral prophylactics for episodic migraine.1 The phase 2 RCTs on CGRP monoclonal antibodies (MABs) were the first to include 75% and 100% responder rates as pre-determined outcomes for episodic migraine, a sign of high expectations and hope for a cure. Available data from phase 2 studies are summarized in the table.

50% response 75% response 100% response
Episodic migraine
LY 150 mg3 70% v 45% (35%)

OR 2.88 (90% CI 1.78–4.69)

49% v 27% (22%)

OR 2.54 (90% CI 1.56-4.13)

32% v17% (14%)

OR 2.16 (90% CI 1.24-3.75)

ALD 1000 mg 4

Week 1-12

61% v 33% (28%)

95%CI: 12-43

33% v 9% (24%)

95%CI: 10-36

16% v 0% (16%)

95%CI: 8-27

AMG 70 mg5 46% v 30% (16%); p=.011 NA NA
High frequency episodic migraine
TEV 225 mg6

TEV 675 mg

53% v 28%(25%); p<.01

59% v 28% (31%); p<.01

34% v 11% (23%); p<.01

31% v 11% (20%); p<.01

Chronic migraine
TEV 672/225 mg7

TEV 900 mg

55% v 31% (24%) p=NA

53% v 31% (22%) p=NA

32% v 16% (16%) p=NA

29% v 16% (13%) p=NA

* The outcomes and baseline frequencies vary between trials. The data are shown to illustrate the response rates, not to compare studies.

In episodic migraine, the active treatments were all statistically superior to placebo for the 75% response rates. For galcanezumab and eptinezumab, 100% response rate showed a difference of 14% and 16% with placebo, respectively, but this difference was significant only for eptinezumab.

Fewer results are available for chronic migraine. The clinically meaningful response for chronic migraine is estimated to be 30%, lower than the 50% used for episodic migraine.2 Nevertheless, a 75% response was twice as likely to occur in the fremanezumab group, but no statistical analysis is yet available.

Beyond means: distribution of responders

How do patients respond to CGRP (or its receptor) antibodies? Three scenarios can be discussed.

  1. Response is homogeneous: all patients get a similar benefit from treatment. In this case, the mean response for reduction in headache days represents most patients.
  2. Response is binary: there are responders and non-responders. The mean reduction of headache days does not represent any patient as they are all on one extreme or the other, and one could argue to present the mean decrease separately for each group.
  3. Response is distributed along a continuum, from no response to super-response. The mean decrease is still difficult to interpret. This scenario seems to be the most likely.

Migraine frequency is known to vary in a single patient over time, depending on a vast array of factors. Response status may change over time and make the interpretation of response even more difficult.

Consequence on therapeutic algorithms and reimbursement issues

If, like the data suggest, the clinical response to CGRP MABs is a continuum, it would suggest that in different patient subgroups, the role of CGRP is different, and that in non-responders other peptides or mechanisms may play a greater role.

In the practical world, a clear and sustained separation between responders and non-responders would make clinical decisions easier. Monotherapy is a goal in migraine prevention. A mitigated or partial response leads to a difficult situation: the drug should be kept because there is a benefit, but another drug needs to be added with extra costs and an increased risk of side effects.

A continuum of response to MAB may impact the reimbursement of and access to those new treatments. Insurance companies may be more disposed to reimburse a trial of the drug knowing that a third of patients will not respond and will stop the drug. Real responders would significantly benefit, with significant decreases in acute drug use and indirect costs related to absenteeism and presenteeism.

In private systems, a partial response for most patients could lead to continuation of the drug for most patients willing to pay or having private coverage. In public systems, such a distribution of responders could simply lead to a denial of reimbursement on the basis of insufficient mean clinical benefit for large numbers and low cost-effectiveness. Trying to set rules based on response may also lead patients and clinicians to twist the facts to obtain reimbursement.


The mean decrease in headache days and 50% response rate have been very useful in interpreting data from previous trials and establish standards. As our understanding of migraine progresses, we need to present data in a way that represents our patients in their diversity, not only with meaningless means, and be aware of the impact of those findings on our practice.


  1. Jackson JL, Cogbill E, Santana-Davila R, et al. A comparative effectiveness meta-analysis of drugs for the prophylaxis of migraine headache. PloS one 2015;10:e0130733.
  2. Silberstein S, Tfelt-Hansen P, Dodick DW, et al. Guidelines for controlled trials of prophylactic treatment of chronic migraine in adults. Cephalalgia. 2008;28:484-495.
  3. Dodick DW, Goadsby PJ, Spierings EL, et al. 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;13:885-892.
  4. Dodick DW, Goadsby PJ, Silberstein SD, et al. Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol 2014;13:1100-1107.
  5. Sun H, Dodick DW, Silberstein S, et al. Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol 2016;15:382-390.
  6. Bigal ME, Dodick DW, Rapoport AM, et al. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol 2015;14:1081-1090.
  7. Bigal ME, Edvinsson L, Rapoport AM, et al. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol 2015;14:1091-1100.
From Silberstein, Cephalalgia 20082

Responder rate—number of headache days with moderate or severe intensity, number of migraine days, or number of migraine episodes

Responder rates may be included as a secondary endpoint. Responder rates should be defined as either 30% or 50% reduction in (i) headache days with moderate or severe intensity, (ii) migraine days, or (iii) migraine episodes compared with the baseline period. Responder rates have been traditionally defined in migraine as 50% reduction, but in chronic migraine population, a 30% responder rate can be clinically meaningful. Other responder rates (e.g. 25%, 75%) may also be considered. However, few trials have been done that identify the optimal responder rate for use in clinical studies, and therefore the optimal responder rate is not known at this time point. Responder rates can be used in meta-analyses of placebo-controlled, randomized, controlled trials. Specific responder rates used in the trial must be defined a priori