CGRP-targeting therapies as a first-line option for the prevention of migraine

The American Headache Society recently issued a position statement update on the use of migraine prevention therapies targeting calcitonin gene-related peptide

The American Headache Society (AHS) has published a position statement update regarding therapies targeting calcitonin gene-related peptide (CGRP) for the prevention of migraine.¹

The paper says that CGRP-targeting therapies should be considered as a first-line approach for migraine prevention along with previous first-line treatments without a requirement for prior failure of other classes of migraine preventive treatment.

Commenting on the rationale behind the new consensus statement, the President of the American Headache Society Dr Andrew Charles, Professor and Director of the Headache Research and Treatment Programme at UCLA School of Medicine, said “the goal of the Society is to improve the lives of people with headache disorders” and the creation of the new guideline was driven by the recent “astonishing” surge in both clinical trial and real-world evidence on the use of CGRP agents in prevention of migraine. “The evidence for their efficacy and especially their tolerability is just so overwhelming and our clinical experience backs that up,” he said.

“I would also point out that what comes out of some of the formal clinical trials and also some of the real world evidence is that these therapies work even in patients who’ve tried a host of other preventive therapies and failed them either due to lack of efficacy or tolerability so that’s a very important.”

How the guideline was developed

The AHS Board of Directors recognised the need for this specific guidance based on the pre-specified criteria in prior AHS consensus statements for iterative updates addressing the integration of newer migraine treatments. After a series of discussions over 2022 to 2023, a taskforce of authors working on behalf of the AHS was identified by the Executive Committee.

This update reviewed data about the efficacy, safety, and use of migraine treatments since the previous AHS Consensus Statement was undertaken.

Evidence regarding migraine preventive therapies including primary and secondary endpoints from randomised placebo-controlled clinical trials, post hoc analyses and open-label extensions of these trials, and prospective and retrospective observational studies were collected from a variety of sources including PubMed, Google Scholar, and ClinicalTrials.gov. The results and conclusions based upon these results were reviewed and discussed by the Board of Directors of the AHS to confirm consistency with clinical experience and to achieve consensus.

Results

The evidence for the efficacy, tolerability, and safety of CGRP-targeting migraine preventive therapies (the monoclonal antibodies: Erenumab, fremanezumab, galcanezumab, and eptinezumab, and the gepants: Rimegepant and atogepant) is substantial, and vastly exceeds that for any other preventive treatment approach, the AHS said.

Pivotal clinical trials of CGRP-targeting preventive therapies have all shown statistically-significant improvement in migraine (or headache) days for both episodic and chronic migraine in nearly all agents as summarised in previous AHS consensus statements.

The evidence remains consistent across different individual CGRP-targeting treatments and is corroborated by extensive real-world clinical experience. The real world studies generally confirm the results of the randomised controlled trials (RCTs) regarding efficacy, tolerability, and safety, and they do so within a wide variety of international cohorts, often over longer time periods, the AHS noted.

Overall, the data indicates that the efficacy and tolerability of CGRP-targeting therapies are equal to or greater than those of previous first-line therapies and that serious adverse events associated with CGRP-targeting therapies are rare.

“Based on this evidence and extensive clinical experience, CGRP-targeting therapies have rapidly become an indispensable option for the prevention of migraine,” the statement document says.

Adherence

A consistent finding across all the studies of CGRP-targeting therapies for migraine prevention has been a very low drop-out rate, the AHS statement document says. “This finding is an indicator of adherence, which in turn is an indicator of both efficacy and tolerability.”

Cost and access

The AHS acknowledges that the cost of, and therefore access to, these preventive therapies is an important factor (costs vary across health systems), but adds that this needs to be weighed alongside the cost of acute treatment, and the economic and personal cost of migraine (lost education, productivity, income, and interpersonal relationships).

“It is clear that if cost were not a primary consideration, there would be no controversy regarding the legitimate place for CGRP-targeting therapies as a first-line option for migraine prevention given their established safety, efficacy, and years of integration into practice.”

Switching

When a migraine preventive medication of any class is deemed to be effective and well-tolerated by provider and patient, it is inappropriate to switch a patient from one agent to another except in situations where there are issues with safety, the AHS statement paper acknowledges. “Even switching from one medication that is effective to another in the same class is associated with the risk of reduced efficacy or new adverse effects, so this practice is strongly discouraged.”

The evidence remains consistent across different individual CGRP-targeting treatments and is corroborated by extensive real-world clinical experience

European position

As noted by the AHS in its position statement, in 2022 the European Headache Federation (EHF) issued a guideline update² recommending the use of monoclonal antibodies targeting the CGRP pathway for migraine prevention: “The available data confirm that monoclonal antibodies targeting the CGRP pathway appear to be effective and safe for migraine prevention even in the long-term. Objective biomarkers of treatment response are still lacking; nevertheless, the available RCTs and real-world data can provide insights on treatment individualisation, including treatment duration, combination with other treatments, and the management of safety issues,” the EHF update states.

The basis for this focused AHS position statement is¹:

1. There is solid human evidence that establishes CGRP as a fundamental mechanism of migraine and therefore establishes CGRP-targeting therapies as ‘migraine-specific’ in contrast to all the other established therapies.

2. The cumulative evidence for the efficacy, safety, and tolerability of CGRP-targeting therapies is significantly greater than that for any established migraine preventive therapy. The remarkable tolerability of the CGRP-targeting therapies is a particularly positive feature.

3. Nearly all CGRP-targeting therapies are FDA-approved [US Food and Drug Administration] for the preventive treatment of both episodic and chronic migraine, which simplifies decision-making in patients who may spontaneously transition back and forth between episodic and chronic migraine.

4. There are multiple categories of evidence supporting the use of CGRP-targeting therapies that do not exist for other migraine preventive therapies, including: Responder rates, efficacy in patients with multiple prior treatment failures, efficacy in those with acute medication overuse, and those who do and do not have aura.

5. There is one head-to-head study demonstrating the superiority of a CGRP-targeting therapy (erenumab) over an established migraine preventive therapy (topiramate). In addition, multiple studies indicating the efficacy of CGRP-targeting migraine preventive therapies in those who have previously failed multiple other established treatments provide indirect evidence of the superiority of CGRP-targeting therapies for some patients.

6. Acknowledging CGRP-targeting therapies as first-line approaches will increase the likelihood that their efficacy and safety will be more thoroughly evaluated in understudied populations, particularly youth.

7. Cost considerations regarding migraine therapies should include not only the direct cost of the treatments, but also the indirect costs of healthcare utilisation and acute therapies, as well as socioeconomic costs for those who are disabled by the disease.

References

1. Charles AC, Digre KB, Goadsby PJ, Robbins MS, Hershey A; American Headache Society. Calcitonin gene-related peptide-targeting therapies are a first-line option for the prevention of migraine: An American Headache Society position statement update. Headache. 2024 Apr;64(4):333-341

2. Sacco S, Amin FM, Ashina M, et al. European Headache Federation guideline on the use of monoclonal antibodies targeting the calcitonin gene-related peptide pathway for migraine prevention – 2022 update. J Headache Pain. 2022 Jun 11;23(1):67

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