Calcitonin gene-related peptide–targeted therapies for migraine

SUMMARY

Calcitonin gene-related peptide (CGRP)–targeted therapies are the first medications developed specifically for migraine prevention. They block the actions of CGRP, a neuropeptide with a key role in migraine pathophysiology. There are 2 categories of drugs: monoclonal antibodies directed against either the CGRP ligand or receptor, and small-molecule CGRP receptor antagonists.

CGRP monoclonal antibodies are available as self-administered subcutaneous injections or as an intravenous infusion, and are administered monthly or quarterly. Clinical trial and real-world data over the past 10 years support their effectiveness and safety in patients with episodic and chronic migraines, and research into long-term safety is ongoing.

Patients must fulfil certain criteria, including prior treatment with nonspecific oral preventive medications, to receive subsidised treatment with these drugs on the Pharmaceutical Benefits Scheme (PBS) in Australia.

Small-molecule CGRP receptor antagonists (known as gepants) are orally administered drugs that can be used for migraine prevention or acute treatment. There are no gepants listed on the PBS at the time of writing. Their role in the prevention and acute treatment of migraine is continuing to evolve.

 

Introduction

Migraine is the second leading cause of global disability and the number one cause in women under 50 years,¹ resulting in significant morbidity and high costs to the community.

Migraine is a complex disorder that should be managed holistically. Medications are an integral part of migraine treatment but are just one aspect of a comprehensive migraine management strategy. Implementing lifestyle interventions targeting stress and mood management, diet, exercise, hydration and sleep are also important to decrease migraine intensity and frequency, reduce disability, and improve self-efficacy in chronic migraine.

Preventive migraine therapy has traditionally relied on nonspecific oral medications from multiple drug classes including antidepressants, antiepileptics and antihypertensive agents, as well as onabotulinum toxin A injections.² Calcitonin gene-related peptide (CGRP)–targeted therapies are the first medications developed specifically for migraine prevention. These therapies block CGRP, the most common neuropeptide in the trigeminovascular system which is thought to play a critical role in migraine pathophysiology.³ The mechanism by which CGRP contributes to migraine is unclear; however, effects on vasodilation of meningeal blood vessels, and mediation of pain transmission in the central nervous system, have been proposed (Figure 1).⁴

CGRP-targeted therapies fall into 2 categories: monoclonal antibodies directed against either the CGRP ligand (galcanezumab, fremanezumab, eptinezumab) or receptor (erenumab); and small-molecule CGRP receptor antagonists (the ‘gepants’ – rimegepant and atogepant). Gepants are also used for acute treatment of migraine. CGRP-targeted therapies are approved in Australia for use in patients aged 18 years and older with migraine, and some have been evaluated for safety and efficacy in patients up to 80 years old.⁵

 

Classification of migraine

Quality of life in migraine sufferers is influenced by the frequency and severity of attacks, as well as other attack characteristics such as associated features and responsiveness to acute medications. The distinction between a headache day and a migraine day is important in reflecting the functional impact of an attack and is used in the current Australian Pharmaceutical Benefits Scheme (PBS) prescribing criteria to determine eligibility for certain preventive medications. Migraine with aura and migraine without aura are also often considered separately in migraine classification; however, this is not required for determining a migraine day. These definitions, according to The International Classification of Headache Disorders 3^rd edition, are provided in Box 1.

 

CGRP monoclonal antibodies for migraine prevention

CGRP monoclonal antibodies are administered as monthly or quarterly subcutaneous injections (galcanezumab, fremanezumab, erenumab), or as a 3-monthly intravenous infusion (eptinezumab) (Table 1). Eptinezumab requires access to an infusion unit, while the subcutaneous injections can be self-administered.

Table 1 Calcitonin gene-related peptide (CGRP) monoclonal antibodies available in Australia

Drug	Half-life [NB1]	Dosage and administration [NB1]	50% responder rate in chronic migraine [NB2]	PBS listed [NB3]
Galcanezumab	27 days	240 mg loading dose followed by 120 mg every 4 weeks, subcutaneous	27.6 to 32% (versus 8.9 to 15.4% in placebo group)7,8	Yes, for chronic migraine
Fremanezumab	31 days	225 mg every 4 weeks or 675 mg every 12 weeks, subcutaneous [NB4]	41 to 53% (versus 18 to 28% in placebo group)9,10	Yes, for chronic migraine and high-frequency episodic migraine (listed as ‘treatment-resistant migraine’ on the PBS)
Eptinezumab	27 days	100 mg every 12 weeks, intravenous [NB5]	55 to 57.6% (versus 39.3 to 40.5% in placebo group)11,12	Yes, for chronic migraine
Erenumab	28 days	70 to 140 mg every 4 weeks, subcutaneous [NB6]	40 to 41% (versus 23% in placebo group)13	No
PBS = Pharmaceutical Benefits Scheme (Australia) NB1: Half-life, and dosage and administration information are according to the Australian approved product information. NB2: Responder rate is measured as at least a 50% reduction in monthly migraine days. There was an even greater difference compared with placebo in 75% response rates and complete migraine freedom rates across the trials. Efficacy rates cannot be directly compared between the monoclonal antibodies because there have been no head-to-head trials. NB3: At the time of writing, adult patients are eligible to receive PBS-subsidised treatment if they have high-frequency episodic migraine (fremanezumab) or chronic migraine (fremanezumab, galcanezumab, eptinezumab) over a period of at least 6 months, have experienced an inadequate response, intolerance or contraindication to at least 3 migraine preventive medications (propranolol, amitriptyline, pizotifen, candesartan, verapamil, nortriptyline, sodium valproate or topiramate), and are appropriately managed by their practitioner for medication overuse headache, prior to treatment initiation. Patients must not be receiving concurrent treatment with botulinum toxin type A listed for chronic migraine or another CGRP monoclonal antibody. NB4: A 12-weekly dosing regimen could be considered for continuing treatment according to patient preference or practicality (e.g. to accommodate travel plans). NB5: The 300 mg dose is also available from the manufacturer but is not listed on the PBS at the time of writing. NB6: The 140 mg dose can be considered in patients who experience insufficient efficacy with the 70 mg dose.

Effectiveness of CGRP monoclonal antibodies

Randomised placebo-controlled trials and meta-analyses have shown that CGRP monoclonal antibodies are effective migraine preventers for many patients with episodic and chronic migraines.^14,15 Their efficacy is further supported by real-world studies in Australian and international patient cohorts, including patients with refractory chronic migraines.^16,17 While Australia does not have specific headache management guidelines, both the European Headache Federation and the American Headache Society now advocate for recommending CGRP-targeted treatments as first line for migraine prevention.^18,19 However, current PBS prescribing restrictions in Australia do not allow this unless privately funded (see Table 1).

Adverse effects of CGRP monoclonal antibodies

CGRP monoclonal antibodies are generally well tolerated, as demonstrated in clinical trials, open-label extension studies and real-world data.^14,20 They are large molecules broken down via the reticuloendothelial system, which results in no known drug interactions or limitations on use in renal or hepatic disease. The most common adverse effects of the subcutaneous formulations are minor nonspecific injection-site reactions, which can be managed by rotating sites across the abdomen and thighs, applying ice before and after injection, and an antihistamine if required. Low rates of nasopharyngitis were also reported in the original trials; other adverse effects were rare. Postmarketing studies have identified constipation, hypertension and Raynaud phenomenon,²¹ likely related to an imbalance between vasoconstrictive and vasodilatory mechanisms. Monitoring blood pressure is recommended.^22,23 Constipation may be more problematic with erenumab compared with other CGRP monoclonal antibodies.²⁴

Precautions with use of CGRP monoclonal antibody therapy

There are few contraindications to CGRP monoclonal antibodies, with the only absolute contraindication being prior hypersensitivity. Currently, while awaiting further studies of potential vascular risk, CGRP monoclonal antibodies should not be used in patients with active or recent cardiovascular or cerebrovascular disease; however, their lack of vasoconstrictive effect makes them a viable option in patients with stable disease.^25,26 They are not immunosuppressive,³ and can be safely co-administered with monoclonal antibodies used for other medical conditions. Rare reports of potential immune-related events include alopecia and autoimmune disease exacerbations;^27,28 however, pre-existing immunological conditions are not considered an absolute contraindication.

CGRP monoclonal antibodies should be avoided in pregnancy or lactation. CGRP is believed to play a regulatory role in embryo implantation and fetal development, which raises the possibility of adverse pregnancy outcomes with the CGRP monoclonal antibodies, including impacts on placental and fetal growth,²⁹ with limited pharmacovigilance data to date.³⁰ Due to their long half-life, a 5-month washout period prior to conception is recommended following CGRP monoclonal antibody therapy. As they are large protein molecules, transfer into human breastmilk is likely to be low but there are limited data.

Initiation of CGRP monoclonal antibody therapy

In Australia, CGRP monoclonal antibodies can be initiated on the PBS by a neurologist, or a general practitioner (GP) in consultation with a neurologist. They are indicated in adults who experience high-frequency episodic migraine (fremanezumab) or chronic migraine (fremanezumab, galcanezumab, eptinezumab) for over 6 months who have experienced an inadequate response, intolerance or a contraindication to at least 3 of a list of oral migraine preventive medications (e.g. propranolol, amitriptyline) prior to commencement of treatment.^31-33 An inadequate response is considered to be ongoing high-frequency episodic or chronic migraine despite treatment. Patients must also be appropriately managed for medication overuse headache, for which the first step is education and commitment to tapering or ceasing the overused acute analgesic(s) when possible. There is no reliable disease biomarker to predict drug response, such that a trial of CGRP-targeted therapy may be justified in any eligible patient without contraindications.

Selection of an individual CGRP monoclonal antibody can include considerations such as:

• therapeutic half-life (for example if therapeutic effect is wearing off before next administration, an agent with a longer half-life like fremanezumab would be preferable)
• ability to self-inject subcutaneously
• access to an infusion unit (for eptinezumab therapy), which varies regionally.

The autoinjectors and prefilled syringes for subcutaneous therapies are designed for patients to self-administer after initial instruction, including watching the manufacturer’s online instructional video. Some patients may ask their GP or practice nurse to assist with this. Ideally, any well-tolerated oral preventive medication should be continued while initiating the CGRP monoclonal antibody until it is clear that the oral medication can be withdrawn without causing a deterioration in migraine control because of partial effectiveness of the oral therapy.

Continuation of CGRP monoclonal antibody therapy

Continuation of CGRP monoclonal antibody therapy on the PBS requires documentation of at least a 50% reduction in the number of migraine days per month. Use of a headache diary is important for differentiating migraine from non-migrainous headache days (Box 1) and helps the patient and clinician set realistic treatment goals. Continuing prescriptions can be provided by a neurologist or a GP in consultation with a neurologist using a streamlined authority code.

Several months of treatment may be required to determine efficacy and further benefit may be seen with longer durations of treatment.³⁴ Some wearing off of effect may occur in the final days before the next dose is due, with migraine control restored after redosing. CGRP monoclonal antibodies exhibit sustained treatment efficacy in most cases,^35-37 and ongoing treatment is typically required to maintain migraine control. When a deterioration in migraine control occurs in a known responder, it is important to consider potential contributory factors, such as development of an intercurrent illness, deteriorating mental health, caffeine overuse and hormonal influences.

Switching between CGRP monoclonal antibodies

Switching between CGRP monoclonal antibodies may be considered in those experiencing suboptimal efficacy, adverse effects or accessibility issues. Switching agents is recommended if an initial 12-week trial is not sufficiently effective.⁵ There are no formal studies on repeated switching; however, experience in Australia in 2023 to 2024 because of nationwide shortages showed that repeated switching coincided with some patients experiencing a partial loss of treatment efficacy. There is currently no test for neutralising antibodies in the real world and the impact of these is unclear. If a switch of CGRP monoclonal antibody is to occur, the dose of the new drug should be given on the next scheduled date of CGRP monoclonal antibody administration.

Withdrawal of CGRP monoclonal antibody therapy

A trial of withdrawal may be recommended in patients experiencing a significant reduction in migraine days and minimal ongoing disability;⁵ however, cessation typically results in a gradual increase in migraine frequency back to baseline.³⁸ In select patients with well-controlled chronic migraine, if an underlying trigger such as perimenopause or illness has resolved, a trial of treatment withdrawal may be considered.

 

Small-molecule CGRP receptor antagonists (gepants)

Small-molecule CGRP receptor antagonists (gepants) are administered orally. They can be used as either acute or preventive migraine treatment. Two agents, rimegepant and atogepant, are approved by the Therapeutic Goods Administration; however, only rimegepant is available in Australia at the time of writing. Rimegepant is approved for prevention of episodic migraine in adults who have at least 4 migraine attacks per month, and acute treatment of migraine with or without aura. It can be prescribed as a private (non-PBS) prescription by any medical practitioner. Atogepant is approved for migraine prevention in adults who have at least 4 migraine days per month. The gepants are generally well tolerated, with potential for some constipation and nausea. However, due to their hepatic metabolism via the cytochrome P450 3A4 pathway, the gepants can have drug interactions.

Gepants as preventive therapy

Rimegepant is administered every second day when used for migraine prevention. It has similar efficacy to the CGRP monoclonal antibodies with a 50% responder rate of 49%.³⁹ As an orally disintegrating tablet, rimegepant may be preferable for those with needle phobia. Cost of therapy may be a limiting factor while not PBS-listed. With a shorter half-life compared with the monoclonal antibodies, there is a reduced washout period for assessing tolerability and planning pregnancy. However, gepants have not been studied in pregnancy or lactation, so their use is not recommended in these groups. Further studies regarding specific applications, such as in medication overuse headache and menstrual migraine, are of great interest.⁴⁰

Gepants as acute therapy

Gepants are recommended for treating a migraine attack if triptan monotherapy or combination therapy are insufficiently effective.⁴¹ In practice, gepants can be used together with triptans if needed for acute therapy, and a gepant can be used for acute treatment while also using a CGRP monoclonal antibody for migraine prevention.⁴² Gepants may be used in patients with stable cardiovascular disease as they do not cause vasoconstriction, or in those unable to tolerate a triptan.^41,43 Repeated use of gepants does not seem to contribute to risk of medication overuse headache.⁴⁴ The recommended dose of rimegepant for acute treatment is 75 mg when needed, with a maximum of 75 mg within a 24-hour period.

 

Comparison with alternative migraine preventive medications

Nonspecific oral medications, such as propranolol, amitriptyline, pizotifen, candesartan, verapamil, nortriptyline, sodium valproate or topiramate, remain the first-line medications for migraine prevention in Australia.² They are easily accessible, convenient for patients and cost-effective. The CGRP monoclonal antibodies are available on the PBS for certain patients, but their use is restricted based on strict eligibility criteria (Table 1) because of their high cost rather than efficacy.

Nonspecific oral preventive medications are not always as effective as the CGRP monoclonal antibodies and were previously evaluated in older clinical trials that may not align with current standards of randomised controlled trials in headache research.⁴⁵ Few direct comparisons have been made between individual oral preventives and CGRP monoclonal antibodies. For instance, a study comparing erenumab with topiramate found that erenumab offered better tolerability and efficacy.⁴⁶ In another study of more than 600 patients, 34.6% of patients prescribed a nonspecific oral preventive medication switched from their original medication because of lack of tolerability and efficacy compared with only 2.2% of patients prescribed erenumab.⁴⁷

Network meta-analyses have also suggested that the tolerability of CGRP-targeted medications is comparable with that of placebo,^14,15 whereas nonspecific oral preventive medications have higher rates of adverse effects including somnolence, weight gain, hypotension and cognitive dysfunction.⁴⁸ Patients were 70% less likely to discontinue a CGRP monoclonal antibody than a nonspecific oral migraine preventive medication.⁴⁶ There are limited comparative data available for the gepants.

Onabotulinum toxin A is an effective migraine preventive treatment that is available on the PBS for eligible patients with chronic migraine. Limited studies have compared CGRP monoclonal antibodies favourably with onabotulinum toxin A.^49,50 Administration of onabotulinum toxin A injections requires regular access to a neurologist and there are a proportion of patients who respond incompletely or not at all.⁵¹ The CGRP monoclonal antibodies have similar PBS criteria but self-administration of the subcutaneous options may provide a significant advantage for access by patients in regional areas. Concurrent therapy with both onabotulinum toxin A and a CGRP monoclonal antibody can be beneficial for the most refractory patients;⁵² however, this remains an expensive option since only one injectable treatment for migraine is subsidised by the PBS at a time.

 

Conclusion

CGRP monoclonal antibodies are effective, well tolerated and safe migraine preventive treatments in patients with episodic or chronic migraine who have not responded to other therapies. The role of small-molecule CGRP receptor antagonists in both the acute and preventive space, and in combination with other agents, is continuing to evolve to further bridge gaps in the management of migraine. These treatments are revolutionising the management of migraine for both patients and clinicians.

This article was finalised on 21 March 2025.

Conflicts of interest: Stephanie Barnes received partial support from AbbVie for a clinical fellowship position from 2019 to 2020. She is a current committee member of the Australian and New Zealand Headache Society.

Lucie Aldous is a member of the expert group for Therapeutic Guidelines: Neurology version 6 (under review). Lucie received consultancy fees from Teva (fremanezumab) in 2019 and provided expert review for the Bellberry Human Research Ethics Committee for the MOMENT pilot study in 2024. She is a current committee member of the Australian and New Zealand Headache Society.

Bronwyn Jenkins received fees for being on advisory boards for Novartis (erenumab), Teva (fremanezumab), Lilly (galcanezumab), AbbVie (onabotulinum toxin A) and Pfizer (rimegepant). Bronwyn previously received honoraria from Care Pharmacy, Healthed, and General Practice Conference and Exhibition for invited lectures. Bronwyn is on development and leadership, ethics, and education subcommittees of the International Headache Society (IHS) and is leading the development of educational materials for general practitioners. Bronwyn is an Associate Editor for Cephalalgia. She is the immediate-past president of the Australian and New Zealand Headache Society, previous board member of the IHS and an author of the 2024 IHS Global Practice Recommendations for the Acute and Preventive Pharmacological Treatment of Migraine.

This article is peer reviewed.

 

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