Disrupting Migraine Dynamics: A Narrative Review of the Consequences of Modern Anti-CGRP Monoclonal Antibody Therapies

Abstract

This article provides an overview of a symposium held as part of the proceedings at the 10th European Academy of Neurology Congress in Helsinki, Finland, on 2 July 2024. Migraine is a common neurological disease and a leading cause of disability worldwide. Anti-calcitonin gene-related peptide (CGRP) therapies are the first to be specifically developed for migraine prevention and are recommended as a first-line option by the American Headache Society and European Headache Federation. Data on the effectiveness of anti-CGRP therapies are now available from clinical trials and real-world studies, and this article briefly reviews these data and discusses what they mean for people with migraine, and how healthcare professionals can take the conversation back to their clinics.

Key Summary Points

Migraine is a chronic disease with episodic attacks. A migraine attack is not just a headache. Migraine attacks are made up of several stages comprising a constellation of disabling and impactful symptoms

Migraine is the second leading cause of disability in women aged 15–49 years worldwide. Disability worsens with increases in monthly headache and/or migraine days

Anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) are the first therapies developed specifically for migraine prevention

Evidence of the efficacy of anti-CGRP mAb therapies for migraine prevention is available from both clinical trials and real-world studies, and switching anti-CGRP mAb therapy can be effective in people who have previously experienced treatment failure with an anti-CGRP mAb

Current treatment strategies and reimbursement/insurance rely on headache frequency alone, meaning that patients may experience delays in accessing optimised treatments, leading to worsening of their disease

Patient-centricity is key in treatment planning and improves adherence; people with migraine should be involved in the process of selecting treatments and establishing goals

Introduction

Migraine is a prevalent, disabling and sometimes progressive disease affecting more than 1 billion people globally [1]. It is the second leading cause of disability-adjusted life-years in women aged 15–49 years and of people aged 20–59 years (with the leading causes being gynaecological disorders and stroke, respectively) [1, 2]. Migraine-associated disability occurs both during and between attacks [3, 4]. Migraine can be classified as episodic or chronic based on headache frequency; the diagnostic criteria for chronic migraine (CM) include headache that occurs on ≥ 15 days/month for > 3 months, with headache ≥ 8 days/month exhibiting migraine features or responding to triptans or ergot-derivative medications [5]. Approximately 3% of people with episodic migraine (EM) convert to CM annually using the traditional definition of progression of crossing the threshold of 15 monthly headache days (MHDs), intensifying the overall burden of disease [6, 7]. Progression or migraine disease worsening can be conceptualised in many ways and can be associated with many undesirable outcomes [8]. People with migraine also experience stigma, which is associated with disability and lower quality of life, depression and anxiety, less care-seeking and poorer treatment outcomes [9, 10]. In the realm of migraine prophylaxis, the advent of anti-calcitonin gene-related peptide (CGRP) therapies marks a pioneering development, as these neuropeptides are the first pharmacological agents specifically tailored for migraine prevention. This contrasts with the historical reliance on traditional oral preventive medications initially formulated for other indications that were repurposed for migraine, such as beta blockers, flunarizine, antidepressants, anti-epileptics and onabotulinumtoxinA [11–13]. The introduction of anti-CGRP treatments heralds a new era in migraine management, promising a targeted intervention for a condition that has long challenged the medical community and people with migraine alike [14].

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Migraine Burden

The impact of migraine ripples throughout a person’s life, family and community, having consequences on personal, academic, occupational, financial and social levels, as well as affecting the people around the person with migraine [4]. Migraine is a leading cause of years lived with disability in young to middle-aged people, affecting their key years for completing education, building careers and establishing families [1]. Migraine burden and impact generally worsen with increases in MHD frequency and can be seen in worse disability, impact, interictal burden and quality of life, as well as higher rates of comorbidities [15]. In the CaMEO study, a US population-based survey involving 13,061 respondents who provided insights into the influence of migraine on their professional lives, 4271 (32.7%) respondents reported that migraine adversely affected various aspects of their careers [4]. Notably, respondents with CM were significantly more likely to report career-related repercussions than respondents with EM, although impact increased with MHD frequency from low- to middle- to high-frequency EM followed by CM [4]. Beyond the professional sphere, the impact of migraine extended into personal relationships: 60.6% of people with CM believed that their romantic partnerships would be better if headaches were no longer a concern, while 56.0% felt that their relationship with their children would similarly improve in the absence of headaches [4]. Rates of perceived impacts increased with MHD frequency, but some participants, even in the lowest-frequency strata, reported negative impacts [4]. Similar general and interictal migraine impacts on work, school, personal relationships, stigma and hiding were seen in the Eurolight study, which sampled from the adult population of ten countries in the European Union (EU) [3].

In the OVERCOME study, which surveyed 59,001 people with migraine in the USA, 31.7% experienced migraine-related stigma (as measured by the Migraine-Related Stigma questionnaire) often or very often, and more frequent headache days were associated with a higher likelihood of stigma, although stigma was more strongly related to negative outcomes such as poor quality of life and high interictal burden than MHD frequency [9]. In the Eurolight study, a third (32.9%) of participants with migraine were reluctant to tell people about their headaches, approximately 10% reported that their families and friends did not understand their headaches and almost 12% reported that their employers and colleagues did not understand the impact of headaches/migraine [3]. People who experience migraine stigma often exhibit a higher degree of disability, as indicated by their Migraine Disability Assessment (MIDAS) score. Additionally, stigma is associated with a greater interictal burden, the anxiety, avoidance, planning and impairment between migraine attacks due to persistent symptoms and/or fear of the impacts of future attacks and lower migraine-specific quality of life [9, 10].

Migraine Progression

Migraine can be a progressive disease, and a range of risk factors is associated with an increased risk of progressing from EM to CM, including higher frequency of MHDs, non-optimised acute treatment, depression and frequent acute medication use [16–18]. Migraine has a dynamic course with a natural variability in MHDs [19] and a complex interaction between EM and CM; it has been reported that about 3% of patients progress from EM to CM annually [6, 7, 18] and that 26% of patients experience regression from CM to EM over a 2-year period [20]. In the context of acute medication overuse and migraine disease progression, a paradoxical scenario unfolds for many patients. Despite the escalated intake of acute headache medications, some people experience a counterintuitive increase in the frequency of MHDs. This phenomenon engenders a vicious cycle in which the increased frequency and severity of migraine attacks leads to an increase in days of acute headache medication use, which in turn may precipitate a secondary headache disorder known as medication-overuse headache [5]. In addition, acute medications may be used even without the existence of a headache or migraine attack, potentially as an attempt to avoid an attack, as seen in rates of acute medication overuse in patients with EM who do not meet the International Classification of Headache Disorders criteria for medication-overuse headache [5, 21].

Disease progression is associated with increased disability and impact on health-related quality of life. This progression is also associated with comorbidities such as depression, anxiety, other chronic pain conditions and obesity [17]. In fact, the risk of progression from EM to CM associated with depression was found to increase with increased depression severity [22]. Amplified economic and societal strain due to utilisation of healthcare resources and loss of productivity is associated with increasing migraine frequency, even if the number of MHDs does not cross the 15-day threshold [4, 17, 23, 24]. As such, there has been a recent shift towards expanding the definition of migraine progression across the spectrum of migraine, considering increases in migraine or headache days that do not cross the 15-day threshold as well as considering increasing disability, worsening quality of life and an increase in comorbidities for people across the migraine spectrum [8, 25–27].

Migraine Prevention

Preventive treatments, including both medications and non-medication therapies, are strategic interventions in the vicious cycle of migraine worsening, offering the potential to reduce migraine frequency, severity and impact, and to lower the use of acute medications [28–32]. By mitigating the frequency and intensity of migraine attacks, these treatments play a crucial role in reversing migraine progression [33–37], providing a pathway to improved outcomes and health-related quality of life [5, 32, 38–41]. Optimising migraine treatment is, therefore, important for long-term disease management. Treatment optimisation may include acute and preventive therapies, as well as pharmacological and non-pharmacological interventions such as lifestyle changes (e.g., exercise, stress management), biobehavioural therapies (e.g., biofeedback, cognitive behavioural therapy and relaxation therapies) and neurostimulation to reduce attack frequency and symptoms [17, 42].

Unmet Therapeutic Prevention Needs in Migraine

Despite their potential benefit, preventive therapies are underused among those who are candidates for such therapies [43, 44]. Data from the OVERCOME EU migraine cohort show that of 20,756 participants with migraine, 73.9% eligible for preventive treatment reported that they did not currently use it [44]. According to European Headache Federation guidance, people with migraine who are affected by their migraine for ≥ 2 days per month despite optimised acute medication should be considered for preventive treatment, although factors such as the severity and duration of migraine attacks should also be taken into account [45]. The American Headache Society (AHS) 2021 consensus statement guidance on migraine preventive treatment is similar, recommending prevention for people with migraine ≥ 2 days per month with severe disability, with ≥ 4 days per month with at least moderate disability or ≥ 6 days per month with no requirement for any degree of disability [12].

Anti-CGRP Monoclonal Antibodies for Migraine Prevention

Anti-CGRP monoclonal antibodies (mAbs) are an effective migraine preventive treatment class of drugs [46–52]. Erenumab, galcanezumab and fremanezumab (subcutaneously administered) have all demonstrated onset of efficacy within the first week of treatment [46, 47, 52]. In the PROMISE-1 and -2 trials, intravenously administered eptinezumab demonstrated efficacy, with a lower proportion of patients with migraine on day 1 in both EM and CM compared with those receiving placebo [48–50]. The RELIEF trial, a randomised, double-blind, acute migraine trial in adults who also qualified for preventive treatment (primary end points were time to freedom from headache pain and time to absence of most bothersome symptom), demonstrated that eptinezumab begins to work within hours after infusion, and participants who received eptinezumab had statistically significantly shorter time to freedom from headache pain and time to absence of most bothersome symptom compared with those receiving placebo [51].

A post hoc analysis of the Phase IIIb DELIVER trial (n = 890) evaluated the sustained response to eptinezumab and assessed the potential for response in participants who were initially non-responders (defined as those with a migraine responder rate [MRR] of < 30% from baseline during weeks 1–12). The end points were the proportion of participants with ≥ 50% or ≥ 75% reduction in monthly migraine days and maintenance and shifts in MRRs from weeks 1–12 to weeks 13–24 [53]. The data demonstrated that in a proportion of these participants, the time to treatment effect varied: about one-third of those who demonstrated < 30% MRR in the first 12 weeks following infusion then achieved ≥ 30% MRR after their second dose in weeks 13–24 [53]. These data support that two infusions of eptinezumab may be required before any evaluation of treatment and that sustained reductions in headache frequency could be observed up to 24 weeks [53].

In the same eptinezumab study, it was observed that sustained reductions in headache frequency may allow participants to transition from the most debilitating headache frequency categories, such as CM and high-frequency EM, to lower-frequency levels, with some participants reporting complete absence of migraine attacks or headaches [53]. At baseline, no participants reported fewer than four MHDs; however, after the initial dose of eptinezumab, 23% of pooled participants who were randomised to receive either 100 mg or 300 mg eptinezumab intravenously reported fewer than four MHDs, increasing to 47% by weeks 61–72. The percentage of those treated with eptinezumab who experienced ≥ 8 MHDs decreased from 90% at baseline to 27% after the final dose.

While many healthcare providers traditionally use ≥ 50% MMR as the threshold for defining clinically meaningful benefit, emerging data suggest that this threshold may not fully capture the nuances of treatment effect, especially for those who initially fall into the category of < 30% MMR after the first dose [54]. In addition, an observational study in the USA that assessed 94 participants’ experiences of being treated with eptinezumab for CM demonstrated that 56% reported that their confidence in their overall well-being was higher or much higher after starting treatment [55]. As such, there is increasing interest in re-evaluating the criteria for treatment success to include a more comprehensive assessment of participants’ improvement. This shift in perspective aims to ‘raise the bar’ for treatment success, ensuring clinical outcomes align more closely with the needs of people with migraine and the multifaceted nature of migraine management. In a study of participants who received erenumab at a dose of 70 mg or 140 mg every 4 weeks, 17.0% and 20.9%, respectively, achieved ≥ 75% MRR compared with 7.8% who received placebo over 12 weeks [56]. In the same study, 4.3% and 2.7% of participants who received 70 mg or 140 mg of erenumab, respectively, achieved 100% MRR compared with 0.4% who received placebo over 12 weeks [56]. Participants who achieved ≥ 75% and 100% MRR also demonstrated a greater improvement in headache impact and disability [56]. Similarly, among the PROMISE-2 cohort of participants with CM who received eptinezumab and achieved ≥ 75% MRR (29.9%; n = 211/706) over weeks 1–12, a post hoc analysis demonstrated that these participants experienced improved health-related quality of life and reduced disability (defined by the Patient Global Impression of Change scale and 6-item Headache Impact Test [HIT-6]), with 76/211 (36.0%) reporting that their headache had little to no life impact at week 12 [57]. It is important to note that there are currently no head-to-head comparisons between any of these anti-CGRP mAbs.

With the approval of anti-CGRP treatments by regulatory bodies, real-world data on the effectiveness of anti-CGRP mAbs are now emerging (Fig. 1) [34, 58–60]. In a real-world Danish study of 162 participants with CM who received erenumab, 41.4% and 12.3% achieved ≥ 50% and ≥ 75% MRR, respectively, by week 24 [59]. In an Italian study of 130 participants with CM who received galcanezumab, 63.5% and 37.8% achieved ≥ 50% and ≥ 75% MRR, respectively, by month 6 [60]. In an update to this study, of 148 participants with CM, 60.5% and 38.1% achieved ≥ 50% and ≥ 75% MRR, respectively, by month 12 [61]. A study conducted in the United Arab Emirates involving 25 participants with CM who were administered eptinezumab demonstrated potential for higher outcomes: 88.0% and 60.0% achieved ≥ 50% and ≥ 75% MRR, respectively, by month 6, although this would need to be investigated in a larger cohort of participants [34].

Fig. 1.

Real-world evidence of the effectiveness of anti-CGRP monoclonal antibodies in patients with CM [34, 58–60]. Please note that these were independent studies and that methodological differences between studies preclude head-to-head comparisons. CGRP calcitonin gene-related peptide, CM chronic migraine, MMD monthly migraine day, UAE United Arab Emirates

Anti-CGRP mAbs have also demonstrated maintained effectiveness [37, 62, 63]. Studies on galcanezumab and fremanezumab have demonstrated that 80% of participants who continued treatment for 12 months achieved and maintained ≥ 50% MRR [62]. In a real-world study, erenumab demonstrated long-term effectiveness in a cohort of participants with ‘difficult to treat’ or treatment-resistant CM: 97/177 (54.8%) participants reported significant improvement (≥ 30% in patient-related outcome measures or quality-of-life questionnaires) and chose to continue treatment after the end of the study for a median duration of 25 months [63]. Long-term patient-reported outcomes also improved with treatment with erenumab: HIT-6 and MIDAS scores improved by 20% and 87% from baseline to months 25–30, respectively [63]. Participants (n = 94), 89% of whom reported previous subcutaneous anti-CGRP mAb use and 82% of whom reported previous onabotulinumtoxinA use, who received eptinezumab for ≥ 6 months also reported improvement in satisfaction with several elements of daily living, as 69% of participants reported that their ability to participate in their social or family life was higher or much higher, and 68% reported that their ability to perform their usual daily activities was higher or much higher [37].

Anti-CGRP mAbs have also demonstrated improved tolerability compared with older preventive therapies [64]. Real-world studies of erenumab, galcanezumab, fremanezumab and eptinezumab have indicated similar adverse-event profiles and identified no new safety signals from those observed in clinical trials [34, 59, 65, 66]. In a real-world study of 162 participants aged > 65 years who were treated with erenumab, galcanezumab or fremanezumab, 41 (25.3%) participants experienced adverse effects, all of which were considered to be mild [67]. At month 3, the most commonly reported adverse effect was constipation (9.9%; n = 16/162), and two instances of hypertension were reported [67].

Reimbursement criteria in some countries require treatment to be temporarily discontinued after a set time and then resumed. For example, the Italian Medicines Agency requires treatment discontinuation after 1 year followed by drug withdrawal of ≥ 1 month [68]. Such recommendations are based on expert opinion rather than scientific evidence and, as such, prospective, randomised studies that investigate the impact of treatment discontinuation are warranted [69]. A sub-group of 154 participants enrolled in the Italian EARLY (erenumab) and GARLIT (galcanezumab) studies was followed during a 3-month drug discontinuation; of the 107 participants with CM, 35.5% experienced ≥ 50% MRR by month 3 of treatment discontinuation compared with 60.6% during the last month of anti-CGRP treatment [68]. Treatment discontinuation led to relapse to CM: 39/84 (46.4%) participants who had reverted from CM to EM during treatment relapsed to CM by month 3 of treatment discontinuation [68]. However, the efficacy of treatment returned after resumption, when monthly migraine days returned to a level similar to the period before treatment discontinuation [70].

Treatment with anti-CGRP mAbs should not be discontinued altogether after treatment failure, as switching within the class can be effective [71, 72]. Some people (n = 5/25) with migraine who discontinued treatments targeting the CGRP receptor due to non-response have experienced successful treatment response when switched to an anti-CGRP treatment that targets the CGRP ligand, such as galcanezumab or fremanezumab [71]. In a small, real-world study, 13/18 (72.2%) participants who switched from galcanezumab to eptinezumab experienced additional or compounded reductions in monthly migraine days on top of improvements gained from their initial prescription, although it should be noted that head-to-head comparisons between these two treatments are not available [72].

Anti-CGRP Treatment-Emergent Adverse Events

The most common treatment-emergent adverse events across all four currently available anti-CGRP mAbs include hypersensitivity reactions and injection site reaction and pain [28–30, 73]. Specific common adverse events for erenumab and galcanezumab include constipation and pruritus [29, 30], and those for fremanezumab include injection site pain, induration, erythema and pruritus [28]. Eptinezumab is associated with nasopharyngitis and fatigue [73]. The US Food and Drug Administration approved safety labelling changes for erenumab to include warnings for constipation, hypertension and Raynaud’s phenomenon, and recently issued a safety labelling change for all CGRP-targeting therapies [74].

Patient-Centricity and Treatment Success

The definition of treatment success may differ between healthcare professionals and people with migraine. For example, current clinical guidelines and reimbursement regulations are typically based on the achievement of defined thresholds. The AHS consensus statement considers preventive treatment success to include a 50% reduction in the frequency of days with headache or migraine and a reduction in migraine-related disability [12]. The German Society for Neurology guidelines for treatment success include a ≥ 50% reduction in average monthly migraine days over a treatment period of 3 months for those with EM and a ≥ 30% reduction for those with CM [75]. These goals may not reflect patient values, patient preferences or direct patient-reported outcome measures, and may act as an obstacle to patient satisfaction and treatment adherence [45]. As a result, people with migraine should be involved in the process of selecting treatment and establishing individual treatment goals, expectations and limitations of any treatment, as optimised medication communication is central to a positive working alliance [12, 76, 77]. This is an iterative process, and treatment plans should be reassessed with goals being reached, modified and reset over time as appropriate. It is important that the available data are contextualised for people with migraine and that, with the emergence of new evidence on the efficacy and safety of anti-CGRP mAbs, we raise the bar for treatment success.

Conclusions

Migraine is not just a disease where people experience headaches; rather, it is a chronic disease made up of attacks comprising a constellation of disabling symptoms over multiple phases that can have a large negative impact on health-related quality of life as well as on family, friends and work colleagues, academic and occupational achievements, financial well-being and internalised stigma [1]. Although various preventive therapy options are available in guidelines and consensus statement recommendations, including medication, neuromodulation, biobehavioural therapies and lifestyle modification, CGRP-targeted preventive therapy remains highly underused [12]. Evidence from both clinical trials and real-world data demonstrate that treatment with anti-CGRP mAbs improves multiple outcomes for people with migraine, including reduced headache and migraine frequency, reduced severity duration and impact of remaining migraine attacks and headaches, reduced acute medication use, improved health-related quality of life and reduced disability [37, 53, 56, 57]. Evidence also shows that if an individual experiences treatment failure with an anti-CGRP mAb, they can be switched to another as they could experience a better treatment outcome with another drug within the same class [71, 72]. People with migraine should be central in the shared decision-making process of their care, as goal management is a collaborative and ongoing iterative process. Finally, while there is a growing wealth of data demonstrating the effectiveness of anti-CGRP mAb therapies, there are still a number of questions that require further study, including their effectiveness in subtypes of migraine, identifying predictors of response, long-term efficacy and safety, and combination therapy.

Author Contributions

Dawn C. Buse, Jan Versijpt and Hans-Christoph Diener contributed to the preparation of this manuscript, commented on previous versions of the manuscript and read and approved the final manuscript.

Funding

Educational financial support for the symposium and the Neurology and Therapy journal Rapid Service Fee was provided by H. Lundbeck A/S.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

Declarations

Conflict of Interest

Dawn C. Buse has been a consultant for AbbVie, Amgen, Biohaven, Collegium, Lilly, Lundbeck, Pfizer, Teva and Theranica. Jan Versijpt received personal fees and non-financial support from Medtronic, Pfizer and Teva; personal fees from Lundbeck and Novartis; and grants and non-financial support from Allergan/AbbVie. Hans-Christoph Diener received honoraria for participation in clinical trials, advisory boards and presentations for AbbVie, Lilly, Lundbeck, Novartis, Orion Pharma, Pfizer, Teva and WebMD.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.