For decades, migraine prevention relied on nonspecific, off-label drugs, often lacking large-scale clinical trials to confirm their efficacy, safety, or tolerability.^1-3 This has resulted in high discontinuation rates.^2,3 However, the introduction of calcitonin gene-related peptide (CGRP) pathway-targeting therapies has revolutionized migraine management.³ At a recent symposium, Dr. Sait Ashina, Director of the BIDMC Comprehensive Headache Center and Assistant Professor at Harvard Medical School in the United States (US), discussed how beyond randomized controlled trials (RCTs), the 5-year real-world evidence (RWE) data further demonstrate the utility of CGRP pathway-targeting therapies in the evolution of migraine prevention.

Transformation of migraine prevention from clinical trials to the real world

The landscape of migraine prevention has transformed significantly in recent years.² Historically, treatment options were limited, and many therapies were off-label for prophylactic management.^1,3 The lack of large-scale clinical trials to confirm efficacy and the poor tolerability of these treatments contributed to a slower evolution in migraine management.^2,3 However, over the past 5 years, the introduction of migraine-specific CGRP monoclonal antibodies (mAbs) and gepants has revolutionized the field.³

Dr. Ashina emphasized that while RCTs showed no significant differences in the efficacy of CGRP pathway-targeting mAbs, RWE has provided deeper insights into their effectiveness in clinical practice.⁴ Unlike RCTs, real-world studies assess treatment effectiveness in diverse and unrestricted patient populations, with monitoring that reflects usual care.⁵ Moreover, these studies often include long follow-up periods, which provide valuable insights into real-world outcomes.⁵ For example, the FRIEND3 RWE study (n=533) demonstrated the long-term efficacy of fremanezumab, with 73.1% of patients achieving ≥50% reduction in monthly migraine days (MMD) at 48 weeks.⁴

Comparing the efficacy of ligand-targeting vs. receptor-targeting CGRP pathways

The comparison between ligand-targeting and receptor-targeting CGRP therapies is a hot topic to addressing whether these approaches differ in terms of efficacy and safety.⁶ Schiano di Cola et al. highlighted significant differences in response rates between these two types of mAbs.⁶ Ligand-targeting mAbs were found to be associated with a higher percentage of “super responders” (43.2%) compared to receptor-targeting mAbs (28.6%) (p<0.05).⁶ A real-world study conducted at a migraine clinic in the United Kingdom (UK) found that fremanezumab maintained sustained efficacy over 2 years, with 80% of initial responders continuing treatment and 22% able to stop due to experiencing <4 MMD in the prior 3 months.⁷ These findings suggest that ligand-targeting therapies may potentially offer a more favorable outcome, helping physicians to tailor a better migraine management approach.^6,7

Safety profile of CGRP pathway therapies

In addition to efficacy, safety remains a vital consideration when selecting the appropriate treatment for migraine prevention.⁸ Apart from efficacy, real-world studies provide valuable insights into the safety profiles of CGRP pathway mAbs.⁹ For instance, a multicenter, prospective, observational study in Italy examined 1,635 patients with high-frequency episodic migraine or CM who had failed at least three prior preventive treatments.⁹ The study found that the occurrence of treatment-emergent adverse events (TEAEs) was lower than that reported in RCTs, with erenumab being associated with the highest rate of TEAEs (73%) compared to ligand-targeting therapies like fremanezumab and galcanezumab (12% and 15% respectively).⁹

Safety data from the FDA's adverse events (AEs) database also shed light on differences in AE profiles among CGRP-targeting therapies.¹⁰ Specifically, constipation was reported more frequently with receptor-targeting subcutaneous therapies (up to 17.93%), while patients treated with ligand-targeting subcutaneous therapies primarily experienced local site reactions (up to 24.37%).¹⁰ This distinction in AE profiles is important for clinicians when considering treatment options, as it allows for a more tailored approach in the clinical setting.¹⁰

Impact of real-world evidence on clinical guidelines

The role of RWE in shaping clinical practice cannot be overstated, as it has significantly influenced the updates to international guidelines on migraine prevention.¹¹ Leading organizations, such as the European Headache Federation (EHF), American Headache Society (AHS), and International Headache Society (IHS), have incorporated findings from real-world studies to refine their recommendations for treatment.^3,11,12

Earlier access to anti-CGRP mAbs, such as erenumab, has been shown to significantly improve patient responses. A study found that 60.0% of patients with earlier access achieved a ≥50% reduction in MMD at weeks 9-12, compared to 40.6% of those with delayed access (p=0.015).¹³

The AHS now endorses anti-CGRP therapies as a first-line option for migraine prevention, highlighting their proven efficacy and their ability to reduce both healthcare costs and the socioeconomic burden of migraines.³ In September 2024, the IHS released its first global recommendations for migraine prevention, emphasizing the importance of practical, quick-reference guidelines applicable across diverse healthcare systems.¹² These recommendations also highlight that a partial response to treatment is acceptable for continuing therapy beyond 3 months in patients with chronic migraine and multiple preventive options.¹² This pragmatic approach aims to optimize migraine management globally, accommodating variability in healthcare resources.

Both the IHS and the National Institute for Health Research (NIHR) noted the poor adherence to non-specific oral preventatives in chronic migraine management, partially due to a lack of robust evidence for their effectiveness and a relatively poor safety profile.¹² Although CGRP-targeting therapies may carry higher upfront costs, they are considered cost-effective due to their long-term benefits and effectiveness in preventing migraine-related disability.³

Defining success in migraine prevention therapy

The evolution of migraine prevention strategies also involves refining the criteria used to define treatment success.¹² The International Headache Society’s Global Practice Recommendations for Preventive Pharmacological Treatment of Migraine advocates that treatments should be continued if they provide meaningful subjective improvements and are well-tolerated by patients.¹² This should be guided by the recommended success criteria for evaluating the effectiveness of preventive therapies which include a ≥50% reduction in MMD or MHD, meaningful improvements in the Patient Global Impression (PGI), and/or improvements in functional disability measures like MIDAS or HIT-6.¹²

For patients with chronic migraine and with multiple preventive options, a ≥30% reduction in MMD after 3 months of treatment could be considered an acceptable threshold.¹² This recognition of partial response aligns with the understanding that individual treatment plans must be personalized, with patient-specific factors, such as comorbidities, guiding the choice of therapy.¹² In an ideal treatment setting, migraine-specific drugs should always be considered the first line of defense.¹²

Conclusion

The introduction of CGRP-targeting therapies has ushered in a new era in migraine prevention, with significant advancements in both efficacy and safety.^3,8 As these migraine-specific therapies are increasingly adopted, their impact on patient care is becoming increasingly evident, particularly through the lens of RWE.⁶ This growing body of data continues to shape clinical guidelines, emphasizing the importance of early intervention with migraine-specific treatments to reduce the burden of the disease.^11,12 As the field evolves, ongoing research and clinical experience will further refine the management strategies, ultimately improving patient outcomes and quality of life.⁸