Expanding preventive options for pediatric migraine: the use of anti-CGRP monoclonal antibodies for children and adolescents with migraine

Pediatric migraine is a common neurologic disorder in childhood and adolescence, with the prevalence rate approximated to be about 11% around the world. It impacts greatly everyday functioning, school attendance, and social participation (1,2). The effects of headache disorders on children are high absenteeism, reduced involvement in extracurricular activities, and poor life quality. This shows that patients and families are overworked (2,3). The issue of preventive treatment is still difficult since the existing medications are extremely low in efficacy and tolerability. The randomized trial by Hershey et al. (4) in The New England Journal of Medicine that evaluates fremanezumab provides the first robust prospective evidence that supports the calcitonin gene-related peptide monoclonal antibodies for pediatric migraine prevention. Thus, this study addresses a critical therapeutic gap in the pediatric migraine population.

The current preventive therapy options for pediatric migraine are limited and have low-level evidence, unlike adult migraine therapeutic environments, where there is constant advancement. Topiramate, propranolol, and amitriptyline remain some of the most frequently prescribed agents, but their effectiveness in children is not uniform in all studies (5). The Childhood and Adolescent Migraine Prevention (CHAMP) trial indicated no significant difference in reducing the frequency of headaches with amitriptyline, topiramate, and placebo, which suggested a strong placebo response in pediatric trials (6). A network meta-analysis conducted recently also demonstrated inconsistent benefit across medications, with only some of the agents decreasing the frequency of attacks without enhancing the quality of life (7).

Calcitonin gene-related peptide (CGRP) is an essential factor in the pathophysiology of migraine that facilitates trigeminovascular activation, neurogenic inflammation, and vasodilation. CGRP pathway targeted monoclonal antibodies have shown consistent prophylactic efficacy in large adult studies, such as HALO-EM and HALO-CM, and have excellent safety and tolerability rates. Nevertheless, in pediatric populations, data has traditionally been gathered only in small observational studies and case series, and regulatory approval and cautious guidelines have been recommended in children and adolescents (8,9).

The study by Hershey et al. (4) shows several methodological strengths that increase the confidence in its findings. The multicenter design with 89 sites in nine countries allows for improving the generalizability, whereas the inclusion of participants aged 6–17 years provided information across a broad pediatric age range. The study also employed weight-based dosing (120 mg for participants weighing <45 kg and 225 mg for those weighing ≥45 kg), which is consistent with pediatric pharmacokinetic modeling studies of fremanezumab demonstrating that body weight was the clinically relevant covariate influencing pharmacokinetic exposure, while age was not retained as clinically relevant after accounting for weight (10).

Particularly noteworthy is the study’s approach to minimizing placebo response, which is a constant problem in pediatric migraine trials. The researchers implemented site-specific educational and communication materials aimed at standardizing participant counseling, expectation management, and trial-related interactions across centers to reduce placebo amplification, which is a recognized challenge in pediatric migraine studies. This led to a 50% responder rate of 27% in the placebo condition. This is significantly lower than the 30–61% generally found in migraine studies. This achievement alone represents an important contribution to trial methodology in this population. The flexibility to use stable concomitant preventive drugs up to 30 percent of study participants is indicative of the reality of clinical practice since combination therapy is widespread in practice, and it also improves the study’s external validity.

The major result showed a 1.1-day difference in monthly migraine days between fremanezumab and placebo, showing a difference of −2.5 vs. −1.4 days, which was found to be significant (P=0.02). This effect size is quite small, yet it is consistent with the data of the adult trials and needs to be discussed in the frames of the pediatric migraine treatment. Although the absolute reduction in monthly migraine days was modest, the responder analysis may be clinically more meaningful because it reflects the proportion of patients achieving a substantial improvement. Nearly half of the fremanezumab-treated participants achieved at least a 50% reduction in monthly migraine days compared with 27% in the placebo group. A ≥50% responder threshold is widely regarded as a clinically meaningful benchmark in migraine prevention trials and may better capture individual patient benefit than mean group differences alone (4).

The decrease in acute medication use (−2.1 vs. −1.0 days per month; P=0.002) has a special significance when it comes to the pediatric populations that are susceptible to medication overuse headache. This secondary value can be as useful as the principal consequence in the prevention of progression from episodic to chronic migraine, a transition that may occur during adolescence and is associated with medication overuse and increasing headache burden (11). Fremanezumab-treated children were more likely than placebo-treated children to resume usual daily activities, including school attendance, physical activity, and social participation, suggesting functional improvement beyond headache reduction (4).

Interestingly, the PedMIDAS disability scores were improved numerically in favor of fremanezumab but failed to achieve statistical significance by hierarchical testing (P=0.10). This observation also states the multidimensional correlation between headache frequency and functional disability amongst the youth. Aspects such as family systems, school modifications, and personal coping mechanisms can moderate the effect of the reduction of headaches on the overall disability. This lack of association between a decrease in frequency and disability is emphasizing the multidimensional quality of migraine burden in children and indicates that the change in headache frequency might not completely reflect the effects of treatment. Clinical benefit should be further evaluated by use of comprehensive patient-reported outcomes, school attendance measures, and functional measures that should be included in future trials.

The safety profile observed in this trial was predominantly mild-to-moderate injection site reactions; this aligns with adult experience and is reassuring. The most frequent adverse event was injection-site erythema, which was found in 9.8 percent in the group of participants receiving fremanezumab and 5.4 percent in the group receiving placebo. The 3-month period of the double-blind phase did not produce any significant safety signals, and the general safety evaluation, which includes suicide risk assessment using the Columbia-Suicide Severity Rating Scale, provides a proper baseline in pediatric trials (4).

The 3 months of the follow-up time, however, being adequate to approval by regulators, should be given a second thought. The immune system, vascular system, and general physiology are greatly developed during the period of early childhood to adolescence. Although CGRP has a well-primed role in the pathophysiology of migraines, it has other physiological functions in growth and development, as well as other systems, which should be monitored. The continued open-label extension will play an important role in knowing long-term safety, response durability, and the ideal treatment period in the developing individuals.

In their clinical experience, a number of practical considerations affect the applicability of CGRP monoclonal antibodies in pediatric practice. The fact that these agents are very expensive, significantly higher than the traditional preventive medicines, has the potential to restrict extensive application in most health care systems. Financial barriers can be a barrier in the underinsured population or where resources are limited and are effective in such situations. Selective treatment is absolutely necessary, and these agents may be most useful in children with recurrent symptoms. This can help in incapacitating migraines that did not respond to conventional therapy or cannot tolerate traditional preventives.

The question of treatment sequencing remains incompletely resolved. Are anti-CGRP monoclonal antibodies the preferred preventive therapy, or should they only be used in patients who are treatment-refractory? The safety profile and the mechanism of action are favorable and suggest that it should be used earlier in the right candidates. The monthly dose could be more effective in promoting compliance than the daily use of oral medications, which is an important factor when working with adolescents. But these benefits have to be countered by cost and the necessity of subcutaneous administration.

A reasonable approach might focus on anti-CGRP antibodies in patients with: (I) persistent high disability despite optimized non-pharmacological and/or conventional pharmacological preventive strategies; (II) contraindication to or intolerance of conventional preventatives; (III) difficulty in taking daily oral medications; or (IV) patient/family preference after being given patient information. Notably, the contribution of non-pharmacologic therapy such as lifestyle change, cognitive-behavioral therapy, sleep hygiene, and stress management cannot be neglected since they are all important elements of multifaceted treatment of migraine in children.

Despite this important advance, several critical questions remain. First, how do we identify which pediatric patients will respond to CGRP-targeted therapy? Approximately half of participants achieved ≥50% response, but we lack biomarkers or clinical predictors to guide patient selection. Future studies need to investigate the possibility of predicting treatment response by studying migraine features, comorbidities, or genetic factors.

Second, what is the optimal treatment duration? Depending on whether it is chronic or not chronic, where the former needs lifelong management, pediatric migraine normally has fluctuation patterns whereby some children may go into remission during their teens or during the early stages of their adult lives. It will be necessary to define proper treatment endpoints and carry out systematic discontinuation trials to prevent superfluous long-term therapy.

Third, how does fremanezumab compare with other CGRP pathway inhibitors in pediatric populations? Erenumab, galcanezumab and eptinezumab inhibit other parts of the CGRP pathway, and a comparative effectiveness analysis may guide the choice of individual therapy. Also, it would be informative to compare with small-molecule CGRP receptor antagonists (gepants), which are administered orally.

Finally, the trial eliminated patients with long-lasting migraine (>15 headache days/month), but such patients tend to have the heaviest burden. The concomitant evidence will be a parallel trial in the case of pediatric chronic migraine (NCT04464707) and real-life evidence on effectiveness across the entire spectrum of migraine.

Hershey et al. (4) provides the highest-quality evidence to date supporting the efficacy and safety of fremanezumab for pediatric episodic migraine. The evidence that the CGRP pathway can be used to reduce the frequency of migraine in an acceptable short-term safety suggests that the CGRP pathway may be a new preventative agent to use in patients who have not responded to conventional treatment. Such results are likely to have an impact on treatment guidelines and an increase in the number of therapeutic armaments that can be used by clinicians treating pediatric headache.

However, the modest effect size, short duration of follow-up, high cost, and incomplete understanding of optimal patient selection highlight the need for cautious interpretation. Long-term studies, real-world effectiveness data, and cost-effectiveness analyses will be essential to define the role of CGRP monoclonal antibodies in routine pediatric practice. With evidence being constantly developed, the combination of specific biological treatment with developed pharmacologic and behavioral approaches has the potential to enhance the results of children and adolescents with migraine.

The success of this trial ultimately reflects not just the promise of a new medication but the maturation of pediatric headache medicine as a field capable of conducting rigorous, well-designed clinical trials that meet the unique methodological challenges of this population. This achievement should inspire continued investment in pediatric headache research, ensuring that future generations of children and adolescents with migraine have access to evidence-based, safe, and effective treatments that allow them to thrive academically, socially, and developmentally.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Pediatrics. The article has undergone external peer review.

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0307/prf

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Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0307/coif). The author has no conflicts of interest to declare.

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