Achieving International Headache Society-aspired optimal migraine control in fremanezumab-treated patients: A post-hoc analysis of a real-world,prospective study from the GRASP study group

Abstract

Objective

To evaluate whether the conventional ≥50% reduction in monthly migraine days (MMDs) accurately reflects clinically meaningful benefit compared with IHS-aspired migraine control definitions in difficult-to-treat high-frequency episodic migraine (HFEM).

Methods

In this post-hoc analysis of a prospective, real-world registry, conducted by the Greek Research Alliance for the Study of Headache and Pain (GRASP), 114 HFEM patients who had failed ≥3 preventive therapies and achieved a sustained ≥50% reduction in MMDs with monthly fremanezumab over 24 months, were included. Treatment response (≥50% and ≥75% MMD reduction) and IHS-defined control states (freedom, optimal, modest, insufficient control) were assessed using headache diaries at baseline (T0), month 12 (T1), and month 24 (T2). Secondary outcomes included headache intensity, analgesic use, and migraine-related disability.

Results

At T1, fremanezumab significantly improved all efficacy and disability outcomes (p < 0.001), with mean MMDs reduced from 11.9 at baseline to 5.1 at T1. While 78.1% achieved ≥50% MMD reduction, only 19.3% reached optimal control (<4 MMDs), highlighting a mismatch between relative response and true disease control. At T2, MMDs further declined to 4.3, while optimal control increased to 29.8% and insufficient control declined to 7.8%. Overall, most patients remained moderately controlled (60.6%) with residual 4–6 MMDs. Non-prior exposure to other anti-CGRP therapies emerged as the only independent predictor of optimal long-term control (OR:2.1; p = 0.03).

Conclusion

Achieving a ≥ 50% MMD reduction with CGRP-targeted therapies may not always correspond to clinically-meaningful benefit. More ambitious outcome measures are essential for more accurately evaluating treatment effectiveness and achieving clinically-meaningful reduction of migraine's disability.

Graphical abstract

This is a visual representation of the abstract.

Keywords

CGRP monoclonal antibodies fremanezumab migraine prevention 50% response rate optimal migraine control

Introduction

Migraine, a highly prevalent neurological disorder, commonly associates with significant disability and reduced quality of life (QoL).¹ The disorder is especially associated with a high disease burden in patients with chronic migraine, defined as experiencing 15 or more headache days per month, with at least eight of those days being with typical migraine features or respond well to triptans, for three consecutive months.^2,3 However, there is evidence to suggest that even patients with high-frequency episodic migraine (HFEM), defined as occurrence of 8–14 monthly migraine days (MMDs), may exhibit a comparable level of disability and migraine-related burden to that of patients with chronic migraine, experiencing less than 23 monthly headache days.⁴

Prior to 2018, the goal of migraine prophylaxis has long been considered both as a challenge and an unmet need. This was because many patients fail to achieve a clinically-meaningful reduction in their monthly migraine frequency with the use of traditional preventive treatments, such as anticonvulsants, beta-blockers, and tricyclic antidepressants.^5,6 These repurposed treatments, particularly topiramate, apart from modest efficacy, were often associated with side effects, leading to poor patient adherence and common treatment discontinuation.⁷

Recent advancements in migraine prevention, through the clinical development of monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway (antiCGRP-Mabs) have revolutionized the therapeutic arsenal in the setting of migraine prophylaxis.^8,9 Particularly, fremanezumab, a monoclonal antibody targeting the CGRP ligand, has shown remarkable efficacy in reducing the frequency and severity of migraine attacks in numerous real-world studies,^10–12 including those previously conducted by our group,^13–15 in treatment-resistant migraine patients with or without comorbidities.

Nonetheless, treatment success in terms of migraine prophylaxis has thus far been defined by a ≥ 50 reduction in MMDs. The International Headache Society (IHS) recently proposed a more ambitious approach to set higher standards in preventing migraine both in research and clinical practice. This position statement advised that in order to enhance patient outcomes and improve QoL, both researchers and clinicians should not investigate only for a ≥ 50% MMDs reduction, but also for optimal control and even migraine freedom in real-world clinical practice.¹⁶ The IHS-aspired categorization of migraine control includes four distinct levels of response to prophylactic treatments, including migraine freedom; optimal control; modest control; and insufficient control. Specifically, the optimal control level corresponds to less than four days of migraine or moderate/severe headache per month, thoroughly representing a significant reduction in residual migraine burden, while on any prophylactic treatment.

Although, a 50% relative reduction in MMDs demonstrates a statistical treatment effect, it may leave HFEM patients (i.e., 14 MMDs reduced to 7 MMDs) with still experiencing significant migraine-related disability and impaired QOL. In contrast, “optimal control” (defined as <4 MMDs) represents an absolute threshold where the residual disease burden is low enough to allow patients to function normally in their daily lives, thereby translating into a truly “clinically meaningful” improvement from the patient's perspective.

We have previously assessed longitudinal variations in all clinical efficacy, disability and QOL measures in migraine patients who completed 24 months of fremanezumab.¹⁷ This post-hoc analysis of data from the latter prospective real-world study, designed by the Greek Research Alliance for Studying Headache and Pain (GRASP) study group, sought to examine if the conventional ≥50% reduction in MMDs accurately reflects clinically-meaningful benefit compared with the IHS-aspired optimal migraine definitions in fremanezumab-treated difficult-to-treat patients with HFEM, at months 12 and 24. More specifically, this study aimed to document fremanezumab success in terms of absolute control of migraine days and clinically-meaningful reduction in associated disability, rather than the relative percentage of ≥50% MMDs reduction from baseline over two years of treatment. Factors that may influence the likelihood of achieving optimal control were also examined.

Patients and methods

Study design, intervention and patient selection

This study is reported in accordance with the STROBE guidelines for observational studies. Within the framework of a post-hoc analysis of an open-label, single-arm, prospective, multicenter real-world study, we evaluated adult patients with episodic migraine, defined according to the 2018 criteria of the International Classification of Headache Disorders-III.¹⁸ All of our enrolled patients had 8–14 baseline MMDs and were classified as having HFEM, which is a commonly used clinical and research term to describe patients with episodic migraine and higher baseline disease burden.

Eligible participants had failed at least three prior migraine preventive treatments due to lack of efficacy or intolerance. All patients received monthly subcutaneous injections of fremanezumab (Ajovy^® 225 mg pre-filled syringe; Teva Pharmaceuticals) and those that demonstrated a ≥ 50% reduction in MMDs at six months continued monthly for a total of 24 months, until mandatory pause.

The current analysis only included patients who eventually sustained a ≥ 50% response at 24 months. The rationale for including only patients who achieved a sustained ≥50% response at 24 months was to specifically investigate the discrepancy between the traditional definition of “treatment success” (≥50% reduction) and the new IHS-aspired absolute targets (optimal control) within a cohort that is already considered to have responded well to therapy. By focusing on these “responders,” we aimed to highlight that even among patients deemed successfully treated by conventional metrics, a significant proportion still fails to achieve optimal disease control.

Eligibility was confirmed using a protocol-specific checklist, while full inclusion and exclusion criteria have been described previously.^13–15 In brief, participants were required to have a diagnosis of HFEM and to maintain a prospective headache diary recording migraine frequency, severity, and acute medication use at a monthly basis. “Significantly missing data” were defined a priori as missing headache diary entries for more than five days in any given month, which precluded an accurate calculation of MMDs for that period. Patients with such missing data were excluded from the final analysis.

Fremanezumab therapy was commenced in line with approved indications and Greek reimbursement policies, requiring prior failure, intolerance or contraindication to at least three preventive therapies. An acute medication overuse status, defined as intake of triptans or simple analgesics on >10 or >15 days per month, respectively, was determined based on patient-reported medication use documented in headache diaries and clinical records. Patients exhibiting high rates of acute medication use, did not meet the strict ≥15 headache days/month criterion for a formal medication-overuse headache diagnosis.¹⁸ Moreover, patients with major psychiatric disorders, i.e., schizophrenia spectrum and other psychotic disorders, severe or uncontrolled obsessive-compulsive disorder, illicit substance use disorders, were excluded. Additional exclusion criteria included pregnancy or breastfeeding, participation in any other investigational drug study during the course of the study and any contraindication to fremanezumab.¹⁹

Patients were recruited from seven centers across six major urban regions in Greece, including secondary and tertiary hospitals and specialized headache clinics, to reflect routine clinical practice in a difficult-to-treat population. The study was conducted in accordance with the Declaration of Helsinki and its amendments. Ethical approval was obtained from the Institutional Review Board of the principal investigator, and all participants provided written informed consent. This study is part of the prospectively ongoing migraine registry of the GRASP Study Group, which operates under institutional ethical approval, with standardized data collection and oversight by a steering committee. The registry was not registered in any database, indexing public clinical trials.

Outcome measures

The primary outcome was the change in MMDs over the preceding month, as recorded in headache diaries, at 12 (T1) and 24 (T2) months following fremanezumab initiation, compared with baseline (T0). A migraine day was defined as headache with ≥2 core features (unilateral, pulsating, moderate-severe, activity-limiting) plus ≥1 associated symptom (nausea/vomiting or photophobia/phonophobia), any day with 5–60 min of visual aura, or any headache day requiring intake of migraine-specific acute medication.²⁰

Fremanezumab response was defined as a ≥ 50% reduction in MMDs at T1 and T2 compared to T0. Patients were grouped as responders or super-responders, obtaining MMDs reduction at either the 50% or 75% threshold. Furthermore, patients were re-grouped, according to the four categories of control, as outlined by the IHS¹⁶: migraine freedom (no MMDs), optimal control (<4 MMDs), modest control (4–6 MMDs), and insufficient control (>6 MMDs).

Secondary objectives included the evaluation of longitudinal changes from baseline T0 to T1 and T2 in the following efficacy outcomes: (i) MMDs associated with peak headache intensity ≥5 on the visual analogue scale (VAS); (ii) monthly analgesic intake (MAI), including triptans or NSAIDs, for migraine attacks; and (iii) migraine-related disability, as assessed by the validated MIDAS and HIT-6 instruments.^21–23 The assessment of treatment safety and adherence was not included among the objectives of the current setting.

Statistical analysis

Descriptive statistics were used to summarize baseline characteristics of the cohort, including age, sex, baseline migraine frequency, prior treatment history, and other clinical variables. Continuous variables are presented as mean ± standard deviation (SD), whereas categorical variables are reported as percentages. The primary analysis aimed to determine the proportion of patients achieving optimal control at months 12 (T1) and 24 (T2) compared with baseline (T0), in order to explore potential discrepancies between the conventional response criterion (≥50% reduction in MMD) and the recently proposed IHS thresholds for clinically meaningful treatment response. Comparisons of proportions between groups were performed using chi-square tests. Changes in secondary efficacy and disability outcomes over time (T0, T1, and T2) were assessed using paired t-tests or analysis of variance (ANOVA), as appropriate. The normality of the data distribution was assessed using the Shapiro-Wilk test and by visual inspection of Q-Q plots. Subgroup analyses were conducted to identify factors associated with the likelihood of achieving optimal control. Univariate logistic regression analyses were first performed to screen for potential predictors of treatment response. The potential predictors assessed in the univariate analysis included age, gender, BMI category, disease duration in years, number of prior preventive treatment failures, presence of psychiatric comorbidities, acute medication overuse, aura, and prior exposure to other anti-CGRP therapies. Variables found to be significant were subsequently entered into a backward stepwise multivariate logistic regression model to identify independent predictors. Odds ratios, 95% confidence intervals (CIs), and p values were reported. All statistical tests were two-tailed, and statistical significance was set at p < 0.05. Statistical analyses were performed using SPSS for Windows (version 27.0; SPSS Inc., Chicago, IL, USA).

Results

Among a total of 125 patients initially enrolled, 114 (91.2%) were eventually included, as they successfully accomplished all pre-planned follow-ups. Reasons for early discontinuation included lost to follow-up (n = 6) and significantly incomplete/missing data in headache diaries (n = 5).

Within the final dataset of 114 fremanezumab-treated patients, females predominated, representing the majority at 78.9%, compared to 21.2% males. The mean age in our cohort was 48.2 ± 10.3 (range 24–70) years. Most participants were within the healthy weight range with normal body mass index (BMI), accounting for 65.7% (n = 75) of participants, followed by those being overweight (27; 23.7%) and obese (11; 9.7%), while only a very small proportion were underweight (1; 0.9%).

Clinically, participants had a significant history of migraine, with a median disease duration of 18 years (range 5–48), while failing to a median number of four (range 3–8) prior prophylactic treatments. Psychiatric comorbidities were commonly seen (52.6%). HFEM was associated with acute medication overuse in a significant percentage of participants (63; 55.3%), while migraine with aura affected 18.4% of participants. Among the 114 enrolled patients, 36 (31.6%) had previous exposure to other anti-CGRP therapies, mainly erenumab (n = 31) or galcanezumab (n = 5). Table 1 summarizes the baseline demographic and clinical profiles of our 114 fremanezumab-treated participants with HFEM.

Table 1.

Demographic and clinical characteristics of participants at baseline.

Participants n = 114
Variable
Gender
Females n (%)	90 (78.9)
Males n (%)	24 (21.2)
Age; mean ± SD (range)	48.2 ± 10.3 (24-70)
Previous lines of prophylactic medications;
median (range)	4 (3–8)
Years with migraine diagnosis; median (range)	18 (5-48)
Psychiatric comorbidities
No; n (%)	54 (47.4)
Yes; n (%)	60 (52.6)
- Anxiety disorder; n (%)	27 (23.7)
- Depression; n (%)	9 (7.9)
- Mixed anxiety & depression disorder; n (%)	20 (17.5)
- Bipolar disorder; n (%)	4 (3.5)
Acute medication overuse*
Yes; n (%)	63 (55.3)
No; n (%)	51 (44.7)
Aura
Yes; n (%)	21 (18.4)
No; n (%)	93 (81.6)

*Acute medication overuse stands for triptans or simple analgesics use on >10 or >15 days per month, respectively.

At least 50% MMD reduction and optimal control rates at month 12, post-fremanezumab

Over the first12-months of treatment with fremanezumab (T1), patients demonstrated a highly significant longitudinal improvement (p < 0.001) across all efficacy outcomes compared with baseline. Mean MMDs were markedly reduced, declining from 11.9 ± 1.7 at baseline to 5.1 ± 1.5 at T1. Consistent and statistically significant reductions were also observed in mean MAI (9.8 ± 1.9 at baseline to 4.2 ± 1.5 at T1), as well as in the frequency of migraine days associated with moderate-to-severe pain (VAS ≥5) intensity (10.1 ± 1.8 at baseline to 4.7 ± 1.7 at T1). Moreover, both MIDAS and HIT-6 scores showed significant decreases at T1 compared to baseline. By T1, the median reduction reached −42 points for MIDAS (mean 79.7 ± 31.3 at baseline to mean 43.7 ± 23.2 at T1; p < 0.001) and −8 points for HIT-6 (mean 66 ± 6.2 at baseline to mean 56.7 ± 8.1 at T1; p < 0.001).

When examining response to treatment using the IHS-proposed disease control criteria, we observed a significant mismatch between treatment success, expressed by ≥50% MMDs reduction rates and true reduction disease burden, expressed by optimal control rate, thoroughly reflecting a different interpretation of treatment success. After 12 monthly sessions with fremanezumab, the majority of participants (89; 78.1%) achieved at least a 50% reduction in MMDs, indicating a broadly positive treatment effect. However, when applying a higher threshold of ≥75% MMDs reduction, the proportion of super-responders dropped (25; 21.9%) to suggest that while many patients benefit, fewer achieve significant or near-complete improvement.

Despite these relatively high ≥50% response rates, when treatment outcomes were re-categorized into optimal control (<4 MMDs), moderate response (4–6 MMDs), and insufficient control (>6 MMDs), just 22 (19.3%) patients achieved optimal control. Notably, the majority of fremanezumab responders at either the 50% or 75% MMD reduction threshold remained in the moderate category (72; 63.2%) and another 17.5% (n = 20) was classified as insufficiently controlled with residual high migraine burden. Figure 1 summarizes treatment response outcomes at 12 months, post-fremanezumab, comparing both relative and absolute measures of improvement.

Figure 1.

Treatment response at 12 months: comparison of (A) relative reduction (≥50% response rate) and (B) optimal disease control.

At least 50% MMD reduction and optimal control rates at month 24, post-fremanezumab

By the end of the 24-month period (T2) with fremanezumab therapy, the mean MMDs were further decreased from 5.1 ± 1.5 at T1 to 4.3 ± 1.7 (p < 0.001) at T2. Furthermore, MAIs further decreased significantly from 4.2 ± 1.5 from T1 to 3.5 ± 1.7 at T2, while same effect (p < 0.001) was observed with the number of MMDs with pain intensity VAS ≥5, which longitudinally declined from 4.7 ± 1.7 at T1 to 3.4 ± 1.9 at T2. The changes in all efficacy variables between T0 to T1 and T2 are summarized in Figure 2.

Figure 2.

Longitudinal changes in efficacy variables from baseline to month 24, post-fremanezumab.

The degree of migraine-related disability was also further improved over time, as documented by changes in both MIDAS and HIT-6 scores at T2, compared to T1 and evidence of additional median reductions by −14 and −4 points, respectively (p < 0.001).

Same as with our data at T1, we disclosed differences in the distribution of the magnitude of improvement across categories, according to relative and absolute measures of improvement, at T2, as the largest proportion of patients (67; 58.8%) achieved ≥50% MMDs reduction in migraine burden. A smaller group reached ≥75% MMD reduction (45, 39.4%), while just two patients (1.8%) became completely migraine-free.

However, when treatment outcomes were re-categorized according to IHS-aspired optimal control rates, the majority of patients (69; 60.6%) was clustered into the moderate control category (4–6 MMDs). At T2, optimal control (<4 MMDs) accounted for 34 (29.8%), representing a 10% percentage corresponding higher proportion, compared to T1 (7.8% vs 17.5%). Insufficient control (>6 MMDs) was demonstrated in just 9 patients (7.8%), showing a 10% clinically-meaningful percentage difference, compared to T1 (29.8% vs 19.3%). Figure 3 illustrates the 24-month treatment response following fremanezumab, capturing both relative and absolute improvements, relating to MMDs reduction. Categories in Figure 3 are mutually exclusive (i.e., 50–74%, ≥75% to <100%, and 100%) and all patients met the ≥50% threshold at that time point.

Figure 3.

Treatment response at 24 months: comparison of (A) relative reduction (≥50% response rate) and (B) optimal disease control. Categories are mutually exclusive (e.g., 50-74%, ≥75% to <100%, and 100%) and all patients met the ≥50% threshold at that time point.

Predictors of optimal migraine control at month 24, post-fremanezumab

After univariate analysis, two baseline variables from the patients’ demographic and clinical baseline profiles were associated with optimal migraine response to fremanezumab at T2. Patients without psychiatric comorbidities at baseline (n = 54) were more likely to achieve optimal response (Odds Ratio [OR]: 1.6; 95% Confidence Interval [CI]: 1.2–3.2; p = 0.05). In addition, patients not previously exposed to other anti-CGRP therapies, also showed higher odds of optimal response (OR: 2.6; 95% CI: 1.6–6.4; p = 0.037). All other analyzed variables failed to achieve a significant predictive value of optimal migraine control at 24-month, post-fremanezumab (Table 2). However, in the multivariate analysis, only patients naive to CGRP-targeted therapies prior to fremanezumab exposure were more likely to independently achieve optimal migraine response at T2 (OR: 2.1; 95% CI: 1.4–5.7; p = 0.03).

Table 2.

Univariate logistic regression analysis of baseline predictors for optimal migraine control at 24 months, post-fremanezumab.

Variable	OR	95% CI	p value
Age	0.988	0.95–1.10	0.533
Gender female	1.750	1.10–6.90	0.092
BMI category	0.411	0.15–1.19	0.102
Psychiatric comorbidities	1.600	1.20–3.20	0.050
Disease duration	0.411	0.14–1.19	0.102
No. of prior preventive treatment failures	0.829	0.59–1.15	0.261
Acute medication overuse	0.622	0.28–1.38	0.242
Aura	1.429	0.53–3.83	0.478
Previous exposure to other anti-CGRPs	2.600	1.60–6.40	0.037

OR = odds ratio; CI = confidence interval. Bold p-values indicate statistical significance at p < 0.05.

Discussion

Appreciating the clinical importance, not only of achieving a 50% reduction in migraine days, post-treatment, but also of how this reduction reflects a meaningful improvement in overall disease burden, we herein estimated the IHS-aspired optimal control rates at 24 months, post-fremanezumab, in a predominantly female, middle-aged population with long-lasting, treatment-resistant HFEM, notable psychiatric comorbidity burden and common complication by acute medication overuse.

Our findings highlight a critical conceptual and clinically-relevant mismatch between the widely used traditional primary response outcome of ≥50% MMDs reduction and the more ambitious goal of achieving optimal migraine control, as recently proposed by IHS.¹⁶ Notably, the ESTEEMen study also highlighted the limitations of relying solely on percentage-based response metrics, supporting that such an approach may obscure the true residual burden of migraine in a subset of patients.²⁴

In line with the latter view, we demonstrate a significant discrepancy between relative and absolute measures of treatment success in our cohort of fremanezumab-treated patients. According to our findings, a significant proportion of patients achieved the traditional ≥50% response (78.1% and 58.8%) and ≥75% super-response (21.9% and 39.4%) thresholds at both 12 and 24 months. However, only a minority (19.3%) obtained optimal control (<4 MMDs), particularly when the assessment was made at month 12, post-fremanezumab. At month 24, the optimal migraine control rates elevated to 29.8%. Based on the latter core finding from our analysis, two critical issues merit to be highlighted and thoroughly discussed.

First, this discrepancy between relative and absolute measures of treatment success highlights that relying solely on a ≥ 50% reduction in MMDs is inadequate for evaluating clinically meaningful treatment response, as it fails to fully capture the residual burden of the disease. As such, our findings overall support the IHS positioning article,¹⁶ suggesting that treatment success in migraine prophylaxis should be re-defined based on absolute thresholds of residual migraine burden rather than relying on relative improvement. The results of a previous study by our group support the latter view, as among 617 migraine patients, 87.4% considered a 75% reduction in MMDs as truly important, while 52.5% accepted a 50% reduction and only12.6% valued a 30% reduction.²⁵ These findings, based on patients’ preferences, cast doubt on whether a responder rate at the 30% threshold is indeed clinically meaningful and should be included as a primary endpoint in clinical trial guidelines, as it is accepted for CM trials.^26,27

Secondly, our data further demonstrate that prolonged exposure to CGRP-targeted therapies, specifically fremanezumab in the current setting, is associated with progressive improvements not only in migraine frequency but also in clinically-meaningful control with less residual disease burden. It was clearly evident, that between the clinical follow-ups performed at months 12 and 24, post-fremanezumab, there was a notable increase in optimal control rates (+10.5%), coupled with reduction in insufficient control rates (−9.7%). Therefore, a sustained treatment with fremanezumab might be most beneficial to allow more patients to change from a state of modest or insufficient response to less residual disease burden. Overall, this finding, on the apparent benefits of sustained treatment with anti-CGRP Mabs, supports the view that these medications may exert cumulative or time-dependent effects, which are not fully evident when within shorter follow-up periods.

On clinical grounds, this has important implications for treatment expectations and decision-making, because early evaluation based solely on ≥50% response rates may not be able to ascertain the full therapeutic potential of anti-CGRPs. Furthermore, our findings cast doubt on the rationale for mandated treatment pauses, suggesting that individualized, continuous therapy may be necessary to document potential disease-modifying effects of long-term use with anti-CGRP Mabs so as to maintain a durable reduction in migraine frequency and obtain less residual migraine burden.¹⁷

Therefore, irrespective of reimbursement policies, we suggest that clinicians should be cautious in both prematurely discontinuing treatment in partial responders, or apply mandated treatment holiday every 12 months of successful treatment, as sustained therapy may provide further improvements in both frequency and disability long-term.^11,28,29 The latter view particularly applies in difficult-to-treat populations, such as our cohort, which was phenotypically characterized at baseline by multiple prior preventive failures, long disease duration, high rates of psychiatric comorbidity and acute medication overuse.

The observed improvements in secondary outcomes further support the use of treating patients with anti-CGRP Mabs long-term.³⁰ Over 24 months with fremanezumab, we disclosed sustained reductions in MAI, moderate/severe MMDS, and migraine-related disability, according to MIDAS and HIT-6 scorings. Notably, the longitudinal decrease in disability scores between months 12 and 24 corresponds well with the observed increased rates of optimal control at the corresponding time-points. Hence it is actually suggested that indeed transition to optimal migraine control state is associated with decreased migraine-related disability, as a result of less residual disease burden.

Regarding predictors of treatment response, our results indicate that the number of prior conventional preventive failures was not an independent predictor in our model. On the contrary, prior exposure to anti-CGRP therapies was clearly associated with a reduced likelihood of achieving optimal control, whereas treatment-naïve patients exhibit significantly higher odds of treatment response. This finding likely reflects greater disease refractoriness and supports the concept that switching within the same mechanistic class may yield diminishing returns for some patients, consistent with existing literature on therapy-switching.^31,32 Nonetheless, the reduced likelihood of achieving optimal control in patients previously exposed to other anti-CGRP therapies may not only reflect general disease refractoriness but could also indicate that their migraine pathophysiology might be less dependent on the CGRP pathway, suggesting a non-CGRP responsive migraine.

Our findings can be compared with those reported from the quite recently published TACHIS study.³³ In the latter 24-week real-world Italian study of eptinezumab, over 40% of 128 enrolled patients (82% female; 82% chronic migraine) achieved optimal or modest migraine control, while CGRP-targeted therapy-naïve patients experienced significantly greater benefit. Noteworthy, migraine freedom was observed in two patients (1.9%), while optimal control in only 14.8% patients (totaling 16.7%) at week 24, post-eptinezumab, compared to our migraine free (1.8%) and optimal migraine control (29.8%) rates (total 31.6%) at month 24, post-fremanezumab. This discrepancy in migraine free and optimal control rates between the TACHIS study at week 24 and ours at month 24 further supports the view that sustained treatment with anti-CGRPs may confer cumulative, time-dependent benefits, progressively reducing residual disease burden in patients with initially modest or insufficient responses. Overall, our 24-month data with fremanezumab complement the shorter-term 24-week TACHIS findings,³³ and reinforce the clinical utility of the IHS-aspired residual burden categories across different anti-CGRP Mabs. The consistent observation regarding prior CGRP exposure is also highlighted.

Tellingly, our study has several limitations. The observational, single-arm design limits causal inference and precludes direct comparison with other preventive treatments. This post-hoc analysis included sustained responders to fremanezumab over 24-months therapy; thus, potentially introducing a selection bias. Nonetheless, there were no patients excluded from this specific post-hoc analysis because they did not sustain a ≥ 50% response at 24 months as according to our reimbursement national policies, patients had to be per-se responsive throughout to maintain fremanezumab therapy for 2 years before a mandatory pause is applied. Moreover, the use of patient-reported outcomes may have introduced reporting bias, and the lack of adjustment for potential confounders may have affected the robustness of the findings. Nonetheless, among the strengths, we should highlight the prospective multicentre design, the relatively large and clinically homogeneous cohort of difficult-to-treat HFEM patients, and the comprehensive assessment of outcomes using headache diaries and validated disability measures, supporting the external validity of or findings.

Conclusion

Although this study has primarily demonstrated that although fremanezumab is highly effective in reducing migraine frequency in difficult-to-treat HFEM patients; achieving a ≥ 50% MMDs reduction to formally qualify for treatment response, does not necessarily translate into optimal disease control or meaningful reduction of disease burden. Therefore, based solely on ≥50% reduction rates may not accurately ascertain the true clinical benefits, and more ambitious outcome measures are needed for accurately evaluating treatment effectiveness and true clinically-meaningful benefit to best align with patients’ expectations and real-world clinical objectives. Because sustained treatment with fremanezumab was associated with a longitudinal increase in optimal migraine control and reductions in disability, future studies designed to specifically explore the temporal dynamics of response to CGRP-targeted therapies, are warranted.

Key Findings

A ≥ 50% reduction in monthly migraine days (MMDs) does not always reflect meaningful clinical benefit, as most patients who met this threshold did not achieve optimal migraine control.

Despite significant fremanezumab-related improvements, the majority of patients remained moderately controlled (4–6 MMDs) even after 24 months.

Naïve patients to other anti-CGRP therapies were significantly more likely to achieve optimal long-term control.

Footnotes

ORCID iDs

Andreas A. Argyriou

Emmanouil V. Dermitzakis

Michail Vikelis

Author contributions

Conceptualization: AAA, EVD, GT, MV; Data curation: AAA, EVD, GX, MC, AF, PS, EM, DR, PL, GT, MV; Formal analysis: AAA, EVD, MV; writing original draft: AAA, EVD, GX, MC, AF, PS, EM, DR, PL, GT, MV; review & editing original draft: AAA, EVD, GT, MV; Supervision: AAA, EVD, GT, MV

Consent to participate

An informed consent was obtained from each patient before publishing the results of the current study.

Consent for publication

All listed authors consent to the submission and publication of this manuscript to Cephalalgia (and are now very pleased with its acceptance for publication!!).

Ethical considerations

The study was conducted in accordance with the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board of “Agios Andreas” Patras General Hospital.

Funding

The authors received no financial support for the research, authorship and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Open practices

Not applicable.

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