In our prospective multicenter long-term study, we show that monthly fremanezumab is effective and well tolerated as a preventive treatment in patients with CM and HFEM for up to 12 months in a real-world setting. To the best of our knowledge, this is the first real-world study assessing the effectiveness of fremanezumab up to 12 months in patients with drug-resistant migraine. We are aware of a previous Italian study that evaluated the efficacy of fremanezumab with a 3- or 6-month follow-up (FRIEND study) [7, 8], as well as a Greek registry with an up to 3-month follow-up [9], and a retrospective US chart review study reporting data up to 6 months [10].

The characteristics of our cohort are comparable to those described in previous studies, both in terms of sex and distribution of other clinical variables, including prior preventive failures. However, as discussed below, our cohort exhibited a higher average age compared with previous studies (mean age 56.2 years, vs 39.7–48.9 years).

In line with previous real-world studies [8,9,10], we confirmed the effectiveness and tolerability of monthly fremanezumab in difficult-to-treat patients with HFEM and CM, with several preventive failures, including onabotulinumtoxin A. At variance with previous investigations, in our present study, most patients completed the 12 months of treatment, before the mandatory interruption according to the Italian regulations, with a low discontinuation rate (18.0%). This highlights a favorable clinical response to fremanezumab as an effective migraine preventive treatment, confirming the remarkable persistence in anti-CGRP mAb treatment, which substantially differs from persistence reported for standard oral preventive therapies [19].

Our findings confirm: an early improvement in migraine frequency, associated with a reduction in analgesic intake, calculated as the total number and days with acute medications, and disability scores; a progressive increase in response up to 6 months of treatment, which was maintained until the end of the 12-month observation period; and no evidence of increase in AEs. The response rate (≥ 50%) in our study is comparable to those obtained by other prospective studies, including the FRIEND studies in the overall population at 3 and 6 months (64.2 and 73.6% vs 51.9 and 67.9% in our study) [7, 8] and in a study of a Greek registry at 3 months in CM (62.6 vs 51.9%). However, their results show a slightly lower response rate for HFEM (83.5 vs 56.2%) [9]. Notably, although patients enrolled in previous observational studies had a higher burden of disease, a higher number of prior treatment failures and a higher rate of MO at baseline than those enrolled in RCTs [6], all real-world studies unanimously report superior improvements in migraine-related variables compared with those found in pivotal RCTs and their open-label extension (e.g., 6-month open-label FOCUS trial) [5, 6].

The reconciliation of outcomes between randomized controlled trials (RCTs) and observational studies is a noteworthy challenge within clinical medicine, as numerous factors may contribute to the disparity in results. These factors encompass selection bias, confounding factors, statistical power, and differential adherence and follow-up [20]. A Cochrane review [21] discovered little evidence that the results of observational studies and RCTs consistently differ. This underlines that observational studies may be an important addition to the clinician’s resources by complementing RCT data. Nevertheless, a thorough examination of the reasons underlying the apparent superiority of observational studies over RCTs in relation to anti-CGRP/receptor mAbs is worthy of further evaluation.

Fremanezumab showed consistency in its effectiveness and tolerability, as they were maintained over time, in observational studies with an increasing follow-up of treatment [7,8,9]. Our study enrolled drug-resistant patients who did not respond to or tolerate at least three preventive classes with 68.7% of patients with MO. We confirmed that fremanezumab, like other anti-CGRP/receptor mAbs, is effective in patients with MO, with a reversion of the overuse without other treatment, an effect that significantly affects patients daily quality of life [22].

This difficult-to-treat migraine population is usually poorly represented in clinical trials and is the most challenging to manage in clinical practice, for both acute and preventive treatment. Furthermore, our cohort was older compared with other real-world studies [7, 8, 10] and RCTs [3,4,5] with fremanezumab or erenumab (mean 46.7, interquartile range 45.7–49) [6]. In our cohort, no unexpected AEs were reported, the incidence of AEs was not age related, and age was not a predictive variable for achieving a response status at any timepoint, underlining the safety and effectiveness of fremanezumab.

The reduction in MHDs and other migraine-related variables occurred mainly after the first 3 months of treatment, followed by a slightly further decrease in the following 3 months (6 months). As confirmed by the sensitivity analysis, no further significant improvement was observed at months 6 and 12 of treatment. Although, in principle, a longer treatment might lead to a better response rate, in line with previous studies [1, 6], both observed data and sensitivity analyses suggest a ceiling effect of anti-CGRP mAb effectiveness. Several clinical and demographic predictors were identified in different studies (e.g., migraine burden at baseline, years of migraine, allodynia, triptan use, body mass index), as discussed in [23], but results are usually inconsistent among them, and there is no current evidence for robust clinical predictors of response to mAbs. No predictors of response (≥50% in MHD reduction) have been identified in our cohort at any follow-up. It should be noted that some variables reported in other real-world studies (e.g., autonomic symptoms, triptans effectiveness, mood disorders) were not collected in this population [24]. Fremanezumab was well tolerated as all AEs were mild and transient and no serious AEs were reported. Few AEs occurred during the first 6 months of treatment. Only in one case, because of a transient local allergic reaction, treatment was discontinued at month 6.

Several strengths characterize our study. This is the first study reporting 12 months follow-up of fremanezumab treatment in clinical practice, enrolling patients usually under-represented in RCTs. In fact, our cohort consisted of patients with HFEM and CM who did not respond or tolerate at least three previous preventive treatments, and most of them with MO. Further strengths include the use of different analyses on acute medication use (including days and total number of acute medications used) and on disability questionnaires, and a sensitivity analysis to adjust effectiveness results for missing data and dropouts. There are, however, some limitations, including the use of only MHDs instead of distinguishing MHDs from monthly migraine days. Some patients (Table S1 of the ESM) received concomitant preventive therapy (regardless of clinical indication) during fremanezumab. However, as no preventive treatment was initiated shortly before or after fremanezumab, and considering the high burden of disease at baseline, it is unlikely that this would have impacted on the results. We also did not record the number of patients with MO who underwent detoxication procedures, which might have contributed to the efficacy of fremanezumab. Furthermore, being an open-label study, we cannot rule out the potential placebo effect and the cyclical exacerbations and relative remissions of migraine over time. Finally, our analyses included only patients treated with monthly fremanezumab, and results may not apply to the quarterly regimen.