Background
Migraine is 1 of the most common disabling neurological diseases worldwide, with an estimated 1-year prevalence of 15% to 18% [
1,
2]. Symptoms of migraine may include unilateral throbbing headache, sensitivity to physical activity or visual or auditory stimuli, and nausea [
2,
3]. Migraine attacks can be extremely debilitating and may last several days [
2‐
4]. Since 1990, the number of disability-adjusted life-years for those who suffer from migraine has increased by 24.6% among individuals 10 to 25 years of age and 61.2% among those 25 to 49 years of age [
1]. As of 2019, migraine was the second leading cause of years lived with disability (YLD) overall worldwide, and the leading cause of YLD among women younger than 50 years [
5]. Patients with migraine who have more severe disability may also experience poorer health-related quality of life [
6].
Given the high degree of disability associated with migraine, the American Headache Society (AHS) guidelines include severity of disability among the criteria for migraine prevention, and reduction of disability as 1 of the goals of migraine preventive therapy [
7]. Although there are numerous medications that have traditionally been used for the preventive treatment of migraine, such as antihypertensives, anticonvulsants, and antidepressants, none of these was developed specifically to prevent migraines [
8]. Adherence and persistence to these treatments are generally low, often due to lack of efficacy and/or poor tolerability [
9‐
12].
The calcitonin gene-related peptide (CGRP) pathway has emerged as an effective therapeutic target for both episodic migraine (EM) and chronic migraine (CM), resulting in a shift in the migraine preventive therapeutic landscape [
13]. Inhibition of the CGRP pathway has been shown to treat migraine pain [
4,
14], and validation of this pathway has led to the development of several monoclonal antibodies that target either the CGRP ligand or receptor for the preventive treatment of migraine [
13].
Fremanezumab is a fully humanized monoclonal antibody (IgG isotype 2∆a) that selectively binds the CGRP ligand [
15,
16]. The safety, tolerability, and efficacy of fremanezumab was previously demonstrated in the pivotal phase 3 randomized, double-blind, placebo-controlled HALO EM and HALO CM studies in patients with EM and CM, respectively, as well as in the randomized, double-blind, placebo-controlled, phase 3b FOCUS study in patients with EM or CM with inadequate response to 2 to 4 prior migraine preventive medication classes [
17‐
19]. The efficacy and tolerability of fremanezumab has also been demonstrated in a 12-month extension study for the long-term preventive treatment of EM and CM, which included patients who completed the HALO EM or HALO CM study, as well as new patients [
20].
Each of these studies demonstrated improvements in disability based on changes from baseline in patient-reported disability outcomes, the 6-item Headache Impact Test (HIT-6), and/or Migraine Disability Assessment (MIDAS) [
17‐
20]. The AHS Consensus Statement guidelines for determining response to CGRP pathway–targeted monoclonal antibodies for migraine includes using the HIT-6 and MIDAS disability questionnaires, which are validated patient-reported measures of headache disability [
7]. The following pooled analysis of data from the HALO EM, HALO CM, and FOCUS studies [
17‐
19] evaluated clinically meaningful reductions in disability outcomes (HIT-6 and MIDAS), based on the AHS Consensus Statement–defined criteria, as well as changes in disability severity with fremanezumab treatment [
17‐
19].
Discussion
Both EM and CM are associated with considerable disability, which can have a substantial negative impact on quality of life for those affected [
24]. The World Health Organization considers a day lived with severe migraine to be as disabling as a day lived with dementia, quadriplegia, or acute psychosis [
24]. Therefore, reducing disability associated with migraine is an important goal of any preventive treatment regimen for EM and CM [
7].
Fremanezumab has previously demonstrated favorable tolerability and efficacy in patients with EM and CM, including those with difficult-to-treat migraine based on inadequate response to up to 4 prior migraine preventive medication classes, in randomized, double-blind, placebo-controlled clinical trials [
17‐
19]. In the HALO CM and FOCUS studies, significantly greater least-squares mean (LSM) reductions from baseline were observed in HIT-6 scores during the 4 weeks after the last dose of double-blind treatment with fremanezumab compared with placebo (
P < 0.001 for all differences between quarterly and monthly fremanezumab vs placebo) [
18,
19]. Similarly, in the HALO EM and FOCUS studies, significantly greater LSM reductions from baseline were observed in MIDAS scores during the 4 weeks after the last dose of double-blind treatment with fremanezumab compared with placebo (
P ≤ 0.002 for all differences between quarterly and monthly fremanezumab vs placebo) [
17,
18]. Further, during a subsequent long-term extension study, continued reductions in disability, based on MIDAS and HIT-6 scores, were observed over an additional 12 months of fremanezumab treatment [
20].
The current pooled analysis assessing clinically meaningful improvements in these patient-reported disability outcomes, as well as shifts in disability severity, supported those previous findings showing reductions in disability with fremanezumab treatment. In this pooled analysis, in which the majority of patients had severe disability based on HIT-6 scores at baseline, a significantly higher proportion of patients in both the quarterly and monthly fremanezumab groups demonstrated clinically meaningful reductions in HIT-6 disability scores compared with placebo. Among both patients with moderate and severe disability at baseline based on MIDAS scores, significantly higher proportions of patients achieved clinically meaningful reductions in MIDAS scores with both fremanezumab dosing regimens compared with placebo. Similar results were observed in the pooled subgroups of patients with CM and EM.
A significantly higher proportion of patients also exhibited a 1-, 2-, or 3-category reduction in HIT-6 disability category or MIDAS disability grade with quarterly fremanezumab and monthly fremanezumab compared to placebo.
The ability of a migraine preventive treatment to improve migraine-related disability has been identified as a goal of migraine preventive treatment [
7]. In a randomized study of the CGRP receptor–targeting monoclonal antibody erenumab, after 52 weeks of treatment, patients receiving erenumab 70 mg and 140 mg experienced reductions in migraine disability, measured using the Migraine Physical Function Impact Diary. Patient-reported physical function impact scores improved by 5.4 and 5.7 points, respectively, and everyday impact scores improved by 6.9 and 7.1 points, respectively [
25]. These results, along with those of other studies showing improvements in patient-reported disability assessments [
26‐
28], suggest that treatment with CGRP pathway–targeting monoclonal antibodies reduces the burden of disability associated with migraine.
This pooled analysis was subject to certain limitations. The patients included in the 3 studies in this pooled analysis generally had severe disability at baseline and may represent a more severely affected population than the general migraine population. In addition, due to the severity of disability at baseline in this pooled population, the number of patients with moderate disability severity available for analysis was limited. Nevertheless, results showing significant improvements in disability with fremanezumab treatment were generally consistent, regardless of baseline disability severity category.
Conclusion
In this pooled analysis of data from patients with EM and CM, including those with difficult-to-treat migraine, fremanezumab demonstrated statistically significant and clinically meaningful improvements in headache- and migraine-related disability scores after 12 weeks of treatment. These findings support the overall clinical benefits of fremanezumab for reducing migraine symptoms, improving patient outcomes, and providing for a better quality of life.
Acknowledgements
Editorial assistance was provided by Matt McErlean, PhD, of Cello Health/MedErgy, in accordance with Good Publication Practice (GPP3) guidelines, and funded by Teva Pharmaceuticals. Authors maintained full editorial control of the manuscript and decision to submit for publication.
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