Early onset of efficacy with erenumab for migraine prevention in Japanese patients: Analysis of two randomized, double‐blind, placebo‐controlled studies

Abstract Purpose In two 24‐week migraine prevention studies in Japan, erenumab was associated with significantly greater reductions in migraine frequency versus placebo over Weeks 13–24 (primary endpoint). This post hoc analysis evaluated the onset of efficacy within the first 4 weeks after the initiation of erenumab from the 24‐week double‐blind periods of these studies. Methods Placebo‐adjusted differences in least squares mean (LSM) change from baseline in weekly migraine days (WMD) were assessed weekly in each study and by migraine type (episodic (EM]/chronic [CM]) (Study 20170609). Results A total of 407 patients from Study 20120309 (70 mg: N = 135; 140 mg: N = 136; placebo: N = 136) and 261 patients from Study 20170609 ([EM] 70 mg: N = 78; placebo: N = 81; [CM] 70 mg: N = 52; placebo: N = 50) were included. For Study 20120309, onset of efficacy was observed as early as Week 1 in favor of erenumab versus placebo. Placebo‐adjusted differences in LSM (95% confidence interval [CI]) change from baseline in WMD at Week 1 were −0.38 (−0.71 to −0.05; p = .022) and −0.49 (−0.82 to −0.16; p = .004) in favor of erenumab 70 and 140 mg, respectively. For Study 20170609, significant placebo‐adjusted differences were observed with erenumab 70 mg at Week 1 in patients with EM (LSM [95% CI]: −0.55 [−0.97 to −0.12; p = .012]), and at Week 2 in patients with CM (LSM [95% CI]: −0.81 [−1.53 to −0.09; p = .028]) and for the overall population (LSM [95% CI]: −0.71 [−1.09 to −0.33; p < .001]). Conclusions Erenumab treatment significantly reduced WMD compared with placebo. Onset of erenumab efficacy occurred as early as Week 1 in patients with migraine.


INTRODUCTION
Several oral preventive treatments are available for the prevention of migraine in Japan, including beta-blockers, antidepressants, calcium channel blockers, and anticonvulsant drugs. Despite this, preventive treatment use remains low in Japan, with acute-phase therapies commonly used for migraine treatment (Ueda et al., 2019). Reasons for low adherence and early discontinuation include a perceived lack of efficacy, poor tolerability, and delayed onset of efficacy (Meyers et al., 2019;Tassorelli et al., 2018;Ueda et al., 2019), with >60% of patients discontinuing treatment within the first 2 months of treatment (Meyers et al., 2019). However, reliance on acute-phase therapies as a standalone treatment modality for migraine is not without clinical consequences, and may be associated with the development of overuse headache and transformation to chronic migraine (Torres-Ferrús et al., 2020).
Monoclonal antibodies that target the calcitonin-gene related peptide (CGRP) and its receptor have more recently been developed (Aimovig [prescribing information], 2018;Detke et al., 2020;Dodick et al., 2018), which target the underlying pathophysiology of migraine.
These agents have been shown to possess both a rapid onset of efficacy and a favorable safety profile (Aimovig [prescribing information], 2018; Silberstein et al., 2020;Vu et al., 2017;Winner et al., 2019), and are therefore expected to improve adherence and longterm patient outcomes. Erenumab, a monoclonal antibody against the CGRP receptor, is approved for the prevention of episodic migraine (EM) and chronic migraine (CM) in over 70 countries (Pharmaceutical and Medical Devices, 2021), including the United States and countries within the European Union based on positive results from global phase 2 and 3 trials Goadsby et al., 2017;Tepper et al., 2017). Two randomized, double-blind, placebo-controlled studies of erenumab for migraine prevention have subsequently been conducted in Japan Takeshima et al., 2021). In these studies, erenumab was associated with significantly greater reductions from baseline in mean monthly migraine days (MMD) versus placebo over Weeks 13-24 (primary endpoint). However, reductions were also observed as early as 4 weeks (the earliest prespecified time point at which efficacy was assessed). Based on these findings, a post hoc analysis was conducted to evaluate the time to onset of efficacy within the first 4 weeks after the initiation of erenumab in patients with EM and CM from the 24-week double-blind treatment periods of these studies in Japan.

Study designs
Detailed information regarding study designs, populations, and results have been published previously Takeshima et al., 2021

Statistical analysis
Full details regarding statistical analysis methodology for each study have been published previously Takeshima et al., 2021). All statistical analyses were performed using SAS software version 9.4 (SAS Institute, Cary, NC, USA).

Change from baseline in weekly migraine days
In

DISCUSSION
In this post hoc analysis of two similarly designed, randomized, doubleblind, placebo-controlled studies, erenumab treatment was associated with early reductions in WMD compared with placebo. Improvements  (Schwedt et al., 2018) as well as the known pharmacokinetic profile of erenumab following SC injection (Vu et al., 2017). In the post hoc analysis of the global studies, erenumab treatment was associated with significant reductions in WMD compared with placebo as early as Week 1 for some doses and by Week 4 for all doses (Schwedt et al., 2018). The findings reported in the current analysis are also consistent with results for other anti-CGRP monoclonal antibodies, including fremanezumab (Winner et al., 2019), galcanezumab (Detke et al., 2020), and eptinezumab (Silberstein et al., 2020).
Most of the commonly prescribed oral preventive medications (including beta-blockers, tricyclic antidepressants, and topiramate) require a prolonged dose titration period of up to several weeks in order to minimize adverse events (Parsekyan, 2000;Topamax [pre-scribing information], 2009), and even then efficacy may be suboptimal (Kawata et al., 2021;Parsekyan, 2000). Based on their delayed onset of efficacy, the International Headache Society guidelines for controlled trials of preventive treatment recommend a minimum treatment period of at least 12 weeks before assessment of efficacy is performed (Tassorelli et al., 2018). However, studies show that patients in Japan frequently discontinue migraine preventive treatment within the first to 2─6 months of treatment (Kawata et al., 2021;Meyers et al., 2019), with avoidance of side effects and perceived lack of efficacy identified as main reasons patients discontinue migraine preventive treatment (Kawata et al., 2021;Meyers et al., 2019). This suggests that a narrow therapeutic window may exist in which patients make important decisions regarding their adherence to, and persistence with, migraine preventive treatment. The findings from the current analysis and those of others demonstrate the rapid and sustained efficacy of erenumab for prevention of migraine in EM and CM, with onset of efficacy observed as early as Week 1 (Schwedt et al., 2018).

Coupled with the favorable safety profile demonstrated across both
Japanese and global phase 2 and 3 trials (Aimovig [prescribing information], 2018;Dodick et al., 2018;Goadsby et al., 2017;Tepper et al., 2017), it is anticipated that these therapeutic attributes could contribute to improved patient adherence and outcomes. Further, potential improvements in patient adherence to preventive treatment may also translate into a reduced need for acute migraine medications for the treatment of EM or CM, which are associated with medication overuse headache (Torres-Ferrús et al., 2020), transformation to chronic migraine (Torres-Ferrús et al., 2020), and development of adverse events, particularly with frequent, long-term use (Ong & De Felice, 2018). include the relatively small sample size of some groups, the lack of prespecified hypothesis, and lack of control for p value inflation due to multiplicity testing. In this context, all p values are nominal and should be interpreted with caution.
Nevertheless, erenumab treatment was associated with significant reductions in WMD compared with placebo, with onset of erenumab efficacy occurring as early as Week 1 in patients with both EM and CM.
These improvements were sustained to Week 4 in the current analysis, and continued for the duration of the 24-week double-blind phase, as reported previously Takeshima et al., 2021). In addition to the favorable benefit-risk profile of erenumab (Aimovig [pre-scribing information], 2018), its early onset of efficacy may prove an important benefit to patients with respect to adherence and contribute to improvements in patient outcomes.

ACKNOWLEDGMENTS
The authors thank all clinicians for their involvement and contribution to the study. The authors also thank Jordana Campbell, BSc, CMPP of inScience Communications, Springer Healthcare, for writing the outline and the first draft of the manuscript. This study was funded by Amgen Inc.

AUTHORSHIP
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

DATA AVAILABILITY STATEMENT
Qualified researchers may request data from Amgen clinical studies.

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1002/brb3.2526