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Long‐term efficacy and safety of erenumab in patients with chronic migraine in whom prior preventive treatments had failed: A subgroup analysis

Abstract Objective To assess the long‐term efficacy and safety of erenumab in the subgroup of patients with chronic migraine (CM) in whom prior preventive treatments had failed (TF) (≥1, ≥2, and ≥3 TF medication categories) and never failed (preventive naïve or prior preventive treatments had not failed), using the data from a 52‐week, open‐label treatment period (OLTP) of the parent study. Background Erenumab is a fully human monoclonal antibody that selectively binds to and inhibits the canonical calcitonin gene‐related peptide receptor. There are limited long‐term data evaluating the efficacy and safety of erenumab in patients with CM in whom prior preventive treatments had failed. Methods Patients who had completed the 12‐week double‐blind treatment period (DBTP) in the parent study were eligible to participate in the 52‐week OLTP, during which they received erenumab every 4 weeks. The TF subgroups (≥1, ≥2, and ≥3 TF medication categories) were not mutually exclusive; patients in whom prior preventive treatments from ≥3 medication categories had failed were also counted in the ≥2 and ≥1 medication categories. Endpoints included monthly migraine days (MMD), monthly acute migraine‐specific medication days (MSMD), achievement of ≥50%, ≥75%, and 100% reduction from baseline in MMD, and exposure‐adjusted patient incidence rates of adverse events (AEs; per 100 patient‐years). Results Erenumab treatment provided sustained mean reductions in MMD and MSMD relative to the parent study baseline throughout the 52 weeks of the OLTP across all TF subgroups. At Week 52, the mean MMD change was −8.6 (SD 6.6) (baseline: 18.4 [SD 4.5] days) in the ≥1 TF subgroup. A post hoc completer analysis (52 weeks [OLTP] erenumab) showed that compared with erenumab 70 mg, the 140 mg dose was associated with numerically greater reductions in the mean MMD (Week 40: −8.6 and −7.2 days; Week 52: −9.7 and −7.9 days [≥1 TF subgroup]) and a higher proportion of patients achieved ≥50%, ≥75%, and 100% response thresholds across all subgroups at Weeks 40 and 52. Overall the exposure‐adjusted patient incidence rates of AEs did not increase during the OLTP versus the DBTP (≥1 TF subgroup: 141.9/100 versus 317.9/100 patient‐years), and no new safety signals occurred. Conclusion The long‐term treatment with erenumab was well tolerated and showed sustained efficacy in patients with CM in whom prior preventive treatments had failed, with numerically greater treatment effects for 140 mg versus 70 mg.


INTRODUC TI ON
Chronic migraine (CM) is a disabling and complex neurological disease requiring acute and preventive treatment. 1 The goals of preventive treatment in CM management include reductions in attack frequency, severity, duration of migraine, acute medication use, and disability, as well as improvements in function and health-related quality-of-life. 2 For patients with migraine, the standard of care oral migraine preventive medications are associated with low persistence 3 and adherence 4 due to insufficient efficacy and/or poor tolerability, resulting in frequent treatment discontinuations, thereby limiting achievement of treatment goals. Frequent switching or re-initiation of preventive treatment is common following discontinuations; however, discontinuation rates increase as patients cycle through additional oral migraine preventive medications. 3 There is an unmet need to improve medical care for patients with CM, particularly for those in whom prior preventive treatments had failed.
Erenumab (erenumab-aooe in U.S.) is a fully human monoclonal antibody that selectively binds to and inhibits the canonical calcitonin gene-related peptide receptor. 5 Erenumab is approved for the preventive treatment of migraine in adults in the United States, 6 the European Union, 7 and elsewhere. 8 Clinical studies have demonstrated the efficacy and safety of erenumab for migraine prevention. 9,10 However, there are limited long-term data evaluating the efficacy and safety of erenumab in patients with CM in whom prior preventive treatments had failed.
Here, we present 52-week efficacy and safety data for erenumab (70 and 140 mg) from a post hoc subgroup analysis of patients with CM in whom prior preventive treatments had failed (TF) (≥1, ≥2, and ≥3 TF medication categories) and never failed (preventive naïve or prior preventive treatments had not failed), where failure is defined as discontinuation of prior preventive treatment due to lack of efficacy and/or poor tolerability.

Study design
The study design schema and methods for the parent study 9 and its open-label treatment period (OLTP) 11 were published previously.
In brief, the parent study was a randomized, 12-week, double-blind, placebo-controlled trial that evaluated the efficacy and safety of erenumab in patients with CM at 69 sites across North America and Europe. 9 After completing 12 weeks of the parent study doubleblind treatment period (DBTP), eligible patients were enrolled in the 52-week OLTP. Week 12 DBTP visit assessments were conducted on the same day as the Week 0 OLTP visit. An overview of the study flowchart showing patient disposition is provided in Figure S1  During the parent study 9 and the OLTP 11 patients used an electronic diary (eDiary) to record information regarding migraine and non-migraine headaches, and acute migraine-specific medication use. In the parent study 9 patients used the eDiary daily between Week 4 and Day 1 (pre-randomization) during the 1-month baseline period and daily through the 12-week DBTP. During the OLTP, patients used the eDiary daily between Day 1 and the Week 12 visit, between Week 20 and the Week 24 visit, between Week 36 and the Week 40 visit, and between Week 48 and the Week 52 visit.

Study patients
The parent study 9 enrolled adult patients (aged 18-65 years) with CM who had a history of ≥15 headache days/month for >3 months, of which ≥8 were migraine days (with or without aura). Other eligibility criteria for enrollment in the parent study and its OLTP study have been reported previously. 9,11 Briefly, exclusion criteria in the parent study DBTP included no therapeutic response to >3 migraine preventive medication categories, following an adequate therapeutic trial. No therapeutic response was strictly defined as no reduction in headache frequency, duration, or severity following administration of the medication for ≥6 weeks at the generally accepted therapeutic dose(s) (based on the investigator's assessment). Previous preventive migraine medication categories included the following: topiramate, β-blockers (e.g., propranolol or metoprolol), tricyclic antidepressants (e.g., amitriptyline or nortriptyline), calcium channel blockers (e.g., flunarizine or verapamil), divalproex sodium or sodium valproate, serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine or desvenlafaxine, duloxetine or milnacipran), botulinum toxin, antihypertensives (e.g., lisinopril or candesartan), and other medications. Failure of a preventive medication category as a result of insufficient efficacy or poor tolerability, according to the clinical judgment of the investigator, did not equate with no therapeutic response, unless the definition for no therapeutic response was also met.
Furthermore, the key eligibility criteria for the OLTP were a stipulation that patients must have completed the Week 12 DBTP study visit and must not have discontinued the investigational product during the parent study. Patients were excluded from the OLTP if any of the following had occurred during the parent study: an unstable or clinically significant medical condition or a laboratory or ECG abnormality that could pose a safety risk or interfere with study procedures; any treatment-related serious adverse event (AE); or poorly controlled hypertension.

Standard protocol approvals, registrations, and patient consents
The parent study and its OLTP are registered with ClinicalTrials.gov (NCT02066415 and NCT02174861, respectively). Protocols for the parent study 9 and its OLTP 11 were approved by independent ethics committee or local institutional review board at each participating site.
Both studies were conducted in accordance with the International Conference on Harmonisation Guideline on Good Clinical Practice.
All patients provided written informed consent.

Subgroups
Subgroups were defined based on the number of prior migraine preventive medication categories that had failed for the reasons of "lack of efficacy" or "unacceptable tolerability," or both, as recorded by the investigator before enrollment into the parent study. The never failed subgroup included preventive-naïve patients and those who had prior use of preventive medication, but the treatment did not fail for reasons of "lack of efficacy" and/or "unacceptable tolerability."

Endpoints
Endpoints were change from the parent study baseline to specified assessment time points during the OLTP in monthly migraine days (MMD), monthly acute migraine-specific medication days (MSMD), and MSMD in the subgroup of patients who used migraine-specific medications (MSM) during the parent study baseline. The proportions of patients achieving ≥50%, ≥75%, and 100% reduction from the parent study baseline in MMD (≥50%, ≥75% and 100% response thresholds) were also evaluated. Safety analyses included reporting of AEs using exposure-adjusted patient incidence rates per 100 patient-years.

Statistical analysis
The details of sample size calculations of the parent study are available in the Supporting Information (Appendix S1) and published elsewhere. 9 This study was not designed or powered to make formal comparison between the two dose groups (erenumab 70 mg vs. erenumab 140 mg) or between the TF versus never failed subgroups. The descriptive statistics performed here were consistent with the descriptive nature of the long-term efficacy assessment in the OLTP 11 of the parent study. 9 For continuous endpoints, the descriptive statistics included number of observations, mean, median, standard deviation, standard error, first and third quartile, minimum and maximum, and two-sided 95% confidence interval (CI) of the means. For categorical endpoints, the number and percentage of patients were reported for each category.
Missing diary data were handled using the proration approach; monthly measurements, for instance MMD, were calculated if patients completed at least 50% of their daily diary reporting each month. If patients had low diary compliance, defined as completed <50% of daily diary reporting, the monthly measurements were set as missing. Missing monthly measurements could be due to discon-

Primary research question
Is erenumab associated with evidence of long-term efficacy and safety in patients with CM who have previously failed preventive treatment(s)? This study provides evidence that efficacy was sustained with erenumab treatment in patients with CM in whom prior preventive treatments had failed, and that the 140 mg monthly dose had a greater effect than 70 mg in the completer subset of the TF subgroup.

Patient demographics, baseline disease characteristics, and preventive treatments
A total of 609 patients were enrolled in the OLTP. There was a majority of 69.0% (n = 419) patients in whom ≥1 prior preventive treatment had failed, whereas in 31.0% (n = 190) the prior preventive treatments had never failed (preventive naïve [n = 155] or prior preventive treatments had not failed [n = 35]) ( Figure S1). The proportion of patients who discontinued from the study medication was similar across all four subgroups (0 [never failed], ≥1, ≥2, and ≥3 TF medication categories) ( Figure S1). Patients across all subgroups had a similar median age (43.0-45.0 years), and the majority were women (80.0%-85.2%) ( Table 1). Patients in whom prior preventive treatments had failed had a longer mean duration of migraine at baseline (23-24 years) than those who had never failed (19 years) ( Table 1) Table 1). Across all subgroups patients had high monthly acute headache medication treatment days at the parent study baseline (15.1-15.7 days), consistent with a more severe, difficult-to-treat population. Topiramate was the most frequently reported prior treatment category; followed by βblockers and tricyclic antidepressants across all subgroups ( Table 1).  Figure   S3 [never failed, ≥2, and ≥3 TF medication categories]).

MMD response
The proportion of patients achieving ≥50% reduction from baseline in MMD was higher in those treated with erenumab 70 and 140 mg   Note: Data are mean (SD) values unless otherwise indicated. N1 = number of subjects receiving any prior preventive medication. N = Number of subjects in the analysis set. % = n/N * 100. Prior preventive treatments never failed includes preventive-naïve patients and patients who had prior use of preventive medication, but the treatment did not fail for the reasons of "lack of efficacy" and/or "adverse reaction." FAS included patients who were enrolled in the study and received at least one dose of the investigational product.

Adverse events
Overall, the exposure-adjusted patient incidence rates of any

DISCUSS ION
The findings of this long-term study provide insights into the efficacy of erenumab in patients with CM in whom prior preventive treat- Week 40 Week 52 TA B L E 2 Exposure-adjusted patient incidence rates of TEAEs (summarized according to dose received when AE occurred) (≥1 TF medication category)

Erenumab 140 mg n(%)/e[r]
Erenumab  Note: N = number of subjects in the analysis set. n = number of subjects reporting at least one occurrence of an AE. % = n/N * 100. e = Sum across all subjects, the total time at risk in the study in years. Time at risk during the study is the time from the first dose of investigational product through to onset of first event or the min (end of study date, last IP dose +112). r = Exposure-adjusted patient rate per 100 subject years (n/e*100). Grading categories determined using Common Terminology Criteria for Adverse Events version 4.03.
Abbreviations: AE, adverse event; DBTP, double-blind treatment period; OLTP, open-label treatment period; SAEs, serious adverse events; TEAEs, treatment emergent adverse events; TF, prior preventive treatments failed. a Numbers of subjects in the 70 and 140 mg groups represent subjects exposed to both doses of erenumab.
( Figure 5 [≥1 TF medication category]; Figure S6 [ In this study, there were no reported TEAEs of Grade ≥4 severity and fatal AEs in any patient during the OLTP. In patients for whom prior preventive treatments had failed, the long-term treatment with erenumab did not result in higher exposure-adjusted patient incidence rates of AEs than observed in either the erenumab or the placebo group of the parent study DBTP (  The safety profile of erenumab in the OLTP was consistent with previous studies of erenumab, with no new safety concerns.
In conclusion, long-term treatment with erenumab showed sus- Consistent with the DBTP, the magnitude of absolute treatment effect during the long-term OLTP was numerically less in patients with increasing numbers of preventive treatments that had failed.
The long-term treatment with erenumab was well tolerated, with no increase in AEs compared with the DBTP, no new safety signals, and no dose dependency of AEs across TF subgroups. This study supports the use of erenumab in CM including patients with multiple prior preventive treatment failures and adds to the growing body of evidence for erenumab in this setting, of patients with CM.

ACK N OWLED G M ENTS
This study was fully funded by Amgen Inc., Thousand Oaks, CA.
Erenumab is co-developed in partnership with Amgen and Novartis.