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Real‐world persistence of erenumab for preventive treatment of chronic and episodic migraine: Retrospective real‐world study

Abstract Objective To describe the real‐world treatment persistence (defined as the continuation of medication for the prescribed treatment duration), demographics and clinical characteristics, and treatment patterns for patients prescribed erenumab for migraine prevention in Canada. Background The effectiveness of prophylactic migraine treatments is often undermined by poor treatment persistence. In clinical trials, erenumab has demonstrated efficacy and tolerability as a preventive treatment, but less is known about the longer term treatment persistence with erenumab. Methods This is a real‐world retrospective cohort study where a descriptive analysis of secondary patient data was conducted. Enrollment and prescription data were extracted from a patient support program for a cohort of patients prescribed erenumab in Canada between September 2018 and December 2019 and analyzed for persistence, baseline demographics, clinical characteristics, and treatment patterns. Descriptive analyses and unadjusted Kaplan–Meier (KM) curves were used to summarize the persistence and dose escalation/de‐escalation at different timepoints. Results Data were analyzed for 14,282 patients. Median patient age was 47 years, 11,852 (83.0%) of patients were female, and 9443 (66.1%) had chronic migraine at treatment initiation. Based on KM methods, 71.0% of patients overall were persistent to erenumab 360 days after treatment initiation. Within 360 days of treatment initiation, it is estimated that 59.3% (KM‐derived) of patients who initiated erenumab at 70 mg escalated to 140 mg, and 4.4% (KM‐derived) of patients who initiated at 140 mg de‐escalated to 70 mg. Conclusions The majority of patients prescribed erenumab remained persistent for at least a year after treatment initiation, and most patients initiated or escalated to a 140 mg dose. These results suggest that erenumab is well tolerated, and its uptake as a new class of prophylactic treatment for migraine in real‐world clinical practice is not likely to be undermined by poor persistence when coverage for erenumab is easily available.


INTRODUC TI ON
Migraine is a common and important neurological disorder, which can produce substantial disability and negatively affect healthrelated quality of life. 1,2 Canadian studies have shown migraine prevalence rates of 23.0%-26.0% in women, and 7.8%-10.0% in men. [2][3][4] The World Health Organization ranks migraine as the third most prevalent and second most debilitating neurological disorder, globally. 5 With over 4,000,000 people with migraine in Canada, migraine is associated with substantial social and economic impact. 6 Migraine is most common among those in their prime working years. 3 Chronic migraine (CM) is defined as at least 15 headache days per month of which 8 days are migraine days. 7 Migraine management consists of education on lifestyle and nondrug strategies, acute migraine management strategies and, where appropriate, prophylactic therapy. 8 All patients with CM should be, by definition of their migraine frequency, candidates for prophylactic therapy. Patients with episodic migraine (EM) may also be candidates for migraine prophylaxis based on the severity of their migraine and the associated disability, and lack of benefits from, or contraindications to, standard acute migraine therapies. 8 Despite comprehensive guidelines by the Canadian Headache Society for the prophylactic management of migraine, the vast majority of Canadian patients with migraine remain undertreated or inadequately treated, with meaningful migraine-related disability. 9 The most comprehensive study of migraine prophylaxis in Canada was the CHORD Study in 2006, which found that, at the time of initial consultation to a Headache Medicine specialist in Canada, only 30.9% of patients were on a prophylactic therapy. 9 Unfortunately, neurologists have continued to observe ongoing underutilization of prophylactic therapy. In US studies, 1-year persistence (defined as the duration of time a patient remains on a prescribed medication after initiating therapy) on preventive therapy has been reported between 7% and 55%, 10 with approximately 50% of patients discontinuing preventive therapy in less than 60 days. 11 Lack of tolerability, side effects, and poor efficacy remain very common reasons for medication discontinuation. Unfortunately, non-migraine-specific, standard-of-care prophylactic therapies (e.g., amitriptyline, topiramate, and propranolol) are fraught with potential side effects including sedation, weight gain, exercise intolerance, and cognitive difficulties. Accordingly, there has been substantial unmet individual, societal, and economic need for safe, effective, and tolerable prophylactic treatments for the prevention of migraine.
Calcitonin gene-related peptide (CGRP) is a proinflammatory, vasodilating neuropeptide that contributes to migraine pathophysiology and presents a promising new target for prophylactic migraine treatment. 12 Erenumab is a first-in-class, fully human monoclonal antibody that binds to the CGRP receptor to interrupt the CGRP signaling pathway associated with migraine pathophysiology. 13 In Phase II and III clinical trials with patients with episodic and chronic migraine, erenumab demonstrated statistically significant efficacy over placebo in reducing the number of monthly migraine days (MMDs), improving functional scores, and reducing the need for acute migraine medications, with a tolerability profile similar to that of placebo. [13][14][15] Erenumab is self-administered as a monthly subcutaneous injection available as a 70 or 140 mg dose. It received Health Canada approval for the prevention of migraine in August 2018 and became available in September 2018 through the Novartis-sponsored patient support program (the "Go Program ® "). 16 Despite significant sustained persistence to erenumab treatment observed in open-label extension arms of the randomized clinical trials, the extent of long-term treatment persistence to erenumab in Canada in a real-world setting is unknown. This current study is an analysis of real-world data available through the Go Program ® . The objective of this study was to evaluate the demographic and clinical characteristics of patients prescribed erenumab following its launch in Canada and to describe the realworld treatment persistence and dose change patterns for patients prescribed erenumab in Canada.

Study design and data sources
This was a real-world retrospective cohort study using deidentified secondary patient data. The data were collected through Novartis' Go Program ® for a cohort of Canadian patients who initiated erenumab between September 2018 and December 31, 2019. The Go Program ® provides injection training, reimbursement support, and coordination of erenumab access including a free-of-charge access to erenumab until patients have access to public or private reimbursement. To enroll in the Go Program ® , patients must have been prescribed erenumab for the prevention of migraine in accordance with the Health Canada-approved product monograph. 16 At enrollment, patients provided written dose. These results suggest that erenumab is well tolerated, and its uptake as a new class of prophylactic treatment for migraine in real-world clinical practice is not likely to be undermined by poor persistence when coverage for erenumab is easily available.

K E Y W O R D S
dose, erenumab, migraine, persistence, prophylactic informed consent to participate in the program and to the use of their de-identified data for research purposes, enabling post hoc observational reporting of aggregate data. Data used for this study were collected from two main sources: enrollment data and prescription data.
Physician-recorded enrollment data contained information on patients' baseline demographics and clinical characteristics, including mean MMDs. Information was also collected on previous prophylactic medications the patient had tried and the duration of use.
The Go Program ® recorded the start date of erenumab treatment and the date of erenumab discontinuation for patients who discontinued during the analysis period. Prescription data were reported longitudinally by the pharmacy dispensing the erenumab prescription and contained fill date, days of supply, and initiating drug dose (70 or 140 mg).
All the data used for this analysis, including treatment start date, discontinuation date, and dose of each prescription, were either physician-recorded or pharmacy-reported. The data were initially reported in the Go Program ® database and subsequently extracted for analysis purposes. As this was a retrospective post hoc analysis, the data collection process was not specified by a research protocol nor externally validated or monitored. However, a data management plan was implemented, and the data collected from both sources mentioned above were crosschecked and cleaned to ensure data validity and accuracy. A descriptive analysis method was used for this study given there were no planned comparative analyses nor an intent to establish relationships between the analyzed variables.

Inclusion criteria
Patients in the Go Program ® with documented consent were included in the analysis if they met the following criteria: • Status in the Go Program database was either "In Treatment" or "Discontinued" • Treatment start date was available • Age was ≥18 years old at treatment start date

Baseline characteristics
Baseline demographics and clinical characteristics were collected at enrollment, including age at treatment initiation, sex, province, insurance coverage type (private or public), number of MMDs, and previous preventive therapies. At enrollment, physicians were asked to report at least two previously discontinued prophylactic therapies along with the associated start (month/year) and end (month/year) estimates. Previous therapies were counted by class; if the Go Program ® documented prior use of multiple molecules falling within a single class, this was recorded as one previous therapy. The duration of use was calculated as the number of months between the start and end date (month/year) reported for the therapy class. It is important to note that physicians were only provided space to report up to three previous therapies on the patients' paper enrollment form; therefore, the reported information on previous therapies was likely incomplete for many patients and the true number of previous therapies is likely higher than reported here. Therefore, this analysis does not report summary statistics on the number of previous therapies used prior to initiation of erenumab.

Persistence
The primary outcome was persistence to erenumab, which was derived from the erenumab treatment start date and discontinuation date. Days persistent were calculated as the number of days between the treatment start date and discontinuation date or the end of study follow-up, whichever occurred first, and persistence was reported for 90, 180, 270, 360, and 450 days after the treatment start date.

Data analysis
All analyses conducted were descriptive. No formal sample size calculation was carried out for this study given the retrospective, descriptive, and post hoc nature of the analysis conducted using the data collected by the Go Program ® . Continuous variables were summarized using mean, standard deviation, median and interquartile range (IQR), and categorical variables were summarized by counts and proportions (%). Time-to-event outcomes (i.e., persistence and dose change) were analyzed using Kaplan-Meier (KM) survival methods and the associated life table based on product limit estimates 17 to estimate the survival rate for persistence and cumulative incidence for dose change at specified timepoints. Patients were censored administratively at the time of data extraction or at 450 days, whichever came first. All KM analyses assume that the probability of the outcome (i.e., discontinuation, dose escalation, or dose de-escalation) and the probability of censoring are the same for censored and uncensored patients. All analyses are reported for overall patients and stratified by baseline migraine status (i.e., EM and CM). Persistence was also reported with age, sex, and baseline MMD stratifications. Results based on fewer than six patients were masked for patient privacy. All analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC).    Unknown, n (%) 10 (0.1) 6-10 a 1-5* a Results with patient counts fewer than 6 were masked as "1-5*" for privacy purposes. Additional cells were masked wherever necessary to avoid back calculation.

Baseline characteristics
b The insurance variable indicates the insurance plan that was available to the patients at baseline. It does not indicate the insurance plan that reimbursed erenumab.   Figure S3).

DISCUSS ION
Migraine is a leading cause of years lived with disability, negatively affecting health-related quality of life, family relationships, social relationships, and workplace attendance and productivity. 1  Results with patient counts less than 6 were masked as "1-5*" for privacy purposes. Additional cells were masked wherever necessary to avoid back calculation. b All persistence estimates are KM-derived. The number of patients at risk included patients who remained persistent at each timepoint and excluded patients who had discontinued erenumab or had been censored prior to that timepoint. Censoring date is April 24, 2020 or 450 days after treatment start, whichever happened first. The maximum observable persistence was 450 days.   [13][14][15] and on more recent real-world positive efficacy results, 21,22 suggesting that erenumab is effective and well tolerated by patients in the Canadian real-world setting. Given the historically low adherence to prophylactic therapies (due to poor efficacy and/or tolerability) 10,11,19 and considering the significant burden of migraine, these results offer valuable evidence on a better and more sustainable  uptake of erenumab in a real-world clinical practice context and its potential to alleviate the significant burden associated with migraine. 5 The strengths of this analysis included a sizable study population that was not restricted by geography, prescriber, nor insurance and should be broadly representative of the migraine population across the Canadian healthcare system. Furthermore, this is the first study to report on longer term use and tolerability of erenumab in a realworld context. However, observations reported herein were made in the context of routine Canadian clinical practice and insurance coverage and may not be generalizable outside of Canada.
Use of routinely collected patient support program data allowed for the analysis of persistence and treatment patterns in a naturalistic setting, unlikely to be affected by the biases associated with invasive follow-up. However, the secondary use of data in this study may have conferred some limitations and potential sources of bias. Because the primary use of these data was not for research purposes, data collection was not specifically designed for this analysis and was not externally validated. Enrollment data were collected via a standard enrollment form for each patient and may have been prone to the biases of the physician and/or patient.
For example, information on previous therapies may have been dependent on physician estimates, patient recall, and may not have referenced a medical chart, resulting in incomplete or inaccurate information. In particular, the paper enrollment form only provided space to report three previous therapies, even if the patient had previously tried more than three therapies. As a result, no summary measures on the number of previous therapies were reported.
Although the analysis does summarize how frequently therapy classes were reported and their duration of use, it is acknowledged that these results are still prone to recall bias. However, the consistency between these results and those of previous studies 10, 11,19 increases confidence in the validity of these findings in the context of a real-world study. Second, although prescription data were reported directly by the pharmacy, it only captured what was prescribed and dispensed to the patient. Because erenumab is administered through self-injection, as opposed to an infusion clinic where administration is monitored and can be verified, it is impossible to know whether patients were truly taking erenumab as prescribed. This limitation is difficult to overcome for most research using real-world data to study persistence or adherence, where the objective to gather data in a naturalistic and minimally invasive manner competes with methodological rigor. Finally, since attrition from the Go Program was deemed to be indicative of discontinuation of erenumab, it is still technically possible that a patient could discontinue from the Go Program and then access erenumab by paying out of pocket. However, this is very unlikely given the ease of free access to erenumab through the Go Program.

CON CLUS ION
In summary, the results of this analysis demonstrated that the major-