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Amgen Response to ICER’s Review of Migraine Treatments: “Open Input”

Overview

The Institute for Clinical and Economic Review (ICER) has announced that they will assess the comparative clinical effectiveness and value of erenumab (Amgen/Novartis), an anti-Calcitonin Gene Related Peptide (CGRP) monoclonal antibody, for prevention of migraine.1  Amgen and Novartis recognize that ICER is engaging in an important dialogue for migraine patients in anticipation of erenumab’s launch. The objective of this document is to recommend how ICER should assess CGRPs and specifically erenumab for migraine prevention.

Disease burden and challenges in treatment are key considerations for any assessment

A day with severe migraine is as disabling as a day lived with dementia or quadriplegia.2,3  The WHO ranks migraine as the 6th leading cause of years lived with disability and the third leading cause of disability-adjusted life years across neurological disease. 4,5  Ninety percent of migraine patients have impaired function during an attack, approximately half are severely impaired and a third require bedrest.6  Moreover, the impact of migraine is not limited to impairments during attacks.  Patients experience anxiety associated with the anticipation of another attack, often causing them to avoid certain activities of daily living for fear of triggering another migraine.7

Patients desperately need additional options to help address this disabling disease.  A large number of patients discontinue currently available preventive drug treatment.  Over 70% of patients starting currently available preventives discontinue therapy by one year.8  Another study which evaluated reasons for discontinuation in treatment experienced patients, reported that up to 47% of patients discontinue preventives because of adverse events or lack of efficacy.9

For migraine, the patient perspective is important.  Evaluating migraine treatment from solely the payer’s perspective would completely omit the majority of costs.  Assessing the value of treatments is complicated by the inherent asymmetry in the costs of migraine.  While total costs represent over 20 billion dollars annually,10 indirect costs are disproportionately higher than direct costs with absenteeism and presenteeism 50-70% of total costs.11,12,13 Each employee with frequent migraine costs employers as much as $13,000 per year.14,15 Hence, if an assessment of migraine were performed solely from the payer perspective, this would only capture a fraction of the value of a new treatment to patients and employers. Exclusion of indirect costs such as missed work days, reduced productivity at work and disability could deprioritize migraine, thereby restricting access to an innovative medication such as erenumab.

Erenumab offers patients an important migraine prevention option in a disease where the drug armamentarium has not changed materially in the last 2 decades

Erenumab is a novel investigational therapy in migraine prevention, developed specifically to target the CGRP pathway, one of the best validated and most actively studied migraine targets.16,17Erenumab is the only CGRP-directed monoclonal antibody that targets the CGRP receptor.18  For migraine patients with previous preventive treatment failure, compared to baseline and adjusted for placebo, erenumab reduced monthly migraine days by 2.5 days19 for episodic migraine (EM) patients and 3.33 days20 for chronic migraine (CM) patients.  Erenumab treatment was also associated with a low rate of treatment discontinuation due to adverse events and a favorable tolerability profile. It is also anticipated that it will be an at home monthly self-administration.

Amgen and Novartis recommendations for ICER’s assessment of erenumab

Given the profound burden of disease, unmet need in migraine prevention and its comparatively silent cost footprint in the healthcare system, we would like to specifically recommend that ICER takes into account the following areas in the design of this assessment:

  1. Include costs from the societal perspective as the base-case in ICER’s analyses: With the majority (50-70%) of costs incurred outside of the healthcare system,21,22,23 the true value of treatments cannot be accurately calculated without inclusion of all medical, direct non-medical and indirect costs.  Inclusion of these costs will avoid significantly undervaluing this treatment for patients. 
  2. Incorporate the patient perspective in the outcome measure: Quality-Adjusted Life Year (QALY) and utility assessments provide robust methodologies to quantify the patient perceived benefit in any disease and especially migraine where the majority of outcomes are patient reported. Utility gains associated with preventive treatments in migraine can be mapped to the EuroQol 5-dimension instrument (EQ-5D) using published algorithms that use the MSQ and HIT-6, the PRO questionnaires typically collected in most registration studies for investigational CGRP monoclonal antibodies.24,25  Use of the QALY as an outcome measure will allow the incorporation of deeper and broader capture of migraine patient burden.
  3. Assess erenumab only in patient populations that have 4 or more migraines per month: As per treatment guidelines, preventive therapy should be initiated in individuals experiencing four or more migraine days per month with normal functioning; in patients with two to three migraine days per month with some impairment; or in patients with two to three migraine days with severe impairment.26 Evaluation of erenumab should start with this patient population who have 4 or more migraines.
  4. Assess erenumab only in prevention of episodic migraine (EM) and chronic migraine (CM), and focus this analysis on patients who will derive the most value from erenumab, specifically those that have failed prior treatment:
    1. In episodic migraine, we recommend that ICER only include the appropriate patient populations which are those who have already failed generic preventive therapy (e.g., anticonvulsants, beta-blockers, calcium channel blockers, antidepressants), where the comparator is supportive care.  We further recommend incorporating data from trial 20120296 of erenumab in episodic migraine.
    2. In chronic migraine, we recommend that ICER only include the appropriate patient populations which are those who have already failed generic preventive therapy (e.g., anticonvulsants, beta-blockers, calcium channel blockers, antidepressants), where the comparator is OnabotulinumtoxinA, which has an indication in chronic migraine.  We further recommend incorporating data from trial 20120295 of erenumab in chronic migraine.

    Assessing EM and CM patients differently and limiting the assessment to only those patients who have already failed generic therapy, will demonstrate where erenumab is most likely to be used in a real world setting and will have the greatest impact.
  5. Define supportive care to include the use of acute medications as needed by patients to manage their migraine:  In the clinical protocols of trials 20120296 and 20120295, patients were permitted the use of acute medications during baseline and through the course of the study.  Reduction of acute medications is an important endpoint when considering the benefit that erenumab brings to patients.

There is an urgent need for additional safe, effective treatments that improve quality of life in ineffectively treated migraine patients. These patients suffer physically, impacting their interactions with family and friends and their ability to work. The burden of migraine also extends to employers and payers through substantial indirect and direct costs. Optimal migraine management with preventive therapy may help to lessen this burden. Given the lack of innovation in the past 2 decades, however, migraine sufferers have been treated with therapies developed for other conditions and many of these are often associated with side effects leading to treatment discontinuation27 and overuse of acute medications including opioids and narcotics.28 As new preventive therapies such as CGRP monoclonal antibodies become available, any value assessment must consider the appropriate cost perspective, population, comparators and treatment patterns to ensure that value is robustly assessed.

To help ICER in the assessment of therapies for migraine prevention, particularly erenumab, we have included a supportive data package following this summary.  This is split into three sections

1) Section 1: More information specific to the above 5 recommendations.

2) Section 2: Erenumab treatment comparators, clinical data and relevant patient populations.

3) Section 3: Current treatment landscape and need for new and effective preventives in migraine.

SUPPORTING DATA PACKAGE

SECTION 1:

SPECIFIC RECOMMENDATIONS ON THE ASSESSMENT OF ERENUMAB

1) Include costs from the societal perspective as the base-case in ICER’s analysis

Inclusion of costs from all stakeholders will avoid significantly undervaluing this treatment for patients.

The burden of migraine is pervasive, with both measurable and immeasurable costs. Migraine accounts for more than 20 billion dollars in direct and indirect costs in the United States.29,30,31 Migraine is atypical in that indirect costs are disproportionately higher than direct costs such that absenteeism and presenteeism are up to approximately 50%-70% of total costs.32,33,34 Each employee with frequent migraine costs employers thousands of dollars every year, with estimates between $2.4k and $7k for women and $4k and $13k for men.35,36  A comprehensive evaluation of how CGRPs may positively impact the individual with migraine, as well as the wider society, is imperative.

Migraine prevalence is highest during prime productive working years (30 to 49)37, contributing to high indirect costs (work days absent and reduced productivity at work).  Although absenteeism is more easily identifiable, of growing concern to employers is presenteeism and the financial cost incurred by lost productivity. Migraine patients with less than 15 headache days per month lose the equivalent of almost half a working day every week due to presenteeism or absenteeism. As the number of headaches increase, patients may lose the equivalent of more than 1 working day every week due to presenteeism or absenteeism.38 Moreover, individuals with migraine are 2.5 times more likely to have a short-term disability claim and 2.4 times more likely (0.61% vs. 0.25%) to have a long-term disability claim, with an average cost of $26,543 per claim, compared with non-migraine individuals.39,40

Given that migraine occurs during the peak productive working years and the disproportionate economic burden experienced by employers and individuals, failure to incorporate all direct and indirect costs when assessing the value of preventive treatment would misrepresent its full value.  An approach that is inclusive of all stakeholders will be important to avoid the unintended consequence of cost-shifting to employers and most importantly patients affected by this seriously debilitating and disruptive neurological disease. ICER’s inclusion of costs from the societal perspective as the base-case in this analysis would be supported by the body of academic research in health technology assessment.41,42,43,44  As such, any value assessment for migraine should be performed using a societal perspective, considering both direct and indirect costs and benefits that are experienced across all impacted stakeholders.

2) Incorporate the patient perspective (i.e., QALY) in the outcome measure

Use of the QALY as an outcome measure will allow the incorporation of deeper and broader capture of migraine patient burden.

According to the WHO, a day lived with severe migraine is as disabling as a day lived with dementia or quadriplegia and more disabling than paraplegia or rheumatoid arthritis.45,46 The WHO ranks migraine as the 6th leading cause of years lived with disability and third leading cause of disability-adjusted life years across neurological disease.47,48 Approximately, 90% of migraine patients have impaired function during an attack, about half are severely impaired and a third require bedrest.49

Migraine is associated with debilitating and disruptive symptoms including pain, nausea, vomiting, and sensitivity to light and sound. Between 60-95% of patients experience nausea, and 50-62% experience vomiting.50,51 Differential diagnosis of migraine (over other headache disorders) requires the presence of 2 out of 3 of these symptoms: photophobia, nausea, and impact on activities (sensitivity of 0.81 and a specificity of 0.75).52  Pain, sensitivity to light and nausea cause patients to isolate themselves leading to significant impact on their health-related quality of life (HRQoL).  This impact on HRQoL among individuals with migraine as compared to the general population is demonstrated by normative data on the SF-12.53 Patients with migraine had lower scores (p < 0.001) on both the mental component score (MCS-12) and physical component score (PCS-12) than their non-migraine counterparts. Significant differences were maintained after controlling for gender, age, and education. HRQoL was significantly associated with attack frequency (MCS-12 and PCS-12) and disability (MCS-12).

Functional impairment during a migraine attack is high. This experience is significantly detrimental to patients’ health related quality of life, leading to missing time with family and friends.  Substantial migraine-induced burden has also been reported based on other migraine specific PRO measures, including the Migraine Specific Quality of Life Questionnaire (MSQ), Headache Impact Test (HIT-6) and Migraine Disability Assessment Test (MIDAS).54 In migraine prevention studies, the Headache Impact Test (HIT-6) and the Migraine Specific Quality of Life Questionnaire (MSQ) are migraine specific patient-reported outcome (PRO) questionnaires that are routinely used to assess the impact of headache on patients and migraine specific quality of life.  These PROs can be mapped to the EuroQol-5D (EQ-5D), to allow the evaluation of patient perceived benefit in migraine through utility values. Failure to incorporate the health-related quality-of-life benefits perceived by patients (utilities) when evaluating the value of preventive treatment would immensely underestimate the real benefit or value of migraine preventive treatment. 

3) Assess erenumab only in patient populations that have 4 or more migraines per month

Evaluation of erenumab should start with this patient population who have 4 or more migraines.

As per treatment guidelines, preventive therapy should be initiated in individuals experiencing four or more migraine days per month with normal functioning, or patients with two to three migraine days per month with some impairment or those with two migraine days with severe impairment.55 As per the American Academy of Neurology (AAN), the goals of migraine preventive therapy are to:

  1. reduce attack frequency, severity, and duration;
  2. improve responsiveness of treatment with acute therapies; and
  3. improve function and reduce disability

4) Assess erenumab only in prevention of episodic migraine (EM) and chronic migraine (CM), and focus this analysis on patients who will derive the most value from erenumab, specifically those that have failed prior treatment

Assessing EM and CM patients differently and limiting the assessment to only those patients who have already failed generic therapy, will demonstrate where erenumab shows the greatest impact.

Migraine can be broadly classified as episodic (EM) or chronic migraine (CM) based on the number of migraine days (MD) and headache days (HD) per 28 days. EM is characterized by <15 HD per 28 days and accounts for more than 90% of migraine in the US population. In contrast, CM, is defined by ≥15 HD per 28 days, including at least 8 days with migraine and accounts for approximately 5% – 8% of migraine.56

Given that erenumab has demonstrated efficacy in patients with the high unmet need, i.e., patients who have tried and failed preventive treatment, the target patient population for erenumab are those episodic and chronic migraine patients who have tried and failed preventives.

For patients who have tried and failed preventive treatment, the appropriate comparator for value assessments in EM is ‘supportive care’ in which patients receive only acute treatment for migraine. In CM, the relevant comparator is onabotulinumtoxinA which is only indicated for chronic migraine.57

  • There is no defined standard of treatment in migraine patients who have previously received and failed generic preventive therapy due to adverse events or a lack of efficacy.
  • This lack of demonstrated clinical efficacy or real-world effectiveness or effectiveness of sequencing of different preventive classes leaves a large unmet need for these patients.
  • Requiring patients to restart therapies with no data to support such use, is not optimal.
  • For patients who have tried and failed preventive therapy, the appropriate comparator for value assessments in EM is ‘supportive care’ where patients receive only acute treatment for migraine.
  • In CM, the relevant comparator is onabotulinumtoxinA, since this is only indicated for this migraine type.58 As per label, onabotulinumtoxinA is physician-administered; as such, there are additional administration costs associated with onabotulinumtoxinA.  These administration costs should be included in ICER’s assessment.
  • Erenumab would be a valuable treatment option for patients with high unmet need (i.e., >4 migraine days per month and who have tried and failed a generic preventive therapy) given the significant disease-induced burden among these patients.  In an observational study, treatment experienced patients initiating a new currently available preventive medication, exhibited a higher disease burden and poorer health related quality of life compared to treatment naïve patients. Patients with a prior history of preventive medication use suffer from more monthly migraine days than those with no prior experience. These patients also reported more severe disability as measured by the MIDAS.59  In another study, treatment-experienced patients initiating a currently available generic preventive had a greater mean number of ER visits than naïve patients, both  pre-index  (2.0  [SD = 3.2]  vs  1.6  [SD = 2.2], p < 0.001) and  post-index (2.3  [SD = 3.6]  vs  1.8 [SD = 2.8], p < 0.001).60  In addition, experienced patients had higher post-index total healthcare costs than naïve patients ($19,093  [SD = $31,936]   vs   $12,044   [SD = $22,732], p <.001), with significantly higher healthcare costs in every utilization category.61

5) Define supportive care to include the use of acute medications as needed by patients to manage their migraine

Reduction of acute medications is an important endpoint when considering the benefit that erenumab brings to patients

In the clinical protocols of trials 20120296 and 20120295, patients were permitted the use of acute medications during baseline and through the course of the study.  Acute medications are used to abort migraine at onset or alleviate symptoms and should not be used in lieu of migraine preventives. Overuse of acute medication may lead to chronification, may induce ‘chronification’, which refers to the progression from <15 to ≥15 headache days per month (of which at least 8 are migraine days) and occurs in 3% of individuals per year.62

  • The clinical paradigm when acute medications are used to abort and/or terminate attacks at migraine onset start with educating the patient (including maintaining a migraine diary), use a migraine-specific acute treatment (as opposed to non-migraine specific medication), treat early in the attack and finally, limit the number of rescue medications.
  • Migraine specific acute medications primarily include triptans and ergots. In the presence of vascular risks, non-migraine acute medications can be used such as NSAIDS and antiemetics.63
  • It is recommended that acute medications not be used for more than 2 days per week64 or limited to 10 days or less per month. Overuse of triptans (greater than 10 days for >3 months) may increase migraine frequency to that of chronic migraine.

SECTION 2:

ERENUMAB TREATMENT COMPARATORS, CLINICAL DATA AND RELEVANT PATIENT POPULATIONS ARE IMPORTANT CONSIDERATIONS FOR ANY MIGRAINE ASSESSMENT

About Erenumab

Erenumab is a human monoclonal antibody targeting CGRP receptor. Currently there are four investigational CGRP-directed monoclonal antibodies in final phases of clinical development; their protocols are available on clinicaltrials.gov.65,66,67,68,69,70,71 Erenumab is different from other CGRP-directed monoclonal antibodies as it targets the CGRP receptor rather than the CGRP molecules themselves.72

Erenumab clinical trial overview

The erenumab clinical program comprises of four randomized, double-blind, placebo-controlled clinical studies (2,682 randomized subjects) providing evidence for the efficacy and safety of erenumab for the prevention of migraine in adults. Two of these four studies are pivotal (Study 20120295 in CM and Study 20120296 in EM) and include the proposed registration dose of 140 mg once monthly by subcutaneous injection, while the other two studies (Study 20120297 and Study 20120178, both in EM) are considered supportive.73,74,75,76

In Studies 20120295 and 20120296,77 the efficacy of erenumab 140 mg has been demonstrated consistently in primary and secondary endpoints for migraine-related assessments, i.e., achievement of a reduction from baseline in monthly migraine days [MMD], achievement of 50% to 100% reduction from baseline in MMD, and change from baseline in monthly acute migraine-specific medication treatment days.

Significant disability exists due to the symptomology with migraine. While prevention of disability is a goal of preventative treatment, prior to the development of the MPFID (Migraine Physical Function Impact Diary), no existing patient reported outcome questionnaires accurately captured physical functioning, a concept most relevant to migraine patients.78 The MPFID questionnaire was specifically designed to capture impact of migraine on physical functioning based on FDA guidance with extensive patient and clinical input79. The MPFID is a psychometrically sound, reliable and valid instrument that is also responsive to change in migraine disease status.80 The MPFID supported two key secondary endpoints in the STRIVE study 1) change in physical impairment from baseline to end of treatment 2) change in impact of everyday activities.

The adverse drug reactions (ADRs) identified in the pooled studies during the 12-week, placebo-controlled period were mostly mild in severity and included injection site reactions (erenumab 140 mg 4.5%, placebo 3.2%), constipation (erenumab 140 mg 3.2%, placebo 1.1%), muscle spasms (AMG 334 140 mg 2.0%, placebo 0.4%), and pruritus (AMG 334 140 mg 1.8%, placebo 0.5%). 81

Erenumab’s place in migraine treatment paradigm AND appropriate patient population

Given that erenumab has demonstrated efficacy in patients with the high unmet need, i.e., patients who have tried and failed preventive treatment, the target patient population for erenumab are episodic and chronic migraine patients who have tried and failed preventives.

  • For patients who are able to derive some benefit, currently available generic preventives may provide an important option. However, in patients who have tried and failed currently available preventives, especially due to lack of effect or adverse events, other preventive therapies should be explored.
  • A systematic literature review of published clinical trials for migraine preventive therapies was not able to identify data with these agents in patients who had tried and failed preventives due to adverse events or lack of efficacy (treatment failed patients).82
  • Clinical trials with investigational anti-CGRPs, a new class of preventives, report MMD reduction in preventive-naïve and preventive-experienced migraine patients (> 4 migraines per month).
    • While anti-CGRPs agents have demonstrated efficacy in preventive-experienced and failed patients (i.e., patients with high unmet need), due to budgetary constraints on the healthcare system, it is anticipated that anti-CGRPs may be reserved for use in patients who have failed generic preventive therapies.
  • While the prevalence of episodic migraine is about 12%83 and that of chronic migraine is about 1%84, as per prevention guidelines, all CM and only 21% of EM patients (>=4 MDs/ month) patients are considered appropriate for preventives.85 Only, 33% of these patients are currently on a preventive therapy86 of which approximately 45% have failed at least one preventive. Therefore, the subset of patients who are actually eligible for erenumab is very small compared to the prevalent migraine population.

Erenumab clinical trial data in patients who have tried and failed preventive treatment

In patients who have tried and failed previous treatment, erenumab delivers up to a 2-day placebo-adjusted reduction in monthly migraine days in EM and up to a 3-day reduction in CM.  In addition, in trials, patients experienced a concurrent reduction in migraine specific medication use and clinically meaningful improvements in all patient reported endpoints that assess physical impairment and impact on daily activities (MPFID), headache impact (HIT6), migraine specific quality of life (MSQ) and disability (MIDAS). Adverse event rates were similar to placebo rates. After a year of treatment, 80% of patients remained on erenumab and experienced sustained prevention.87,88  Similar results were observed for all patients in the erenumab 140 mg arm in the STRIVE and CM pivotal study 20120295 (Data below).

In both EM and CM patients, robust treatment effects were observed for the 70 mg and 140 mg erenumab arm in subjects who had previously failed preventive migraine treatments (due to adverse events or due to lack of efficacy).

Primary endpoint:

  • The absolute or non-placebo adjusted average reduction in monthly migraine days from baseline, Least Square Mean (LSM) change (95% CI for EM patients with previous treatment failure on erenumab 140 mg was -3.2 (-3.9, -2.4). The placebo adjusted mean change was -2.5 (–3.4, –1.7).89
  • In CM patients, the absolute mean change from baseline in treatment failure patients was -6.8 (-7.8, -5.9) and the difference versus placebo -3.3 (-4.6, -2.1).90

Key Secondary endpoints:

  • 50% response rates:
    • In EM, in patients who have previously failed preventive treatments, 39.7% of erenumab patients achieved a reduction of 50% or more of their monthly migraine days on average at months 4-6, and the odds of achieving a 50% response relative to placebo was 3.06 (1.70, 5.52).
    • In CM, in patients who have previously failed preventive treatments, 40.8% of erenumab patients achieved a reduction of 50% or more of their monthly migraine days on average at 3 months and the odds of achieving a 50% response was 3.30 (1.98, 5.51), nominal p<0.001.
  • Migraine-specific acute medication:
    • In EM, among treatment failure patients, the absolute average change in the number of days with migraine-specific acute medication use for erenumab 140 mg was -2.2 days and that vs placebo was -2.1 (-2.7, -1.6).
    • In CM, among treatment failure, the absolute average change in the number of days with migraine specific-acute medication use was -4.9 and the change versus placebo was -3.43(-4.37, -2.49).

MPFID in EM patients: The improved outcomes among patients with prior treatment failure were also observed for patient-centric endpoints such as the impact on physical functioning as measured by the MPFID. The change from baseline in the MPFID impact on everyday activities domain scores for treatment experienced EM patients using erenumab 140 mg was -5.1 (-6.6, -3.6) and that versus placebo was -3.4 (-5.1, -1.7). For the MPFID physical impairment domain scores, the change from baseline among treated experienced erenumab patients was -4.0 (-5.6, -2.4) and the placebo adjusted scores were -2.9 (-4.7, -1.2).91 

Discontinuation rates were 5.7% and 7.0%, respectively in EM and CM (as compared to placebo) after up to 6 months of treatment.92

Erenumab has long-term data for the 70 mg dose; long term studies on the 140 mg dose are currently ongoing.93

  • For erenumab 70 mg, of the 472 patients enrolled in the parent study, 383 continued in the open-label safety extension (OLE) with a median exposure to erenumab of 575 days (range 28–822 days).
  • Mean (SD) MMD was 8.8 (2.6) at parent study baseline, 6.3 (4.2) at week 12 (beginning of OLE), and 3.7 (4.0) at week 64 (mean change from baseline [reduction] of 5.0 days).
  • At week 64, 65%, 42%, and 26% of erenumab 70 mg patients achieved a 50%, 75%, and 100% reduction in MMD, respectively.
  • Mean HIT-6 scores were 60.2 (6.3) at baseline and 51.7 (9.2) at week 64. MSQ and MIDAS improvements from baseline were maintained through week 64.
  • Safety profiles during the OLE were similar to those in the double-blind phase, which overall were similar to placebo.

The long-term extension study demonstrated a one-year efficacy, supported by functional improvements and favorable safety and tolerability profiles of erenumab 70mg for EM patients.94

Data for all patients on erenumab 140 mg from STRIVE95  and study 2012029596:

Primary endpoint:

  • Absolute average reduction in monthly migraine days for erenumab 140 mg treated EM patients was -3.7 (0.2) and the placebo adjusted mean change was -1.9 (-2.3, -1.4).
  • Absolute average reduction in monthly migraine days for erenumab 140 mg treated CM patients was -6.6 (0.4) and the placebo adjusted mean change was –2.5 (–3.5, –1.4).

Key Secondary endpoints:

  • 50% response rates:
    • 50% of erenumab 140 mg treated EM patients had an at least 50% reduction in monthly migraine days; the odds of achieving a 50% reduction in monthly migraine days was 2.8 compared to those on placebo.
    • About 41% of the erenumab 140 mg treated CM patients had at least a 50% reduction in monthly migraine days; the odds of achieving a 50% reduction in monthly migraine days was 2.3 (1.6, 3.5) compared to those on placebo. 
  • Migraine-specific acute medication:
    • In erenumab 140 mg treated patients with EM, the average reduction from baseline in the days with acute medication use was -1.6 (0.1) and the placebo adjusted number was -1.4 (–1.7, –1.1).
    • In erenumab 140 mg treated patients with CM, the average reduction from baseline in the days with acute medication use was -4.1 (0.3) and the placebo adjusted number was -2.6 (–3.3, –1.8).  

MPFID in all EM patients treated with Erenumab 140 mg: The mean change from baseline in the MPFID impact on everyday activities domain score for erenumab 140 mg patients -5.9 (0.39) and the placebo adjusted scores were -2.6 (-3.62, -1.51). The mean change from baseline in MPFID physical impairment domain scores was -4.8 (0.4) and the placebo adjusted scores were -2.4 (-3.51, -1.35).

Timeframe 

A longer timeframe than the duration of the clinical trials is necessary to fully understand the benefit of the investigational CGRP monoclonal antibodies.  Adherence with currently available preventives is poor for various reasons, including lack of tolerability. Erenumab and other anti-CGRP monoclonal antibodies have demonstrated favorable tolerability profiles in clinical studies which may lead to better adherence in practice.97,98 Therefore, any analyses to evaluate value of preventives should consider a sufficiently long time-frame in order to capture the full costs and benefits of such agents. This is also aligned with published guidance on the design of economic evaluations that states that the time horizon of analyses should be long enough to capture all relevant differences between treatment strategies compared.

SECTION 3:

CURRENT TREATMENT LANDSCAPE AND NEED FOR NEW AND EFFECTIVE PREVENTIVES IN MIGRAINE

There is a need for well-tolerated, targeted, and effective preventive therapies that allow patients to be adherent to the prescribed regimen in order to derive the benefits of treatment. Effective medications may reduce the over-dependence on non-migraine and migraine-specific acute medications, hence lowering the risk for chronification and most importantly allowing patients to experience improved clinical outcomes.

  • Current preventive treatment options for migraine were initially developed for other indications and are secondarily used for migraine.99 Most generic preventive therapies have to be taken daily and onabotulinumtoxinA (indicated only for chronic migraine) requires 31 injections by a trained specialist in the head and neck muscles, which can be associated with adverse events that may hinder treatment adherence.100  ICER’s assessment should take into account these administration costs and effect on patient HRQoL.
  • Adverse effects such as cognitive impairment, weight gain, and sexual dysfunction are common for these repurposed treatments101  and patients often report a “wearing off” of initial response even with dose increases.102 Interviews with migraine patients have revealed two types of non-adherence: accidental (forgetting to take medication) and intentional non-adherence (defined as permanently stopping medication or intentionally changing dose or timing of medications prior to or without consulting a physician). 103 Most common side effects listed as reasons for non‐adherence included: tingling (in the fingers, hands, or jaws), metallic taste in the mouth, concentration or focusing issues. Patients ranked side effects as the most disliked features of migraine preventives, followed by daily administration, feeling dependent on or socially stigmatized by being on prophylactic migraine medication, financial/administrative burden, and perceived ineffectiveness.104 While these AEs are not health care resource intensive, they are extremely bothersome to patients. For example, in a 300 patient preference study, patients were willing to trade off improvement in efficacy (a 10% reduction in migraine headache days to a 25% reduction) in order to avoid a 10% weight gain.105 The AEs associated with these generic preventives therefore leads to low adherence (as measured by medication possession ratios) with studies reporting ratios as low as 26% at month 6106 or 56% at month 12.107
  • Persistence with generic preventives is also low with over 70% of patients discontinuing preventive therapy by month 12.108 The second international burden of migraine study reported that up to 47% of patients with previous preventive treatment experience discontinued treatment due to lack of efficacy or adverse events.109 Despite discontinuation of preventive migraine medications, acute medication use persists, indicating that these preventive medications were likely ineffective or indicating a relapse of migraine.110 While use of acute medications decreased in the 30 days after discontinuation of the index preventive, use of acute medications rebound to pre-preventive usage in the 31-90 days after discontinuation. 
  • Lack of good preventive options may lead to an over-reliance by patients on acute medication thereby leading to medication overuse headache (MOH -  a secondary headache disorder) and chronification (transformation from EM to CM).111 While medication overuse can occur with any acute headache treatment, opioids are the most commonly prescribed acute therapy for patients suffering with migraine in the United States.112  Opioids were also prescribed in up to 59% of emergency room (ER) visits in United States.113 All-cause ER rates in treatment-experienced migraine patients were as high as 37% despite initiation of preventive medication.114  Even in an ambulatory setting, opioid use was more prevalent among migraine patients than non-migraineurs (45.5% versus 21.9%), and among opioid users, migraine patients had a greater number of prescriptions annually than non-migraine controls (4.9 [SD = 6.9] versus 2.7 [SD = 4.0]) (all p < 0.0001).115 The overuse of opioids is particularly problematic especially considering that there is strong evidence that opioids are sub-optimal in providing pain relief in migraine116 which is further corroborated by treatment guidelines that do not recommend opioid use in migraine.117

REFERENCES

  1. ICER. Institute for Clinical and Economic Review to Assess Erenumab for Migraine Prevention; Guselkumab and Tildrakizumab for Plaque Psoriasis.  [ICER website].  November 9, 2017. Link.
  2. Harwood, RH, Sayer, AA, Hirschfeld, M. Current and future worldwide prevalence of dependency, its relationship to total population, and dependency ratios. Bull World Health Organ 2004, 82: 251–258.
  3. Menken, M, Munsat, TL, Toole, JF. The global burden of disease study: implications for neurology. Arch Neurol 2000, 57: 418–420.
  4. Vos T, Barber RM, Bell B, Bertozzi-Villa A, Biryukov S, Bolliger I, Charlson F, Davis A, Degenhardt L, Dicker D, Duan L, Erskine H, Feigin VL, Ferrari AJ, Fitzmaurice C, Fleming T, Graetz N, Guinovart C, Haagsma J, Hansen GM, Hanson SW, Heuton KR, Higashi H, Kassebaum N, Kyu H, Laurie E, Liang X, Lofgren K, Lozano R, MacIntyre MF, Moradi-Lakeh M, Naghavi M, Nguyen G, Odell S, Ortblad K et al. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015, 386(9995):743–800.
  5. WHO (World Health Organization). 2006. Neurological Disorders: Public Health Challenges. Geneva: WHO.WHO Global Burden of Neurological Disorders, 2006
  6. Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache. 2001;41(7):646-657.
  7. Buse DC, Rupnow MF, Lipton RB. Assessing and managing all aspects of migraine: migraine attacks, migraine-related functional impairment, common comorbidities, and quality of life. Mayo Clin Proc. 2009; 84(5): 422-435.
  8. Bonafede M, Sapra S, Tepper SJ, Cappell K, Desai P. Adherence with prophylactic migraine medications among patients with and without prior prophylactic medication use. Poster presentation at the ISPOR 22nd Annual International Meeting, Boston, MA; May 20 – May 24, 2017.
  9. Blumenfeld AM, Bloudek LM, Becker WJ, et al. Patterns of use and reasons for discontinuation of prophylactic medications for episodic migraine and chronic migraine: results from the second international burden of migraine study (IBMS-II). Headache. 2013;53(4):644-655.
  10. American Migraine Foundation. Living with Migraine. Link
  11. Hawkins K, Wang S, Rupnow M. Indirect cost burden of migraine in the United States. J Occup Environ Med. 2007; 49(4): 368-374.
  12. ibid. 
  13. Hazard E, Munakata J, Bigal ME, Rupnow MF, Lipton RB. The burden of migraine in the United States: current and emerging perspectives on disease management and economic analysis. Value Health. 2009;12(1):55-64.
  14. Serrano D, Manack AN, Reed ML, Buse DC, Varon SF, Lipton RB. Value Health. 2013. 16(1):31-8.
  15. Freitag FG, Lyss H, Nissan GR. Migraine disability, healthcare utilization, and expenditures following treatment in a tertiary headache center. Proc (Bayl Univ Med Cent). 2013;26(4):363-367.
  16. Fiala JL, Lowert D. Patent watch: Migraine therapies targeting the CGRP pathway: intellectual property landscape. Nature Reviews Drug Discovery. 2016;15(8):8-9.
  17. Goldberg, SW. Targeting CGRP: A New Era for Migraine Treatment. CNS Drugs. 2015: 29(6):443-452.
  18. Goadsby, PJ, Reuter U, Hallstrom Y, Broessner G, Bonner JH, Zhang F, Sapra S, Picard H, Mikol DD, Lenz RA. A Controlled Trial of Erenumab for Episodic Migraine. N Engl J Med. 2017: 377(22):2123-2132.
  19. Goadsby PJ, Paemeleire K, Broessner G, Brandes J, Klatt J, Zhang F, Picard H, Mikol D, Lenz R. Efficacy of Erenumab in Subjects With Episodic Migraine With Prior Preventive Treatment Failure(s). Paper presented at: 18th Congress of the International Headache Society, September 7-10, 2017; Vancouver, Canada.
  20. Ashina M, Tepper S, Brandes JL, Reuter U, Boudreau G, Dolezil D, Cheng S, Leonardi D, Lenz R, Klatt J, Mikol D. Efficacy of Erenumab (a fully human mAb targeting the CGRP receptor) in Chronic Migraine Patients with Prior Treatment Failure: A Subgroup Analysis of the Phase 2, Randomized, Double-Blind, Placebo-Controlled Study. Poster presented at 18th Congress of the International Headache Society, Vancouver, Canada, 7–10 September 2017. Link
  21. Hawkins K, Wang S, Rupnow M. Indirect cost burden of migraine in the United States. J Occup Environ Med. 2007; 49(4): 368-374.
  22. Hawkins K, Wang S, Rupnow M. Direct cost burden among insured US employees with migraine. Headache. 2008; 48(4): 553-563. 
  23. Hazard E, Munakata J, Bigal ME, Rupnow MF, Lipton RB. The burden of migraine in the United States: current and emerging perspectives on disease management and economic analysis. Value Health. 2009;12(1):55-64.
  24. Gillard PJ, Devine B, Varon SF, Liu L, Sullivan SD. Mapping from disease-specific measures to health-state utility values in individuals with migraine. Value in Health. 2012 May 31;15(3):485-94.
  25. Whitehead SJ, Ali S. Health outcomes in economic evaluation: the QALY and utilities. British medical bulletin. 2010 Dec 1;96(1):5-21.
  26. Estemalik E, Tepper S. Preventive treatment in migraine and the new US guidelines. Neuropsychiatr Dis Treat. 2013; 9: 709-720.
  27. Hepp Z, Dodick DW, Varon SF, Gillard P, Hansen RN, Devine EB. Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia. 2015; 35(6):478-488.
  28. Buse DC, Pearlman SH, Reed ML, Serrano D, Ng-Mak DS, Lipton RB. Opioid use and dependence among persons with migraine: results of the AMPP study. Headache. 2012; 52(1): 18-36.
  29. Hawkins K, Wang S, Rupnow M. Indirect cost burden of migraine in the United States. J Occup Environ Med. 2007; 49(4): 368-374.
  30. Hawkins K, Wang S, Rupnow M. Direct cost burden among insured US employees with migraine. Headache. 2008; 48(4): 553-563. 
  31. Hazard E, Munakata J, Bigal ME, Rupnow MF, Lipton RB. The burden of migraine in the United States: current and emerging perspectives on disease management and economic analysis. Value Health. 2009;12(1):55-64.
  32. Hawkins K, Wang S, Rupnow M. Indirect cost burden of migraine in the United States. J Occup Environ Med. 2007; 49(4): 368-374.
  33. Hawkins K, Wang S, Rupnow M. Direct cost burden among insured US employees with migraine. Headache. 2008; 48(4): 553-563. 
  34. Hazard E, Munakata J, Bigal ME, Rupnow MF, Lipton RB. The burden of migraine in the United States: current and emerging perspectives on disease management and economic analysis. Value Health. 2009;12(1):55-64.
  35. Serrano D, Manack AN, Reed ML, Buse DC, Varon SF, Lipton RB. Cost and predictors of lost productive time in chronic migraine and episodic migraine: results from the American Migraine Prevalence and Prevention (AMPP) Study. Value Health. 2013; 16(1):31-8.
  36. Freitag FG, Lyss H, Nissan GR. Migraine disability, healthcare utilization, and expenditures following treatment in a tertiary headache center. Proc (Bayl Univ Med Cent). 2013; 26(4):363-367.
  37. Macgregor EA, Rosenberg JD, Kurth T. Sex-related differences in epidemiological and clinic-based headache studies. Headache. 2011;51(6):843-859.
  38. Serrano D, Manack AN, Reed ML, Buse DC, Varon SF, Lipton RB. Cost and predictors of lost productive time in chronic migraine and episodic migraine: results from the American Migraine Prevalence and Prevention (AMPP) Study. Value Health. 2013; 16(1):31-8.
  39. Bonafede MM, Cappell KA, Juneau MS, Tepper SJ, Sapra S, Shah N, Desai PR. Predictors of short-term disability claims among migraine patients in the US. Poster presentation at the ISPOR 19th Annual European Congress, Vienna, Austria; October 29 – November 2, 2016.
  40. Bonafede MM, Sapra S, Shah N, Tepper SJ, Cappell KA, Desai PR. Incremental direct and indirect costs associated with migraine in the United States. Poster presentation at the ISPOR 19th Annual European Congress, Vienna, Austria; October 29 – November 2, 2016.
  41. Cost-Effectiveness in Health and Medicine.  Edited by Newmann PJ, Sanders GD, Russell LB, Siegel JE, Ganiats TG.  Oxford University Press, New York 2017.   Link
  42. Neumann PJ, Cohen JT.  COMMENTARY ICER’s Revised Value Assessment Framework for 2017–2019:A Critique. Pharmacoeconomics.  Published Online 8 August, 2017.
  43. Weinstein MC, Siegel JE, Gold MR, Kamlet MS, Russell LB. Recommendations of the Panel on Cost-effectiveness in Health and Medicine. Jama. 1996 Oct 16;276(15):1253-8. Link
  44. Neumann PJ, Kamal-Bahl S. Should Value Frameworks Take A ‘Societal Perspective’?  Health Affairs Blog. September 6, 2017.
  45. Harwood, RH, Sayer, AA, Hirschfeld, M. Current and future worldwide prevalence of dependency, its relationship to total population, and dependency ratios. Bull World Health Organ 2004, 82: 251–258.
  46. Menken, M, Munsat, TL, Toole, JF. The global burden of disease study: implications for neurology. Arch Neurol 2000, 57: 418–420.
  47. Vos T, Barber RM, Bell B, Bertozzi-Villa A, Biryukov S, Bolliger I, Charlson F, Davis A, Degenhardt L, Dicker D, Duan L, Erskine H, Feigin VL, Ferrari AJ, Fitzmaurice C, Fleming T, Graetz N, Guinovart C, Haagsma J, Hansen GM, Hanson SW, Heuton KR, Higashi H, Kassebaum N, Kyu H, Laurie E, Liang X, Lofgren K, Lozano R, MacIntyre MF, Moradi-Lakeh M, Naghavi M, Nguyen G, Odell S, Ortblad K et al. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015, 386(9995):743–800.
  48. WHO (World Health Organization). 2006. Neurological Disorders: Public Health Challenges. Geneva: WHO.WHO Global Burden of Neurological Disorders, 2006
  49. Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache. 2001;41(7):646-657.
  50. Láinez MJ, García-Casado A, Gascón F.  Optimal management of severe nausea and vomiting in migraine: improving patient outcomes. Patient Relat Outcome Meas. 2013;11(4):61-73.
  51. Flores NM, Lee LK, Gajria K, Pomerantz D, Gandhi SK. Health related quality of life and health care resource use burden in migraine with and without nausea. Value in Health. 2015; 18(3):A261-A262.
  52. Tepper SJ, Tepper DE. Treatment of medication overuse headache. 2014. In: Tepper S., Tepper D. (eds) The Cleveland Clinic Manual of Headache Therapy. Springer, Cham.
  53. Lipton RB, Hamelsky SW, Kolodner KB, Steiner TJ, Stewart WF. Migraine, quality of life, and depression: a population-based case-control study. Neurology. 2000; 55(5): 629-635.
  54. Buse DC, Rupnow MF, Lipton RB. Assessing and managing all aspects of migraine: migraine attacks, migraine-related functional impairment, common comorbidities, and quality of life. Mayo Clin Proc. 2009; 84(5): 422-435.
  55. Estemalik E, Tepper S. Preventive treatment in migraine and the new US guidelines. Neuropsychiatr Dis Treat. 2013; 9: 709-720.
  56. Natoli JL, Manack A, Dean B, Butler Q, turkel CC, Stovner L, Lipton RB.  Global prevalence of chronic migraine: a systematic review. Cephalalgia. 2010; 30(5):599-609.
  57. Allergan. BOTOX prescribing information. [Allergan website].  Available at: LinkAccessed November 28. 2017.
  58. ibid.
  59. Kawata ATTAIN IHC abstract
  60. Bonafede M, Sapra S, Tepper SJ, Cappell K, Desai P. Healthcare Costs and Utilization and Medication Treatment Patterns Among Migraine Patients: A Retrospective Analysis.  Poster presentation at the American Headache Society, Boston, MA; June 8–11, 2017.
  61. ibid.
  62. Bigal ME, Lipton RB. Overuse of acute migraine medications and migraine chronfication. Curr Pain Headache Rep. 2009; 13(4): 301-307.
  63. Tepper SJ, Tepper DE. Treatment of medication overuse headache. 2014. In: Tepper S., Tepper D. (eds) The Cleveland Clinic Manual of Headache Therapy. Springer, Cham
  64. ibid.
  65. Clinicaltrials.gov. Evaluation of ALD403 (Eptinezumab) in the Prevention of Chronic Migraine (PROMISE 2). [Clinicaltrials.gov website].  November 28, 2016. Link.
  66. Clinicaltrials.gov. An Efficacy and Safety Study of Fremanezumab in Adults With Migraine (FOCUS). [Clinicaltrials.gov website].  October 13, 2017. Link.
  67. Clinicaltrials.gov. Evaluation of LY2951742 in the Prevention of Episodic Migraine- the EVOLVE-1 Study (EVOLVE-1). [Clinicaltrials.gov website].  November 8, 2016. Link.
  68. Clinicaltrials.gov. A Study Evaluating the Effectiveness of AMG 334 Injection in Preventing Migraines in Adults Having Failed Other Therapies (LIBERTY). [Clinicaltrials.gov website].  March 30, 2017. Link.
  69. Teva.  Teva Pharmaceutical Industries (TEVA) Q3 2017 Results - Earnings Call Transcript. [MSN.com website].  November 2, 2017. Link
  70. Lilly. IHC 2017: Lilly's Galcanezumab Demonstrates Positive Long-Term Safety Results for up to 12 Months in Patients with Migraine.  [Lilly.com website].  September 8, 2017. Link.
  71. Teva.  Teva Announces Submission of Biologics License Application for Fremanezumab to the U.S. FDA. [Tevapharm.com website].  October 17, 2017. Link.
  72. Reichert JM.  Antibodies to watch in 2017.  MAbs. 2017; 9(2):167-181
  73. Clinicaltrials.gov. A Study to Evaluate the Efficacy and Safety of AMG 334 in Chronic Migraine Prevention. [Clinicaltrials.gov website].  February 19, 2014. Link.
  74. Clinicaltrials.gov. Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention (STRIVE). [Clinicaltrials.gov website].  May 28, 2015. Link.
  75. Clinicaltrials.gov. Study to Evaluate the Efficacy and Safety of AMG 334 Compared to Placebo in Migraine Prevention (ARISE) [Clinicaltrials.gov website].  June 29, 2015.  Available at: Link.
  76. Clinicaltrials.gov. A Phase 2 Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention [Clinicaltrials.gov website].  September 30, 2013.  Link..
  77. Goadsby, PJ, Reuter U, Hallstrom Y, Broessner G, Bonner JH, Zhang F, Sapra S, Picard H, Mikol DD, Lenz RA. A Controlled Trial of Erenumab for Episodic Migraine. N Engl J Med. 2017: 377(22):2123-2132.
  78. Mannix S, Skalicky A, Buse DC, Desai P, Sapra S, Ortmeier B, Widnell K, Hareendran A. Measuring the impact of migraine for evaluating outcomes of preventive treatments for migraine headaches. Health Qual Life Outcomes. 2016;14(1):143.
  79. Hareendran A, Mannix S, Skalicky A, Bayliss M, Blumenfeld A, Buse DC, Desai PR, Ortmeier BG, Sapra S. Development and exploration of the content validity of a patient-reported outcome measure to evaluate the impact of migraine- the migraine physical function impact diary (MPFID). Health Qual Life Outcomes. 2017 Nov 17;15(1):224.
  80. Kawata AK, Hsieh R, Bender R, Shaffer S, Revicki DA, Bayliss M, Buse DC, Desai P, Sapra S, Ortmeier B, Hareendran A. Psychometric Evaluation of a Novel Instrument Assessing the Impact of Migraine on Physical Functioning: The Migraine Physical Function Impact Diary. Headache. 2017;57(9):1385-1398.
  81. Amgen.  Data on file.
  82. ibid.
  83. Lipton RB1, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF; AMPP Advisory Group.  Migraine prevalence, disease burden, and the need for preventive therapy.  Neurology. 2007 Jan 30;68(5):343-9.
  84. Buse DC, Manack AN, Fanning KM, Serrano D, Reed ML, Turkel CC, Lipton RB.  Chronic migraine prevalence, disability, and sociodemographic factors: results from the American Migraine Prevalence and Prevention Study. Headache. 2012 Nov-Dec;52(10):1456-70.
  85. Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF; AMPP Advisory Group.  Migraine prevalence, disease burden, and the need for preventive therapy.  Neurology. 2007; 68(5):343-9.
  86. Amgen. Data on file.
  87. ibid.
  88. Ashina M, Dodick D, Goadsby PJ, Reuter U, Silberstein S, Zhang F, Gage JR, Cheng S, Mikol DD, Lenz RA. Erenumab (AMG 334) in episodic migraine: Interim analysis of an ongoing open-label study. Neurology. 2017 Sep 19;89(12):1237-1243.
  89. Goadsby PJ, Paemeleire K, Broessner G, Brandes J, Klatt J, Zhang F, Picard H, Mikol D, Lenz R. Efficacy of Erenumab in Subjects With Episodic Migraine With Prior Preventive Treatment Failure(s). Paper presented at: 18th Congress of the International Headache Society, September 7-10, 2017; Vancouver, Canada.
  90. Ashina M, Tepper S, Brandes JL, Reuter U, Boudreau G, Dolezil D, Cheng S, Leonardi D, Lenz R, Klatt J, Mikol D. Efficacy of Erenumab (a fully human mAb targeting the CGRP receptor) in Chronic Migraine Patients with Prior Treatment Failure: A Subgroup Analysis of the Phase 2, Randomized, Double-Blind, Placebo-Controlled Study. Poster presented at 18th Congress of the International Headache Society, Vancouver, Canada, 7–10 September 2017. Link
  91. Amgen. Data on file.
  92. ibid.
  93. Ashina M, Dodick D, Goadsby PJ, Reuter U, Silberstein S, Zhang F, Gage JR, Cheng S, Mikol DD, Lenz RA. Neurology. 2017;89(12):1237-1243.
  94. ibid.
  95. Goadsby, PJ, Reuter U, Hallstrom Y, Broessner G, Bonner JH, Zhang F, Sapra S, Picard H, Mikol DD, Lenz RA. A Controlled Trial of Erenumab for Episodic Migraine. N Engl J Med. 2017: 377(22):2123-2132.
  96. Tepper S, Ashina M, Reuter U, Brandes JL, Doležil D, Silberstein S, Winner P, Leonardi D, Mikol D, Lenz R. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2017;16(6):425-434.
  97. Charles A. Migraine. N Engl J Med. 2017; 377(6): 553-561.
  98. Mitsikostas DD, Rapoport AM. New players in the preventive treatment of migraine. BMC Med. 2015; 13: 279.
  99. Charles A. Migraine. N Engl J Med. 2017; 377(6): 553-561.
  100. Allergan. BOTOX prescribing information. [Allergan website]. Link.
  101. Silberstein SD.  Preventative migraine treatment. Continuum. 2015;21(4 Headache):973-989.
  102. Charles A. Migraine. N Engl J Med. 2017; 377(6): 553-561.
  103. Vanya M, Desai P, Clifford S, Howard K, Lisel TC, Sapra S.  Neurology.  2016; 86(16): Suppl. 1.164. 
  104. ibid.
  105. Mansfield C, Gebben DJ, Sutphin J, Tepper SJ, Schwedt TJ, Sapra S, Shah N. Patient Preferences for Preventive Migraine Treatments: A Discrete-Choice Experiment. Abstract at the AMCP Nexus Conference. Dallas, TX, October, 2017.
  106. Berger A, Bloudek LM, Varon SF, Oster G.  Adherence with migraine prophylaxis in clinical practice. Pain Pract. 2012; 12(7):541-9.
  107. Lafata JE, Tunceli O, Cerghet M, Sharma KP, Lipton RB.  The use of migraine preventive medications among patients with and without migraine headaches.  Cephalalgia. 2010; 30(1):97-104.
  108. Bonafede M, Sapra S, Tepper SJ, Cappell K, Desai P. Adherence with prophylactic migraine medications among patients with and without prior prophylactic medication use. Poster presentation at the ISPOR 22nd Annual International Meeting, Boston, MA; May 20 – May 24, 2017.
  109. Blumenfeld AM, Bloudek LM, Becker WJ, et al. Patterns of use and reasons for discontinuation of prophylactic medications for episodic migraine and chronic migraine: results from the second international burden of migraine study (IBMS-II). Headache. 2013;53(4):644-655.
  110. Bonafede M, Sapra S, Tepper SJ, Cappell K, Desai P. Adherence with prophylactic migraine medications among patients with and without prior prophylactic medication use. Poster presentation at the ISPOR 22nd Annual International Meeting, Boston, MA; May 20 – May 24, 2017.
  111. Bigal ME, Lipton RB. Migraine chronification.  Curr Neurol Neurosci Rep. 2011;11(2):139-48.
  112. Woolley JM, Bonafede MM, Maiese BA, Lenz RA.  Migraine Prophylaxis and Acute Treatment Patterns Among Commercially Insured Patients in the United States. Headache. 2017;57(9):1399-1408.
  113. Friedman BW, West J, Vinson DR, Minen MT, Restivo A, Gallagher EJ.  Current management of migraine in US emergency departments: an analysis of the National Hospital Ambulatory Medical Care Survey. Cephalalgia. 2015;35(4):301-9
  114. Bonafede M, Sapra S, Tepper SJ, Cappell K, Desai P. Healthcare Costs and Utilization and Medication Treatment Patterns Among Migraine Patients: A Retrospective Analysis.  Poster presentation at the American Headache Society, Boston, MA; June 8–11, 2017.
  115. Bonafede M, Cappell K, Sapra S, Shah N, Desai P, Tepper S.  Direct Costs Associated with Migraine in the US (P1.180).  Neurology. 2017;88(16): Supplement P1.180.
  116. Friedman BW, Kapoor A, Friedman MS, Hochberg ML, Rowe BH. The relative efficacy of meperidine for the treatment of acute migraine: a meta-analysis of randomized controlled trials. Ann Emerg Med. 2008 Dec;52(6):705-13.
  117. Marmura MJ, Silberstein SD, Schwedt TJ.  The acute treatment of migraine in adults: the american headache society evidence assessment of migraine pharmacotherapies.  Headache. 2015 Jan;55(1):3-20.