Understanding Novel Therapies for Acute Migraine

Two decades ago sumatriptan, rizatriptan, zolmitriptan, and several other oral triptans attained Food and Drug Administration (FDA) approval in rapid succession for treatment of acute migraine attacks. These novel drugs offered improved efficacy and fostered greater migraine awareness; yet, they raised drug-acquisition costs (but not overall treatment costs) despite the intense market competition among them, a competition euphemistically known as the “triptan wars.”

Today a new migraine battle looms; four calcitonin gene related peptide (CGRP) agents are marching towards FDA approval for the prevention of migraine in adults. Their assistance is urgently needed. Notwithstanding the advances fostered by triptans, migraine remains a prevalent illness affecting 22 million women (ie one out of every six women) and 6 million men.  Only half of individuals with migraine are physician-diagnosed. Migraine’s hallmark feature—unpredictable disruption to a person’s ability to perform usual work, home, and social activities—extracts a considerable toll from those afflicted as well as their families, friends, employers, and society as a whole. Research shows that in terms of illness’ years lived with disability (ie prevalence, incidence, mortality, life expectancy, healthy life expectancy, years of life lost), migraine ranks fifth. Even worse, in healthy individuals aged 15 to 49 years, migraine ranks as the number one cause of disability. Migraine’s havoc is not limited to actual attacks; even during migraine-attack-free periods fear of when the next attack will inopportunely strike diminishes patients’ quality of life, a phenomenon termed "interictal burden."    

Migraine’s cost is considerable. Compared to matched nonmigraine controls, a person with migraine incurs annual direct medical costs nearly $7000 higher, indirect costs approximately $2000 higher (primarily from decreased work productivity), and has 1.94 time the odds of filing a short-term disability claim. Migraine’s total annual economic burden was estimated at $14 billion, a figure encompassing cost of direct care costs and those incurred due to loss of productivity.

Standard of Care

Medication treatment of migraine languishes as less than optimal. Evidence-based guidelines endorse a stratified-care approach (ie medication selection corresponds to illness severity), use of drugs FDA approved for migraine (triptans, dihydroergotamine) as first-line for moderate to severe attacks, and restoring patients’ ability to function as a treatment goal. Despite these recommendations, FDA-approved migraine medications are prescribed to only a minority of patients. Over-reliance of ineffective drugs persists, namely over-the-counter (OTC) agents as well as narcotic or butalbital-containing products (BCPs); in recognition of these issues the American Board of Internal Medicine Foundation’s Choosing Wisely campaign cites five migraine-specific recommendations including: 

•  Don't prescribe opioid or BCPs as first-line treatment for recurrent headache disorders.

•  Don't recommend prolonged or frequent use of OTC pain medications for headache.

Poor medication selection contributes to patients’ unmet needs (UN).  Up to half of people with migraine have the UN of moderate or severe headache-related disability, one-third have the UN of dissatisfaction with current acute medications, one-third have the UN of excessive narcotic or barbiturate use/probable dependence, and 6% reported at least two emergency department (ED) visits in the preceding 12 months, a proxy-indicator of an UN. 

Migraine patients’ medication adherence is low, especially for preventive drugs. Only one-third of patients will consume a preventive drug as-intended for 6 months, only one-fifth will do so for 12 months, and more than 80% of people prescribed preventive drugs will experience a therapy gap of at least 90 days during their first year of treatment. Adverse events are most commonly cited by patients as the reason for nonadherence, up to one-fourth of instances.

Novel Therapies

Into this treatment morass now comes the CGRP agents. Aimovig (Erenumab; Amgen) attained FDA approval in May, 2018. Two other compounds, galcanezumab (Lilly) and fremanezumab (Teva), have submitted phase 3 data and are awaiting the FDA’s approval for migraine prevention, likely to be granted for both agents in 2018. The fourth agent, eptinezumab (Alder), is expected to submit their FDA application in 2018.  

Available data (assessed at either 3- or 6-month endpoints) shows that compared to placebo all four were statistically superior at reducing the number of monthly migraine days, with separation from placebo occurring in at little as one week; broadly speaking, each drug resulted in one to two fewer migraine days per month.  From a patient’s perspective, one less migraine day qualifies as substantial, even if one less day does not seem substantial to those assessing migraine from afar. 

These new drugs are shaping-up to be a redux of the triptan wars in that the CGRP agents are noteworthy for their similarities, not their differences. Distinguishing these agents based on efficacy is a difficult exercise (at least with currently available data) and efficacy differentiations are liable to be nuanced, not robust. The CGRP agents also share comparable tolerability profiles, limiting classifying them on that basis. Of note, however, is the realization that CGRPs’ adverse effects are benign (pain at injection site is most common) when compared to the well-known, often treatment-ending problems associated with other migraine preventive agents; in this author’s opinion improved tolerability is the chief—and substantial—benefit offered by the CGRPs. Significant CGRP drug interactions have not been identified. What adverse effects, if any, can occur with CGPR agents’ use over the span of years remains unknown, although these are biologic agents with potential immunogenicity consequences. Also, their effects during pregnancy are not known, a considerable concern since the majority of migraine patients are women of childbearing age.   

Aimovig is dosed via a self-administered subcutaneous injection once monthly and galcanezumab and fremanezumab are expected to also be self-administered once monthly subcutaneous injections. Eptinezumab is an intravenous infusion, although a subcutaneous formulation is being studied. Quarterly administration of fremanezumab and eptinezumab has been researched and may ultimately be FDA approved. Aimovig’s listed cost, $575 for the recommended 70mg dose, is lower than what was widely speculated, but still equates to roughly $7000 per patient annually. To date, cost information for the other CGPR products has not been released. 

Formulary Considerations

So, where does all this leave managed care? The introduction of the CGRP provides an opportunity to reassess migraine approaches, looking for opportunities to improve. Here’s some key questions:

1. Does your plan endorse the use of narcotics or BCPs, especially as first-line choices?

If so, why? Every authoritative migraine body, and a host of research, refutes this practice.  Moreover, narcotics and BCPs decidedly decrease patients’ ability to function, particularly when used intermittently. Returning to normal function is the most attribute patients seek from acute migraine treatment. Strive to promote medications with the highest probability of achieving this outcome—something other than narcotics or BCPs. Moreover, the poor therapy provided by narcotics/BCPs may be affecting other costs, including increased ED visits.

2. How does your plan assess migraine?  

Currently no biological marker of disease exists for migraine, a problem at the foundation of diagnosis and treatment issues. Instead, a variety of validated and easy-to-use assessment tools are available including the Migraine Disability Assessment Scale (MIDAS), the Headache Impact Test (HIT-6), the Migraine ACT, and ID Migraine, among others. These tools can identify migraine, assess the illness’ current impact, and evaluate treatments’ benefits (or lack thereof) over time. In this author’s opinion lack of requiring tools to quantify and qualify migraine, both on a patient-level and a population-level, is a key shortfall of managed care’s approach to migraine.

3. How should the formulary status of the GCPR agents be structured?  

Soon multiple CGPR drugs will be available. Separating them based on efficacy or tolerability is currently a challenge. Much like the triptans, cost considerations may ultimately prove to be the distinguishing factor. Yet using a single variable, such as cost, risks the pitfalls of trying to universally apply drug selection to a population affected with an illness that can vary greatly in terms of severity, both within the same patient and within an entire population. A new paradigm is needed.  

4. Does your plan foster whole-patient therapy?

Migraine is a chronic illness greatly affected by lifestyle, much like other chronic diseases.  Attaining an ideal body weight, developing improved stress-coping skills, and several other healthy life choices have been shown to diminish migraine. Indeed, evidence-based guidelines specifically endorse biofeedback (which, once mastered by a patient can be done at no cost and without adverse effects), illustrating that migraine treatment needs to be whole-patient oriented.  

This is an exiting time for migraine treatment. The novel therapies offer new hope and can help advance awareness for this underrecognized, undertreated illness that affects millions of individuals and society as a whole.