Eptinezumab-jjmr, the fourth CGRP antagonist, was approved by the FDA in February 2020 as the first anti-CGRP agent for intravenous therapy, which differs distinctively from the other agents.35 In the PROMISE‑1 (A Multicenter Assessment of ALD403 in Frequent Episodic Migraine, ClinicalTrials.gov Identifier: NCT02559895) study, reductions in MMD from a baseline of 8.6 were seen for placebo (-3.2) and eptinezumab 100 mg (‑3.9 [-45%]) and 300 mg (-4.3 [-50%]) by week 12.36 In the PROMISE-2 (Evaluation of ALD403 [Eptinezumab] in the Prevention of Chronic Migraine; ClinicalTrials.gov Identifier: NCT02974153) study, eptinezumab at monthly doses reduced MMD from a baseline of 16.1 MMD for placebo (-5.6 [-35%]), 100 mg (-7.7 [-48%]), and 300 mg (-8.2 [-51%]) by week 12.37
Eptinezumab is infused over approximately 30 minutes, and benefits can be seen as early as 1 day following intravenous infusion.37 The usual 100-mg dose can be increased if needed to 300 mg. Unlike the aforementioned agents with minimal immunogenicity, the incidence of antibodies was found to be approximately 21% in PROMISE-1; of these, 41% developed neutralizing antibodies (NAB).36 In PROMISE-2, 18% developed antibodies, and 35% of those were NAB.37 Essentially, 8% to 10% of patients receiving eptinezumab develop NAB. The impact of immunogenicity remains to be clarified, but the approved 300-mg dose may mitigate the effect of the neutralization in some patients.
For this anti-CGRP mAb class, adverse effects listed in the prescribing information of these parenteral prophylactic mAbs include constipation, injection site reactions, and muscle cramps.21-24
Comparison With Established Strategies
Over the past few years, several notable systematic reviews have analyzed the efficacy of more commonly prescribed prophylactic agents for CM and EM, including gabapentin, topiramate, valproate, and onabotulinumtoxinA.11-15
A review of gabapentin administered in a 900-mg daily dose and titrated to 1800 mg demonstrated no significant difference in migraine frequency compared with placebo.11 A review of topiramate in doses ranging from 50 to 200 mg found only a 1-headache-day-per-month reduction compared with placebo.12
Valproate preparations, including valproic acid, sodium valproate, and divalproex sodium, have been approved as oral prophylactic agents, and an intravenous formulation (Depacon®) has also been approved for aborting acute migraine. Research involving valproate has produced some conflicting data. In a preventive study, 42% of subjects responded in the treatment group compared to 21% in the placebo group.13 However, the prophylactic study with the largest sample size found no significant difference.13 A third study found a statistically significant reduction of 4 migraine days per month with valproate compared with placebo.13
A review of onabotulinumtoxinA for headache prevention found only a single study sufficient for analysis and no significant differences from placebo.14 Another systematic review found only 2 studies adequate for analysis with both lacking any significant reduction in migraine headache days compared with placebo.15
Traditional agents for first-line prophylaxis of CM or EM (antiepileptics, antihypertensives, antidepressants) infrequently show a difference from placebo. When significant differences were found, the magnitude of the effect was less efficacious than the CGRP mAb class. Furthermore, the adverse effect profile of these traditional first-line drugs may be intolerable, negatively affecting patient adherence.14
The Need for Wider Intervention in Migraine
Uncontrolled migraine significantly impairs quality of life; therefore, both headache specialists and primary care professionals may provide access to newer prophylactic and abortive therapies. Patients with severe migraine now have wider preventive and abortive options including the anti-CGRP mAbs, small molecule CGRP antagonists, and ditans.
Both nurse practitioners (NPs) and physician assistants (PAs) serve on the front line of primary care, urgent care, and emergency medicine — all contact points of migraineurs. Only 4.5% of patients with CM and 26.3% of patients with EM succeed in navigating the myriad barriers to receiving appropriate headache care.1,38 NPs and PAs serve as valuable team members in communities, improving care and access for patients, especially within the underserved migraine community.
Being clinically informed allows primary care practitioners to make collaborative decisions with patients and to appropriately employ specialty care neurology and headache medicine. For patients who have tried standard preventive medications such as antiepileptics, beta-blockers, and antidepressants, a newly approved parenteral anti-CGRP may be a better option. Some insurance carriers may require referral to a neurology specialist to secure authorization; however, the simplicity and efficacy of the class has resulted increasingly in payors permitting prescriptions from a wide group of clinicians.
Patient access to and coverage of these medications through health insurance plans must be present for CM and EM prevention. Since the introduction of anti-CGRP mAb use in clinical practice, a significant reduction in MMD or MHD has resulted, translating to fewer hospital admissions and emergency department visits as well as less use of ineffective therapies and missed work. Further research to achieve safer and more effective prophylaxis and abortive acute care for migraine remains a distinct possibility.
Click here for an overview of the role that newer abortive agents play in migraine treatment.
Disclosures: Dr Hunter has disclosed that he has received honoraria, consulting fees, and research support from Novartis. PA Dix has disclosed that she is an employee of EMD Serono, Inc Ms. Barton has no financial information to disclose.
Amy L. Dix, MPAS, PA-C, AQH, MSCS, is a PhD student at the University of NOVA Southeastern, Dr. Pallavi Patel College of Health Sciences. At the time the article was written, she was working at the KC MS and Headache Center in Overland Park, Kansas. She is currently employed by EMD Serono, Inc. Lauren J. Barton, MHS, PA-C, practices in Hospital Medicine at Einstein Healthcare Network in North Philadelphia, PA. At the time the article was written, she was completing her Master’s Degree in Health Sciences and Certification as a PA with Drexel University’s Physician Assistant Program in Philadelphia. Her undergraduate studies were also completed at Drexel, obtaining a BS in Health Sciences and a minor in Public Health. Samuel F. Hunter, MD, PhD, is a neurologist in Franklin, Tennessee.
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