Efforts to target the pathophysiology of migraine headache to both reduce pain and prevent the onset of this disabling and often intractable condition have yielded a new class of drugs. Three products were recently approved by the FDA and a fourth is progressing through late phase III evaluation. 

In May 2018, erenumab-aooe (Aimovig, Amgen/Novartis) became the first monoclonal antibody (mAb) to inhibit the calcitonin gene-related peptide (CGRP) to gain approval by the FDA for migraine prevention. It was joined in September by fremanezumab-vfrm (Ajovy, Teva Pharmaceuticals) and galcanezumab-gnlm (Emgality, Eli Lilly). Eptinezumab from Alder Biopharmaceuticals is on track to have FDA evaluations completed in 2019.

NeurologyLive discussed the implications of this new class of drugs for managing migraine with Brian Grosberg, MD, the director of the Hartford HealthCare Headache Center, director of the Headache and Facial Pain Fellowship at Ayer Neuroscience Institute, and professor of neurology at the University of Connecticut School of Medicine in Farmington. 

“The advent of the CGRP inhibitors portends a potential paradigm shift in the way headache specialists treat people suffering from episodic migraine and chronic migraine,” Grosberg told NeurologyLive. “None of the other medications used in clinical practice today were specifically designed for prevention of migraine.” 

Although the CGRP inhibitors make up the first drug class developed specifically for migraine headache, an array of pharmaceuticals have been applied in off-label attempts to prevent or reduce migraine attacks, including antiepileptics with topiramate, antidepressants such as amitriptyline, and beta-adrenergic blockers like propranolol. The only agent approved by the FDA to prevent migraine before the CGRP inhibitors was onabotulinumtoxinA (onaBoNTA; Botox, Allergan), which was assessed for the indication following reports that patients receiving onaBoNTA to reduce facial wrinkles also concurrently experienced a lower rate of migraine headaches with the therapy. 

The neurotoxic mechanism of onaBoNTA creating a flaccid paralysis is well understood, but its relation to migraine is unclear. There is evidence that it exerts an antinociceptive effect independent of the neuromuscular relaxing effect,1 and its mechanism of action could include suppression of second-order nociceptive neurons by blocking the release of CGRP from primary central nociceptors.2 In 2 trials comparing onaBoNTA with topiramate and 1 trial comparing it with amitriptyline, the agents demonstrated similar efficacy.3 OnaBoNTA is administered by intramuscular injection at 3-month intervals. 

CGRP Inhibitors Pose New Paradigm 

Three of the large molecule injectable mAbs inhibit CGRP by binding directly to the neuropeptide (fremanezumab-vfrm, galcanezumab-gnlm, and eptinezumab) while the fourth binds to the CGRP receptor (erenumab-aooe) to exert a competitive, reversible blockade of CGRP. Erenumab-aooe and glacanezumab-gnlm are administered by monthly subcutaneous injections; fremanezumab-vfrm by subcutaneous injections, monthly or quarterly in higher doses; and eptinezumab in monthly intravenous infusions. 

CGRP is widely distributed in its α-isoform throughout the central nervous system and, of particular significance for migraine, is the most abundant neuropeptide in the trigeminovascular system. A β-isoform is expressed primarily in the enteric nervous system, inhibiting gastric acid secretion.4 

Evidence linking CGRP with migraine includes elevated CGRP serum levels in the external jugular vein during spontaneous migraine attacks5 and decreasing levels that correspond to symptom relief after acute treatment with sumatriptan or dihydroergotamine.6 In addition, intravenous administration of CGRP was proved to trigger migraine-like attacks in subjects with history of migraine, but not in healthy controls,7 although the CGRP-mediated pathways affecting migraine remain unclear. 

The first investigational drugs to counter CGRP actions in migraine—these being small molecule, orally active agents that bind to the CGRP receptor—were developed to relieve acute migraine symptoms. The initial products, including olcegepant and telcagepant, demonstrated a reduction in pain compared with placebo, but evaluations were halted after they were also associated with hepatotoxicity. After nearly a decade, development of the “gepant” class has recently resumed, with a next-generation of agents that do not produce the metabolites that were subsequently implicated for adverse effects (AEs) on the liver.

The CGRP inhibitor mAbs have demonstrated statistical superiority to placebo in preventing migraine, and some patients have experienced ≥50% reduction in headaches. Across studies for chronic migraine (characterized by >15 migraine days per month), the CGRP inhibitors elicited reductions of 4.0 migraine days per month compared with placebo, reductions of 2.0 days using acute medication, and a reduction of 3.3 monthly headache days.8 The CGRP agents also reduced episodic migraine by 2.8 migraine days per month compared with placebo, with a 1.8-day reduction in the use of acute medication.8

Huma Sheikh, MD, an assistant professor in the Department of Neurology at the Icahn School of Medicine at Mount Sinai in New York, New York, commented on the results of the respective efficacy trials with NeurologyLive

“The different CGRP inhibitors, including [first-approved] erenumab-aooe, had similar results in relation to decreasing the number of headaches a month as well as in the percentage of patients who had at least a 50% decrease in frequency of headaches,” Sheikh observed. “They all also had similar [adverse] effects, which were mostly minimal. There are no head-to-head trials for these drugs compared to the older preventives, but comparing these drugs across the board, some of the older preventives also have had similar results.” 

In the absence of head-to-head trials between the CGRP inhibitors or direct comparisons to onaBoNTA, the Institute for Clinical and Economic Review (ICER) conducted a meta-analysis of the respective efficacy trials for both chronic and episodic migraine.8 That assessment focused on the effectiveness of the agents in the study subpopulations with migraine symptoms that had not improved with at least 1 other preventive treatment (see TABLES 1 and 2). 

In chronic migraine, 11 trials were included in the analysis: 1 with erenumab-aooe, 2 with fremanezumab-vfrm, and 8 with onaBoNTA or topiramate. All interventions demonstrated superiority over placebo in reducing monthly migraine days, headache days, and days using acute medications to relieve symptoms. No statistical differences were found among the active agents. 

Eighteen trials in episodic migraine were analyzed: 8 assessed erenumab-aooe, fremanezumab-vfrm, or galcanezumab-gnlm and 10 assessed other oral preventive therapies. In episodic, as in chronic migraine, all active medications were superior to placebo but without statistically significant differences between them. 

The frequency and characteristics of treatment-emergent AEs of the CGRP inhibitor mAbs in clinical trials have not substantially differed from those reported with placebo. The current AE profiles, however, do not reflect the longer-term use and experience in the range of patients seen in practice who have medical histories and medication use, which would have excluded them from participating in the trials. 

The lack of long-term data is a consideration in choosing between the CGRP inhibitors and older agents, Sheikh indicated. “One of the advantages of some of the older preventives, including onabotulinumtoxinA, is that there is much more information about the long-term [adverse] effects and safety profiles,” she said. 

It is possible that AEs could emerge from inhibiting CGRP at any of the many sites of action. There is the potential to inhibit vasodilation, for example, with the theoretical concern that the agents could inhibit the protective physiologic response to cardiac or cerebrovascular ischemia. Although the clinical trials have not identified cardiovascular concerns to date, the incidence of cardiovascular or cerebrovascular disease is low in the studied populations, with mean age of onset of approximately 40 years. 

“Much larger populations would be needed to see the effect of CGRP blockade on very rare events, and this would likely only be achieved with postmarketing surveillance. Furthermore, the potential for long-term effects of chronic CGRP inhibition over years, even without overt ischemia, is entirely unknown,” wrote Amy Tso, MD, from the Department of Basic and Clinical Neuroscience at the Institute of Psychiatry, Psychology and Neuroscience, King’s College London, in the United Kingdom, and Peter J. Goadsby, MD, MB BS, DSc, PhD, a neurologist and headache specialist at the University of California, San Francisco Medical Center.9 

An additional concern is that the mAbs, although humanized to reduce immunogenicity, retain the capacity to provoke immunologic response. There have been immunological adverse events reported in the trials, and antidrug antibodies have been detected, albeit without evidence that therapeutic efficacy was affected in these short-term trials. 

In the absence of long-term experience with the CGRP inhibitor mAbs, there may be cautionary examples drawn from chronic administration of biologics in conditions such as rheumatoid arthritis and multiple sclerosis. In these conditions, the emergence of antidrug antibodies have been associated with reduced biological activity and therapeutic efficacy, observed Lanfranco Pellesi, MD, from the Medical Toxicology and Headache Center at Policlinic Hospital, University of Modena and Reggio Emilia, in Modena, Italy, and colleagues.10 

“The incidence of patients developing antidrug antibodies, the quantity generated, and their clinical relevance are highly variable,” Pellesi and colleagues indicated. “This point is highly relevant because the antidrug antibodies may decrease therapy effectiveness and/or facilitate the manifestations of immunoallergic hypersensitivity reactions.” 

Identifying Patients Likely to Benefit 

Although some patients have experienced a substantial reduction in headaches with the CGRP inhibitor mAbs, others experienced a moderate response. Identifying patients who are most likely to respond to the new agents is important to not only maximize therapeutic benefit, but to spare patients the high cost of treatment if they are unlikely to respond. 

Given the heterogeneity of the migraine syndrome and cost of the CGRP inhibitors, Grosberg offered his perspective on distinguishing the patients who most need and are most likely to benefit from the CGRP inhibitors from those for whom other measures are more appropriate.

“No 2 migraine sufferers are exactly alike, which is why treatment plans need to be tailored to each individual sufferer,” he indicated. “Multiple data points factor into a headache specialist’s clinical decision-making approach.” 

Grosberg indicated aspects of the patient and course of illness that may factor into treatment plans, including: 
  • Length of migraine history 
  • Frequency of most severe migraine attacks and overall headache days per month 
  • Temporal profile of attacks (ie, early morning vs afternoon or evening) 
  • Gradual versus sudden onset of attacks 
  • Presence and prominence of associated migraine symptoms (photophobia, phonophobia, nausea, emesis), autonomic symptoms, allodynia, and gastroparesis 
  • Response, tolerability, and adherence to current preventive and acute treatments 
  • Rates of presenteeism and absenteeism at work 
  • Effects of migraine on work, family, and leisure activities 
  • Rates of recurrence and status migrainosus 
  • Medical history, including sleep, mood, and stress 
  • Past trials and response to acute and preventive treatments 
“If patients have very good efficacy and tolerability on a conventional prophylactic therapy, such as propranolol or topiramate, and acute treatment, [such as] a triptan, then a CGRP inhibitor does not need to be started,” Grosberg said. “However, if their acute and/or preventive treatment regimen is not optimized despite several attempts by a headache specialist, then a CGRP inhibitor should be a consideration.” 

Clinical trials have generally excluded patients who failed ≥2 other preventive regimens in order to maximize the efficacy assessment sensitivity, leaving little information on how these patients who most need the new agents will respond. “In some patients with high-frequency episodic migraine or chronic migraine, more than one preventive medication may be used in order to obtain synergistic benefit, [although] the evidence for employing combination therapies is limited,” Grosberg observed. 

The lack of direct comparisons between the CGRP inhibitor mAbs makes choosing between them difficult, according to Grosberg. “It will likely depend on insurance coverage and cost of the medications if not covered rather than physician choice and efficacy,” he said. 

Access to Preventive Treatment 

The costs and cost-effectiveness of erenumab-aooe and fremanezumab-vfrm for use in preventing both episodic and chronic migraine have also been recently estimated by ICER,8 from the efficacy data in patients who failed to improve with up to 3 other agents. Cost-effectiveness outcomes were expressed in quality adjusted life-years (QALYs), reduction in migraine days, and total costs for interventions and comparators. 

The wholesale acquisition cost (WAC) for erenumab-aooe of $6900 per year was reduced in the assessment by an approximate 27% discount expected to be generally available, and the estimated $6000 annual cost basis was then assumed for both erenumab-aooe and fremanezumab-vfrm. ICER did not include galcanezumab-gnlm in the assessment due to lack of sufficient data on the subpopulation not responding to prior treatments. 

ICER found that treatment with the CGRP inhibitors resulted in higher total costs, more migraine-free days, and increased QALYs compared with no preventive treatment, in both chronic and episodic migraine in patients who failed prior treatments. The drug costs represented the largest portion of total costs associated with migraine. 

For patients with chronic migraine, ICER determined a cost-effectiveness ratio for erenumab-aooe of approximately $90,000 per QALY gain, compared with no benefit from other preventive treatment, and approximately $120,000 per QALY with femanezumab-vfrm. For episodic migraine suffers, both agents provided benefit compared with no benefit from preventive treatment at approximately $150,000 per QALY. 

ICER indicates that these agents provide benefit, but at the upper limit of what it would consider cost-effective. “In patients with chronic or episodic migraine who have other treatment options available, cost-effectiveness will likely exceed commonly accepted thresholds,” the ICER report concluded. 

Although the relatively high cost of the new agents is likely to relegate them to being a second- or third-tier choice by insurers, with probable requirements of treatment failure with less expensive alternatives before coverage is extended, this is not a welcome prospect for Grosberg. 

“It is my belief, and certainly one held by many of my colleagues, that one should not need to fail or have intolerable adverse effects to multiple preventive medications from many different classes before they can be eligible for a CGRP inhibitor,” Grosberg said. 

He gave the example that most insurance companies have required evidence of treatment failures with at least 2 or 3 oral preventive medications before considering authorizing onaBoNTA for prevention of chronic migraine. “This presents a challenge when some patients have comorbidities, which preclude the use of 1 or more preventive medications from these different classes,” Grosberg said. “Furthermore, adequate trials of each preventive medication may take several months to assess their efficacy.” 

Grosberg noted an additional complication in the generally poor adherence of migraine sufferers to preventive regimens. He cited study findings indicating that only 26% to 29% of patients are adherent at 6 months and approximately 17% to 20% at 12 months.

“Unfortunately, I envision the possibility of a similar requirement of treatment failures by insurance companies for authorization of CGRP inhibitors, possibly with the addition of failing onabotulinumtoxinA as well,” Grosberg said. “Hopefully, coverage of the CGRP inhibitor mAbs by insurance companies, especially for those patients with high-frequency episodic migraine and chronic migraine, will happen in the near future.” 

In discussing alternative and complementary medical approaches, which are often tried by patients suffering with migraine, Grosberg offered cautious support, along with caveats.

“A multidisciplinary approach is very important to the care of all migraine sufferers. Unfortunately, not all migraine sufferers have access to these nonpharmacological options or are aware of the importance [that] lifestyle modifications have in the care of their migraines,” Grosberg said. “It would be difficult and unfair to mandate that all migraine sufferers pursue these complimentary options, some of which may not be covered by insurance, before being eligible to receive CGRP inhibitors."
REFERENCES 
1. Aoki KR, Francis J. Updates on the antinociceptive mechanism hypothesis of botulinum toxin A. Parkinsonism Relat Disord. 2011;17(suppl 1):S28-S33.
doi: 10.1016/j.parkreldis.2011.06.013. 
2. Matak I, Bach-
Rojecky L, Filipovic B, Lackovic Z. Behavioral and immunohistochemical evidence for central antinociceptive activity of botulinim toxin A. Neuroscience. 2011;186:201-207. doi: 10.1016/j. neuroscience.2011.04.026. 
3. Gooriah R, Ahmed F. OnabotulinumtoxinA for
chronic migraine: a critical appraisal. Ther Clin Risk Manag. 2015;11:1003-1013. doi: 10.2147/TCRM.S76964. 
4. Van Rossum D, Hanisch UK, Quirion R. Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. Neurosci Biobehav Rev. 1997;21(5):649- 678.
doi: 10.1016/S0149-7634(96)00023-1. 
5. Goadsby PJ, Efvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during
migraine headache. Ann Neurol. 1990;28(2):183-187. doi: 10.1002/ana.410280213. 
6. Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: Studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol. 1993;33(1):48-56.
doi: 10.1002/ana.410330109. 
7. Hansen JM, Hauge AW, Olesen J, Ashina M. Calcitonin gene-related peptide triggers migraine-like attacks in patients with
migraine and aura. Cephalalgia. 2010;30(10):1179-1186. doi: 10.1177/0333102410368444. 
8. Ellis A, Otunonye I, Kumar V, et al. Calcitonin Gene-Related Peptide (CGRP) Inhibitors as Preventive Treatments for Patients with
Episodic or Chronic Migraine: Effectiveness and Value, Boston, MA. Published July 3, 2018. icer-review.org/wp-content/uploads/2017/11/ICER_Migraine_Final_Evidence_ Report_070318.pdf. Accessed August 12, 2018 
9. Tso AR, Goadsby PJ. Anti-CGRP monoclonal antibodies: the next era of migraine prevention? Curr Treat Options Neurol. 2017; 9(8):27.
doi: 10.1007/s11940-017-0463-4. 
10. Pellesi L, Guerzoni S, Pini LA. Spotlight on anti-CGRP monoclonal antibodies in migraine: The clinical evidence to date. Clin Pharmacol Drug Dev. 2017;6(6):534-547. doi: 10.1002/cpdd.345.