Since 2010, tremendous breakthroughs have been made in migraine therapeutics. Based on greater understanding of the role of calcitonin gene-related peptide (CGRP) in migraine pathophysiology,1-4 monoclonal antibodies (MAbs) that block CGRP have been developed3 and were approved by the Food and Drug Administration (FDA) for migraine prevention in 2018 (See Migraine Preventive Therapies in this issue). Other CGRP antagonists are also in development. The CGRP inhibitors are designed specifically for migraine and possess favorable side-effect profiles, making them attractive alternatives to other existing options. Multiple neuromodulation devices are now FDA-approved for treatment of headaches (See Neuromodulation Therapies for Headache in this issue) and continue to be developed as well.

In this article, we cover promising preventive migraine treatments in development.

Calcitonin Gene-Related Peptide

Calcitonin gene-related peptide is among the most potent vasodilatory neuropeptides in humans and has been shown to induce trigeminovascular inflammation with subsequent peripheral and central pain sensitization that is pertinent to migraine pathogenesis. Receptors for CGRP are found on trigeminal Aδ fibers, endothelial cells, and others leading to neurogenic inflammation and activation of the trigeminovascular system.1 Although CGRP cannot cross the blood-brain barrier, it modulates nociceptive pathways involving the brainstem, thalamus, and cingulate cortex.2 CGRP levels are elevated during migraine attacks, and CGRP infusions trigger delayed migraine attacks in susceptible individuals.3,4 For these reasons, CGRP antagonists have been explored as a novel therapeutic class in migraine.

Calcitonin Gene-Related Peptide Antagonists

Monoclonal Antibodies

Eptinezumab, which binds to CGRP, is the only MAb CGRP antagonist delivered intravenously. In clinical trials.Eptinezumab has demonstrated superiority over placebo for migraine prevention, and the drug is under review by the FDA at the time this article is being written.5,6 The Table lists a summary of 2 trials of eptinezumab for individuals with episodic or chronic migraine.7 Participants with episodic migraine (≤ 14 headache days/month, ≥ 4 migraine days) who had single-dose infusions of 100 mg or 300 mg of eptinezumab had significantly reduced mean monthly migraine days (MMD) in 12 weeks (baseline 8.5 MMD, 100 mg −0.7 placebo-adjusted days, 300 mg -1.1 placebo adjusted days).5 A year after the fourth infusion, those treated with 300 mg of eptinezumab had a reduction of 5.2 MMD compared with 4.0 MMD reduction for those given placebo (nonsignificant); 31% of participants in the treatment group achieved headache freedom vs 21% of participants who received placebo. For individuals with chronic migraine (15-26 headache days/month, ≥ 8 migraine days), treatment with 100 mg or 300 mg of eptinezumab reduced MMD in 12 weeks (baseline 16.1 MMD, 100 mg −2.1 placebo-adjusted days, 300 mg −2.6 placebo-adjusted days).6

In both studies, the percentage of participants treated with eptinezumab who achieved at least 50% and 75% reductions in MMD was significantly higher than in those who received placebo. For participants with chronic migraine treated with eptinezumab, the number of participants achieving 100% freedom from headache was statistically significant compared with those who received placebo (Table). In both studies, those receiving eptinezumab were also headache-free 1 day after treatment about twice as often.5-8 The most commonly reported adverse events (> 2%) were upper respiratory tract infection, nasopharyngitis (common cold), fatigue, urinary tract infection, diarrhea, and oropharyngeal (mouth) pain. The former 2 events are reported 1% to 2% more in the treatment groups than in the placebo group.

-Gepants

The -gepants are small molecule CGRP receptor antagonists. They have been studied for more than a decade for acute and preventive migraine treatment. Early trials demonstrated superior clinical efficacy to placebo with no cardiovascular side effects, making -gepants potentially a favorable option for people with contraindications to triptans and ergots. Although initial clinical development was hampered by potential hepatotoxicity,9 the next generation -gepants seem to have similar clinical properties without significant hepatic side effects.

Both rimegepant and atogepant are under investigation for migraine prevention.10-12 In a phase 2b/3 trial,a after 12 weeks of daily atogepant use (10 mg to 120 mg), there was a significant reduction in MMDs/probable migraine days (3.55-4.23 absolute days and 0.7-1.38 placebo-adjusted days).13 The most common adverse events were nausea, fatigue, constipation, nasopharyngitis, and urinary tract infection. The liver safety profile was similar to placebo. Data from a clinical trialb of rimegepant for migraine prevention are expected in 2020.

Pituitary Adenylate Cyclase Activating Peptide Antagonists

Pituitary adenylate cyclase-activating peptide (PACAP) is a 38 amino acid peptide that shares 68% homology with vasoactive intestinal peptide (VIP) and is a widely distributed neuropeptide. Involved in inflammatory regulation, hypothalamo-pituitary-gonadal axis modulation, energy homeostasis, and pain transmission, PACAP and VIP bind to VPAC1 and VPAC2 receptors with equal affinity. However, PACAP is 100 times more selective than VIP for the PAC1 receptor, which has multiple isoforms with similar responses to adenylate cyclase stimulation but variable responses to phospholipase C. Pertinent to migraine, PACAP-containing fibers and PAC1 receptors are found in the periventricular nucleus of hypothalamus, periaqueductal gray, locus coeruleus, solitary nucleus, trigeminal nucleus caudalis, and trigeminal ganglion, which are all involved in migraine. Levels of PACAP increase during migraine attacks and decrease after successful treatment with sumatriptan.14 Infusion of PACAP also induces immediate headache followed by a migraine-like attack after a mean of 6 hours, along with dilation of middle cerebral artery and superficial temporal artery.15 These phenomena were observed less than 20% of the time after VIP infusion.16 PACAP levels were increased after infusion of PACAP38 only in those participants who later reported migraine-like attacks.17 Such a correlation presents an interesting opportunity for PACAP blockade in migraine prevention. At this moment, biologics seem a better option than small molecules in blocking the PACAP/PAC1 pathway. A PAC1 receptor blocking antibody, AMG301, has been studied in a recently-completed phase 2a trialc for migraine prevention, but results are not yet available. Clinical trials are planned but not yet underway for a potent PACAP neutralizing antibody with picomolar affinity, ALD1910.17 The effect of long-term blockade of PACAP/PAC1 pathway on endocrine systems, energy metabolism, and inflammatory regulation remains to be investigated.

Medical Devices

Caloric Vestibular Stimulation

Caloric vestibular stimulation (CVS) is an established diagnostic tool for confirming absence of brainstem function and detecting balance disorders. Irrigation of the external auditory canals with warm or cool fluids modulates the vestibular nerve tonic firing rate and induces several neural responses, including the vestibulocular reflex. Caloric irrigation also influences pain in migraine attacks. The basis of CVS utility in migraine prevention lies within dense anatomic connections between vestibular nuclei and other brainstem regions (eg, periaqueductal gray, parabrachial nucleus, locus coeruleus, reticular formation, dorsal spinal and mesencephalic trigem-inal nuclei, and dorsal raphe nucleus) involved in migraine. This hypothesized role of an in-ear CVS device for brainstem neuromodulation was recently clinically corroborated with transcranial Doppler sonography data that showed changes in cerebrovascular dynamics. This pilot study of 3 individuals with episodic migraine showed reduced headache frequency after 6 weeks of CVS therapy with no adverse events.18 A solid-state, headset CVS device was used in a prospective, randomized, placebo-controlled clinical trial of 81 participants for migraine prevention. After 3 months of twice-daily at-home treatment with the headset device, participants with episodic migraine had significantly fewer monthly migraine days than those in the placebo group (−3.5 ± 0.6 vs −1.1 ± 0.6 days, intention-to-treat, P = .025). For those who completed the study, there was also greater reduction of acute medication use (−3.9 ± 0.6 vs −1.7 ± 0.8; per protocol, P = .0375).19 The most common adverse events were transient dizziness and nausea. The ease of use, clinical efficacy, and minimal side effects suggest strong potential for the CVS device in episodic migraine prevention and a second larger trial is planned.d

Percutaneous Mastoid Electrical Stimulation

Percutaneous mastoid electrical stimulation (PMES) works via an electric current delivered through the skin behind an individual’s ear and stimulates the cerebellar fastigial nucleus. The neuroprotective effects of fastigial nucleus stimulation (FNS) are likely mediated through inhibiting the intracerebral inflammatory response and promoting nerve tissue repair. In relation to migraine, FNS can elicit long-lasting suppression of peri-infarction depolarizing waves, a process that is similar to the cortical spreading depression involved in migraine pathogenesis. In a recent, randomized, double-blind, sham-controlled trial, 80 patients with episodic migraine received either daily treatment with bilateral mastoid electrodes delivering PMES for 45 minutes over a 3-month period or sham stimulation. The treatment group had a significant reduction in migraine days (−71.3% vs −14.4%, P < .001) and more than a 50% response (82.5 vs 17.5, P < .001). Approximately 35% of treated participants had no attacks in the third month, and no significant adverse events were reported.20 Acute medication use was also significantly reduced (−87.6% vs +20.1%, P < .001). The authors noted that because participants were not surveyed to verify if the blinding with the sham device was successful, partial unblinding may have occurred. Although the results and safety profile are promising for this nonpharmacologic intervention, the treatment duration and electrical current intensity of PMES have yet to be optimized for best clinical efficacy. Further evaluation in chronic migraine is also warranted.

Vagus Nerve Stimulation

Implanted vagus nerve stimulation (VNS) is effective for treating refractory epilepsy and depression, with some pain relief noted in people with comorbid migraine. A noninvasive cervical VNS device has been cleared for acute migraine treatment and cluster headache (see Neuromodulation Therapies for Headache in this issue) and is being investigated for preventive migraine treatment in a double-blind, parallel, sham-controlled study with 500 participants.e Another transcutaneous VNS device that stimulates the auricular branch of the vagus nerve at either 1 Hz or 25 Hz, may ultimately prove useful in managing migraine. This device was studied in a randomized, controlled, double-blind study in participants with chronic migraine, and those treated with 1 Hz stimulation had a significantly greater reduction in headache days than those treated with 25 Hz (−36.4% vs −17.4%, P = .035) in the per protocol analysis but not intention-to-treat analysis. No sham control group was used in this study.21 Although both cervical and auricular noninvasive VNS (nVNS) may be effective and well-tolerated alternatives, optimal stimulation parameters continue to require further clarification through more robust studies.

Transcranial Direct Current Stimulation

Transcranial direct current stimulation (tDCS) applied to the cortex is believed to work by acting on the membrane potential of neurons to reversibly change their excitability. Cathodal stimulation inhibits firing of cortical neurons, and conversely, anodal stimulation increases neuronal firing. A proof-of-concept, uncontrolled 8-week preventive study in patients with episodic migraine demonstrated that anodal tDCS applied to the occipital area reduced migraine attack days (−3.3 days, P = .005).22 The first randomized, sham-controlled trials of tDCS (3 times per weeks for 6 weeks) in people with migraine showed no change in migraine attack frequency, but did reduce migraine-related days in the treated group (from 16.2 ± 2.4 days to 9.31 ± 1.5 days; P = .004) vs no response in the sham group (from 12.8 ± 2.77 days to 11.0 ± 3.5 days; P = .17).23 In a pilot randomized, placebo-controlled trial, patients with refractory chronic migraine applied anodal tDCS 3 times per week for 1 month to the dorsolateral prefrontal cortex (DLPFC), left primary motor cortex (M1), or sham at the M1 area; in its primary endpoint, the group that stimulated the DLPFC had a greater reduction in scores on the Headache Impact Test 6 (HIT-6) at the end of 1 month of treatment compared with those who stimulated M1 (U = 67.27, P = .01) and sham (U = 78.18, P = .02). Participants who stimulated M1 had a higher rate of adverse events, although this study was substantially limited by short treatment duration, lack of a sham at the DLPFC area, and low power.24 Preliminary findings on tDCS for migraine prevention remain limited, and larger, sham-controlled trials to determine its clinical efficacy, optimal intensity and polarity of stimulation, and favorable cortical regions for treatment are needed.

Conclusion

The field of headache medicine is full of promise. There are several new migraine-specific treatments already FDA-approved for migraine prevention. Although they have proven effectiveness, they also have disadvantages, so excitement continues over the prospect of more migraine-specific therapies in development. Intravenously delivered MAb to CGRP may offer a faster onset of action than subcutaneously delivered MAbs to CGRP. A -gepant is poised for release to market, and more are expected soon after. Inhibitors of PACAP have great potential but have yet to demonstrate clinical efficacy. Multiple devices also give us reason for optimism. The single-pulse transcrancial magnetic stimulator (sTMS) device has advanced from acute and preventive treatment in adults to use in adolescents at least 12 years of age. A transcutaneous VNS device is already available for acute migraine treatment and may have further benefit over long-term use. Another unique VNS device is anticipated. Although this article summarizes some medications and devices in development, it is not meant to be a comprehensive in scope. There are other potential options for migraine prevention in the early stages of study. These include agents with targets such as the kappa opioid receptor, the orexin receptor, acid-sensing ion channels, phosphodiesterase, the oxytocin system, nitric oxide synthase, and glutamate receptors.25 With the further push towards personalized precision medicine, the development of novel options for patients can help make migraine treatment more effective, better tolerated, and less costly over time.

Disclosures

HY receives honoraria from Supernus Pharmaceuticals. SN has received personal compensation for authorship/editing from Demos Medical, MedLink Neurology, and UpToDate and for consulting/speaking from Allergan, Amgen, Biohaven, electroCore, Ely Lilly, Supernus, and Teva. MS and AN have nothing to disclose.

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7. Alder BioPharmaceuticals presents new one-year data for eptinezumab from PROMISE 1 phase 3 trial demonstrating long-term efficacy in episodic migraine[news release]. Bothell, WA:GLOBE NEWSWIRE: June 29, 2018.; https://www.globenewswire.com/news-release/2018/06/29/1531751/0/en/Alder-BioPharmaceuticals-Presents-New-One-Year-Data-for-Eptinezumab-from-PROMISE-1-Phase-3-Trial-Demonstrating-Long-Term-Efficacy-in-Episodic-Migraine.html. Accessed March 30, 2019.

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11. Allergan announces second positive phase 3 clinical trial for ubrogepant—an oral CGRP receptor antagonist for the acute treatment of migraine [news release]. Dublin:PRNewswire; April 27, 2018.https://www.allergan.com/News/News/Thomson-Reuters/Allergan-Announces-Second-Positive-Phase-3-Clinica. Accessed March 29, 2019.

12. Lipton RB, Coric V, Stock E, et al. Rimegepant 75 mg, an oral calcitonin gene-related peptide antagonist, for the acute treatment of migraine: two phase 3, double-blind, randomized, placebo-controlled trials. Migraine Trust International Symposium (MTIS); 2018; London.

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a Efficacy, safety, and tolerability of multiple dosing regimens of oral atogepant (AGN-241689) in episodic migraine prevention (NCT02848326).

b Efficacy and safety trial of rimegepant for migraine prevention in adults (NCT03732638).

c Study to evaluate the efficacy and safety of AMG 301 in migraine prevention (NCT03238781).

d A noninvasive neuromodulation device for prevention of episodic migraine headache (NCT02991430).

e Noninvasive vagus nerve stimulation for the prevention of migraines (NCT03716505).