Emerging drugs for the prevention of migraine

ABSTRACT

Introduction

Migraine is a common and disabling neurological disorder. A greater understanding of the pathophysiological mechanisms underlying migraine has led to the availability of specific new drugs targeting calcitonin gene-related peptide (CGRP). The success of the CGRP inhibitors validates research efforts into migraine-specific therapies.

Areas covered

There are additional promising therapeutic targets that will be covered in this paper, focusing on the pain phase. They include pituitary adenylate cyclase-activating polypeptide (PACAP), the orexinergic system, the nitric oxide signaling pathway specifically neuronal nitric oxide synthase inhibitors (nNOSi), and metabotropic glutamate receptor 5 (mGluR5).

Expert opinion

Based on currently available research; the targets discussed in this paper are all on equal footing with each other in terms of their potential as effective novel migraine therapies. There is a need for more clinical trials to pinpoint which of these potential drug targets will be effective for migraine preventio.

KEYWORDS:

• CGRP
• migraine
• metabotropic glutamate receptor 5
• neuronal nitric oxide synthase inhibitor
• orexin
• PACAP

1. Background

Migraine is a common and disabling neurological disorder affecting up to 12% of the general population [1]. In 2019, it was ranked second worldwide among all diseases with respect to years of life lived with disability [2,3]. It results in a high economic burden to patients and countries in the form of health care costs, work absences, and reduced productivity [4].

In some patients, episodic migraine, <15 headache days a month, can evolve to chronic migraine, defined as >15 headache days a month with at least 8 days in which symptoms meet diagnostic criteria for migraine headache [5]. Chronic migraine is even more disabling for patients than episodic migraine and affects approximately 2% of the world’s population [6].

Given the economic cost of migraine, interest and investment in developing therapies for migraine has often been susurrating at best. As knowledge concerning the pathophysiology of migraine has accumulated [7] specific targets, such as the calcitonin gene-related peptide (CGRP) pathway, have emerged. Targeting CGRP is the first novel approach to migraine treatment since the triptan era [8]. Further novel molecular targets include pituitary adenylate cyclase activating polypeptide (PACAP), orexin, neuronal nitric oxide synthase, which offer promise as potential targets for migraine preventive drug development. Here we will explore these emerging options.

2. Existing pharmacologic treatment for the prevention of migraine

The treatment strategy for migraine is divided into abortive and preventive therapies. Abortive therapies refer to medications typically used acutely to terminate or ameliorate symptoms, while preventive therapies are designed to be taken to reduce the frequency, or severity, or both, of migraine.

The decision to start a prescription medication for migraine prevention is based on an interplay of patient factors including the frequency and severity of migraine attacks, the number of headache and migraine days, frequency of use, and effectiveness of migraine abortives and migraine associated disability. Until the CGRP monoclonal antibodies were licensed, prescription medications used for migraine prevention were designed for other purposes such as to treat depression, hypertension, or epilepsy. However, given the lack of specificity for migraine, they are not always effective and can cause intolerable side effects, often leading to poor compliance and discontinuation of treatment [9].

These medications are usually first line in patients with both episodic and chronic migraine. Botulinum toxin type A is effective for the treatment of chronic migraine [10,11]. However, this necessitates three-monthly clinic visits with a trained clinician or specialist nurse to administer the injections. Extensive research over almost 40 years, supporting the role of CGRP in the pathophysiology of migraine led to the development of several drugs targeting the CGRP peptide and receptor [12].

2.1. CGRP monoclonal antibodies

In 2018, three CGRP monoclonal antibodies, erenumab, fremanezumab, and galcanezumab were approved by the FDA, and in 2020 a further, eptinezumab, was approved. These are the first class of preventives developed to target specifically the pathophysiological mechanism of migraine. Erenumab is a human monoclonal antibody that binds to the CGRP receptor blocking access to CGRP itself, while eptinezumab, fremanezumab and galcanezumab are monoclonal antibodies against the CGRP peptide. Erenumab, fremanezumab and galcanezumab are administered subcutaneously, while eptinezumab is administered intravenously. They all have superior efficacy to placebo [13–22], and similar population responses to standard preventive medications for the treatment of episodic and chronic migraine [23]. The highest percentage of patients achieving at least 50% reduction in migraine days with each monoclonal antibody ranges from 47.7%-62% [24]. However, the therapeutic gain range, a crude comparator, is 22–23.7% indicating that efficacy appears to be similar across the anti-CGRP monoclonal antibodies regardless of target (receptor or ligand) and route of administration [24]. The efficacy and tolerability of erenumab has been confirmed in a real-life setting [25].

While side effects of these medications are minimal, there are theoretical concerns about their use in patients with cardiovascular disease [26,27]. Experts also recommend against use in pregnant women, or in women who are planning on becoming pregnant, as there is no data to guide its use in this population. There have also been concerns about the potential capacity of the drugs to provoke immune reactions and the clinical implications of this. However, evidence is accumulating that immunogenicity rates are low, and immunogenicity-related adverse effects are rare [28].

There were no increases in the incidence of adverse events, serious adverse events, or adverse events leading to treatment discontinuation over 5 years of exposure to erenumab in the open label treatment phase of a randomized clinical trial [29].

Overall, the CGRP monoclonal antibodies provide a great option for patients who failed to respond or had intolerable side effects from the more traditional migraine preventive options [30–32]. They are also convenient due to the monthly (erenumab, galcanezumab,fremanezumab) or 3 monthly (fremanezumab and eptinezumab) administration schedule. A drawback is that they are more costly in comparison to the traditional migraine preventives.

Migraine is often comorbid with other pain conditions. Studies clarifying the efficacy of these medications in this subgroup of patients are needed. The European Headache Federation has published recommendations to guide clinicians on the use of these drugs in patients with migraine [33].

2.2. CGRP receptor antagonists (gepants)

In 2020, two oral small molecule CGRP receptor antagonists (gepants) were approved by the FDA for the acute treatment of migraine – ubrogepant and rimegepant. Interestingly, rimegepant is also being investigated for use as a preventive with a trial [34] showing a reduction in monthly migraine days of −4.3 days with rimegepant 75 mg taken every other day in comparison to −3.5 days with placebo (least squares mean difference −0.8 days, 95% CI −1.46 to −0.20; P = 0.0099). Of note, rimegepant is primarily metabolized by CYP3A4 and thus has significant drug interactions with CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, and clarithromycin) and inducers (e.g. phenytoin, barbiturates, rifampin, St John’s Wort), which needs to be considered when in its use [35].

Atogepant, another orally administered CGRP receptor antagonist developed for migraine prevention has shown efficacy in clinical trials [36,37]. In a double blind, phase 2b/3 trial [36], 834 patients with 4–14 migraine days per month were randomly assigned to receive placebo or atogepant 10 mg once daily, 30 mg once daily, 60 mg once daily, 30 mg twice daily, or 60 mg twice daily, in matching capsules. The primary outcome was change from baseline in monthly migraine days across 12 weeks of treatment. Across the treatment period, all treatment groups showed significant reduction from baseline in mean monthly migraine days versus placebo: atogepant 10 mg once daily −4 · 0 (0 · 3; P = 0 · 024), 30 mg once daily −3 · 8 (0 · 2; P = 0 · 039), 60 mg once daily −3 · 6 (0 · 2; P = 0 · 039), 30 mg twice daily −4 · 2 (0 · 4; P = 0 · 0034), and 60 mg twice daily −4 · 1 (0 · 3; P = 0 · 0031); placebo −2 · 9 (0 · 2). The drug was safe and well tolerated, with nausea being the most common side effect (range between 5% at the lowest dose to 12% at the 60 mg once daily dose vs 5% for placebo).

In a phase 3 randomized, double blind, placebo controlled, parallel-group trial [37], atogepant was tested for the prevention of migraine in patients with 4–14 headache days per month. Nine hundred and ten patients were randomized to receive placebo or atogepant 10 mg, 30 mg or 60 mg daily. The primary outcome was change from baseline in mean monthly migraine days across a 12-week treatment period. All treatment groups demonstrated statistically significant decreases in mean monthly migraine days in comparison to placebo. Specifically, patients in the 10 mg/30 mg/60 mg atogepant groups had a decrease of 3.69/3.86/4.2 days respectively in comparison to the placebo group who had a decrease of 2.48 days (all atogepant groups vs placebo, P ≤ 0.0001). In terms of the secondary endpoint of at least 50% reduction in mean monthly migraine days – 55.8%/58.7%/60.8% of patients in the 10 mg/30 mg/60 mg atogepant groups, respectively achieved at least a 50% reduction, in comparison to only 29% of patients taking placebo (all atogepant groups vs. placebo, P ≤ 0.0001). The most common adverse events were constipation, nausea, and upper respiratory tract infection, all of which were mild-moderate in severity and did not lead to drug discontinuation [37].

3. Medical need for targeted therapeutics

The release to the market of the CGRP monoclonal antibodies (erenumab, galcanezumab, and fremanezumab) has offered patients more options for migraine prevention. However, while they have their advantages in terms of being migraine-specific, having minimal side effects, and no drug interactions – they are not effective in all patients. They have similar population responses to traditional migraine preventive medications for the treatment of episodic and chronic migraine [23]. They also are not used in pregnant women. Therefore, there remains a need for further migraine preventive therapies, as well as preventive medications that are safe for use in pregnancy and lactation.

4. Current research goals

The success of the CGRP targeted medicines validates research efforts into migraine-specific therapies. A large body of work suggests several additional promising therapeutic targets which will be covered in this paper, focusing on the pain phase. They include PACAP, the orexinergic system, the nitric oxide signaling pathway specifically neuronal nitric oxide synthase inhibitors (nNOSi), and metabotropic glutamate receptor 5 (mGluR5).

5. Pituitary adenylate cyclase activating polypeptide (PACAP)

5.1. Structure, function, and distribution

PACAP is a peptide belonging to the vasoactive intestinal peptide (VIP)/growth hormone releasing factor/secretin superfamily of peptides and is structurally similar to VIP, sharing 68% of its amino acid sequence [38]. It was initially described in 1989 [38] after being isolated from ovine hypothalamic tissue. It activates adenylate cyclase and causes an increase in levels of cyclic AMP.

It is present in two forms in the human body – a 38 amino acid form called PACAP-38 and a cleaved truncated 27 amino acid version- PACAP-27. In peripheral tissues, as well as in the brain, PACAP-38 is the most prevalent form [39,40].

There are three G-protein coupled PACAP receptors described to date – the VPAC1, VPAC2, and PAC1 receptors. While VPAC1 and VPAC2 have equal affinity for PACAP and VIP, the PAC1 receptor specifically has >100 times more affinity for PACAP-27 and PACAP-38 than it does for VIP [41].

PACAP is widely distributed; it is found in the peripheral and central nervous systems, as well as in exocrine and endocrine tissues in the respiratory, gastrointestinal, endocrine and reproductive systems [42–47]. Therefore, it is implicated in a wide range of functions. In the nervous system, it acts as an immunomodulator, neuromodulator, and neurotransmitter [48]. There is a saturable PACAP uptake mechanism into the brain [49], which offers an interesting dimension when considering a site of action. Both PACAP-38 fibers and PAC1 receptors are located in areas associated with migraine pathophysiology, specifically the paraventricular nucleus of the hypothalamus, locus coeruleus, ventrolateral periaqueductal gray, solitary nucleus, trigeminal nucleus caudalis, and the trigeminal ganglion [39,50–54]. Moreover, trigeminocervical neurons responding to a trigeminovascular nociceptive stimulus are modulated by PACAP-based mechanisms [55].

5.2. Evidence for role in migraine biology

The first evidence for PACAP-38’s role in migraine was demonstrated in a 2007 study in which healthy controls were given intravenous infusions of PACAP to study its effects on cerebral blood flow. Ten out of the 12 healthy volunteers reported a mild-moderate headache [56], following infusion of 10 pmol kg^{− 1} min^{− 1} for 20 minutes. In a subsequent randomized, double blind placebo-controlled trial [57], PACAP-38 infusion caused a headache in all healthy volunteers and 11 out of 12 migraine patients. Seven of the migraine patients (58%) experienced a migraine-like attack following PACAP-38 infusion, while none who received placebo did. The study also demonstrated an increase in superficial temporal artery diameter associated with PACAP-38 infusion in migraine patients. A follow up study [58] using high resolution magnetic resonance angiography showed that PACAP-38 induced headache was associated with sustained dilation of the middle meningeal artery and this effect (both the headache and arterial dilation) was ameliorated with administration of sumatriptan. These studies show that PACAP-38 is sufficient to cause headache, as well as vasodilation of the meningeal artery.

Given VIP and PACAP-38’s structural homology, as well as similar affinity for VPAC receptors, a human provocation study [59] was performed to examine if VIP produced the same effect in causing migraine as PACAP-38. PACAP-38 was reported to have provoked a migraine-like headache in 73% of patients with migraine without aura, while VIP infusion caused migraine-like headache in only 18% of subjects. Examining the clinical data table, if one considered probable migraine then 32% of subjects were positive for VIP. Of note, vasodilation of the extracranial arteries was seen in both groups suggesting that PACAP-38’s effect in provoking migraine is not solely as a result of vasodilation of extracranial arteries.

A resting state functional MRI study showed PACAP-38 infusion altered connectivity in the salience, sensorimotor, and default mode network during migraine attacks, effects which were not seen with VIP infusion [60]. Thus, suggesting an additional mechanism for PACAP-38’s effect in triggering migraine in comparison to VIP.

Given that PACAP 38 has much higher affinity for the PAC1 receptor than VIP, it was suggested that migraine induction may occur through the activation of the PAC1 receptor making it an ideal target for drug development.

Additional evidence for the connection between PACAP and migraine are studies showing increased plasma levels of PACAP during the ictal phase in migraine patients relative to the attack free period [61,62]. Reduction in levels of PACAP was also observed 1 hour after sumatriptan administration for acute attacks in these migraine patients [62].

5.3. PACAP targeted migraine therapeutics

There have been three drugs developed to date. AMG 301, a monoclonal antibody against the PAC1 receptor was tested in a phase 2 randomized, double blind, placebo-controlled trial [63]. Patients with chronic migraine or episodic migraine who were considered eligible for preventive treatment were enrolled and randomized 4:3:3 to placebo, AMG 301,210 mg every 4 weeks or AMG 301,420 mg every 2 weeks for 12 weeks. Effect on monthly migraine days and other secondary measures were assessed over weeks 9–12. No difference between AMG301 and placebo on monthly migraine days or any secondary measure of efficacy was observed. The incidence of adverse effects was similar across all groups.

Further studies may be necessary to determine if PAC1 receptor inhibition alone is enough to treat migraine or if PACAP is wielding its migraine inducing action via VPAC1 or VPAC2, or all three receptors.

ALD 1910, a monoclonal antibody against the PACAP peptide is currently under investigation in a phase 1 trial to determine safety, tolerability, and pharmacokinetic profile at various doses (H. Lundbeck A/S, NCT04197349). LY3451838 is a ligand-directed, fully human antibody for the PACAP38 neuropeptide. It is being studied for the prevention of migraine (Eli-Lilly; NCT04498910).

6. Orexins

6.1. Structure, function and distribution

Orexins, also known as hypocretins, are neuropeptides synthesized in the dorsolateral hypothalamus [64]. They exist in two forms both derived from the same precursor – a 33 amino acid peptide called orexin A (OXA) and a 28 amino acid version called orexin B (OXB) [64]. They bind to two G protein coupled receptors – orexin receptor 1 (OXR1) and orexin receptor 2 (OXR2). While orexin A has equal affinity for OXR 1 and 2, orexin B has 10-fold preferential affinity for OXR2 [64]. Activation of these receptors by OXA or OXB increases intracellular calcium [64].

While orexins are exclusively synthesized in the lateral hypothalamus, orexinergic neurons project to various parts of the brain including other hypothalamic nuclei, thalamus, cortex, trigeminal nucleus caudalis, and the spinal cord [65,66]. They are involved in the regulation of various homeostatic mechanisms- including sleep/wake cycle, feeding, and autonomic regulation [67].

6.2. Evidence for role in migraine biology

Given that sleep and feeding disruptions can be seen in migraine, particularly in the premonitory phase, as well as act as a trigger of migraine, it was theorized that there might be a relationship between the orexinergic system and migraine.

Orexin A levels were found to be decreased in the CSF of patients with episodic migraine and increased in patients with chronic migraine and medication overuse headache suggesting a dysregulation of the orexin system [68].

The prevalence of migraine in patients with narcolepsy (a disorder of orexin transmission) also provides evidence for this association. A study showed that the prevalence of migraine was 2-4-fold increased in patients with narcolepsy vs in the general population – 44.4% in women and 28.3% in men [69] versus 16–25% of women and 8% of men in the general population [70,71]. Given the cumulative lifetime incidence of migraine in females is 43% [72]; and the confound that narcolepsy will cause interactions with physicians, the association of migraine with narcolepsy needs to be considered cautiously.

Studies have shown the effect of orexin/orexin receptor activation on animal models of cephalic pain. A study showed the differential effect of orexin A vs B on dural nociceptive input in rats [73]. Injection of orexin A into the posterior hypothalamus decreased dural evoked trigeminal activation while orexin B increased this response. Orexin A but not OXB has also been shown to inhibit neurogenic dural vasodilation as well as trigeminal neuronal firing [74,75]. The effect of orexin A in both studies was reversed by pretreatment with an OX1 receptor antagonist, suggesting that its effect is via activation of the orexin 1 receptor.

6.3. Orexin targeted migraine therapeutics

In 2015, suvorexant (DORA-12), a dual orexin receptor antagonist was tested on an experimental in vivo model of dural trigeminovascular nociception in rat. It was shown to attenuate trigeminal nociceptive activity, as well as induce an elevation of the threshold for induction of cortical spreading depression (used as a proxy for migraine aura) [76].

In a randomized, double blind, placebo-controlled trial – filorexant, a dual orexin receptor antagonist was tested in patients [77]. Patients experiencing 4–14 migraine days a month during a one-month baseline period were randomized to receive filorexant 10 mg nightly or placebo for 3 months. One hundred and twenty patients were treated with filorexant and 115 with placebo. Efficacy was assessed by mean monthly migraine days (which they defined as headache + at least one associated migraine symptom) and headache days. There was no statistically significant difference between the treatment and the placebo group for change from baseline in mean monthly migraine or headache days.

While there has been suggestion that the failure of this trial to show any benefit of filorexant in migraine could be explained by dosing issues (the choice of nighttime dosing and the short half-life of filorexant of 3–5 hr) [77,78], the preclinical studies discussed earlier do suggest a differential effect of orexin A vs B on trigeminal neuronal firing and neurogenic dural vasodilation. Therefore, selective targeting of individual receptors may be more promising and should be a focus of future research.

7. Metabotropic glutamate receptor 5

7.1. Structure, function, and distribution

Glutamate is the most widely distributed and important neurotransmitter in the central nervous system and mediates its actions via ionotropic (ligand gated cation channels) and metabotropic (G protein coupled) receptors [79]. Metabotropic glutamate receptors have a well-established role in inflammatory and neuropathic pain [80–82]. They are divided into 3 groups – group I, II, and III metabotropic receptors [79]. Group I receptors are predominately located postsynaptically. They activate phospholipase C and are stimulatory; hence they have a pronociceptive effect. In contrast, Group II and III receptors are predominantly presynaptic, inhibit adenyl cyclase, and reduce the release of glutamate, hence have an antinociceptive effect [79,83].

Group I receptors include the metabotropic glutamate receptor 1 and 5 (mGluR1 and mGluR5).

7.2. Role in migraine biology

There is extensive evidence for the role of glutamate in migraine pathophysiology. Studies have shown increased plasma and CSF levels of glutamate ictally and interictally in migraine patients [84–87]. Increased salivary levels of glutamate have also been found in patients with episodic and chronic migraine [88,89]. Monosodium glutamate, the sodium salt of glutamic acid has been suggested to trigger headaches [90,91]. In terms of migraine and the group I metabotropic glutamate receptors – mGluR5 has undergone more investigation than mGluR1. mGluR5 is present in trigeminal sensory afferents [92], the trigeminal ganglion [93], and the TCC [94,95]. The receptor is known to be involved in central sensitization, hence creating hyperalgesia and allodynia [81,82,96]. A recent study [97] showed that mGluR5 may contribute to the central sensitization of chronic migraine through regulation of synaptic plasticity via protein kinase C/N-methyl-D-aspartate receptor subtype 2B (NR2B) signaling, making it a potential therapeutic target for chronic migraine.

7.3. mGluR5 targeted migraine therapeutics

ADX10059, a potent and selective negative allosteric modulator of mGluR5, was shown to attenuate dural vasodilator responses to meningeal stimulation and reduce responses of trigeminocervical neurons to dural stimulation in a rat model [94]. It was then tested in a placebo controlled clinical trial and demonstrated clinical efficacy with the primary endpoint of 2 h pain freedom being 17% in the treatment group vs 5% in the placebo group [94].

Unfortunately, ADX10059 was found to cause a high incidence of liver toxicity with sustained use (following 28 days of treatment) in a phase 2b migraine prevention study (NCT00820105). This led to the termination of the trial; ADX10059 is thus unsuitable for clinical use as a preventive.

Studies using different negative allosteric modulators of mGluR5 did not cause hepatotoxicity [98] suggesting that the issue lies in the structure of this particular molecule. Therefore, the mechanism of mGluR5 blockade remains a feasible and valid mechanism for migraine therapeutics.

8. Neuronal nitric oxide synthase inhibitors

8.1. Structure, function, and distribution

Nitric oxide (NO) is a gaseous molecule that is involved in a range of physiological processes in the human body. Endogenous NO is produced by the oxidation of L-arginine to produce L-citrulline and NO [99]. This reaction is catalyzed by nitric oxide synthase (NOS), of which there are three isoforms. These isoforms are named after the tissue in which they were discovered and are predominantly expressed [99]. Neuronal NOS (nNOS) is expressed in neurons and is found in the central and peripheral nervous system [100]. Endothelial NOS (eNOS) was initially discovered in the vascular endothelium but is also found in platelets, cardiomyocytes, and the brain [100]. Inducible NOS (iNOS) is the final form that is found in macrophages, glial cells, and neurons. Unlike the first two, it is not constitutively active but is induced by infection and proinflammatory cytokines [99–101].

8.2. Role in migraine biology

There is a large amount of evidence supporting the role of NO in migraine pathophysiology.

Nitroglycerin (an NO donor) is well known to cause headache, and an early study showed that it triggers a delayed migraine-like headache in migraine patients [102]. It can provoke cranial allodynia in migraine patients which can be aborted by sumatriptan. It has also been shown to trigger activation and sensitization of trigeminocervical neurons in rat [103].

nNOS is expressed in areas of the brain implicated in migraine pathophysiology including nerve fibers/nerve endings in the dural and pial layer, periaqueductal gray, thalamus, hypothalamus, somatosensory and cingulate cortex [104]. Studies in rats have shown increased expression of nNOS in the trigeminal nucleus caudalis and trigeminal ganglion in response to nitroglycerin [105,106].

8.3. Nitric oxide synthase targeted migraine therapeutics

Nonselective nitric oxide synthase inhibitors have been shown to produce profound cardiovascular changes in both clinical and preclinical studies [101]. Similarly, eNOS inhibitors would be unsafe for clinical use given likely interference with cardiovascular regulation [107]. An iNOS inhibitor has been tested and proven ineffective in the abortive or preventive treatment of migraine [108,109], leaving neuronal NOS inhibitors as the most promising target.

A selective nNOS inhibitor was shown to decrease meningeal blood vessel diameter and inhibit neurogenically mediated dural meningeal blood vessel dilation [110]. In an in vitro CGRP release assay, an nNOS inhibitor- NXN-413, inhibited KCL induced CGRP release from the dura mater [111]. Another selective nNOS inhibitor, NXN-323 reversed periorbital and hindpaw allodynia in a preclinical model of triptan overuse headache and central trigeminovascular sensitization [112]. To date, there have been no clinical trials for the use of selective nNOS inhibitors in migraine.

NXN-188, which is a combination of an nNOS inhibitor and a 5HT_1B/1D receptor agonist (triptan) has shown promise in preclinical studies by inhibiting the release of CGRP in migraine models [111]. It was tested in patients with acute migraine without aura in a phase II, randomized placebo-controlled study in 2010 that was negative [113].

In another study published in 2013 [114], NXN-188 was tested for acute treatment of migraine with aura. Fifty patients were randomized to receive either 600 mg NXN-188 or placebo. Only 18 patients completed both treatments. Twenty-two percent of patients reported pain freedom at 2 hours in the NXN-188 group vs 11% in the placebo group. However, this was not a statistically significant change. The study was limited by a high drop-out rate and small sample of patients who were able to complete the cross-over protocol. Therefore, the potential benefit of nNOS inhibition is yet to be refuted. In particular, there has yet to be a clinical trial of selective nNOS inhibitors in the preventive treatment of migraine.

9. Conclusion

Despite recent advances in the development of novel migraine-specific drug therapies, specifically the monoclonal CGRP antagonists; there remains a large unmet need in terms of migraine preventive drugs. The CGRP antagonists are not effective in all patients and there is a need for safe options in pregnancy and lactation. This paper summarizes the current scientific understanding behind additional promising therapeutic targets for migraine prevention, specifically PACAP, orexin, mGluR5, and nitric oxide synthase inhibitors. We examined the scientific evidence for their role in migraine pathophysiology and reviewed the results of clinical trials of migraine therapeutics targeting these molecular pathways. In conclusion, while there is strong preclinical evidence in favor of the role of these targets as potentially efficacious migraine preventives – There remains a need for more research into understanding the role of these targets in migraine biology as well as more clinical trials of drugs targeting these pathways.

10. Expert opinion

Based on currently available research; the targets discussed in this paper are all generally on equal footing with each other in terms of their potential as effective novel migraine therapies.

PACAP and its receptor PAC1 in particular seem to have garnered the most interest. This is in part because PACAP shares certain intriguing properties with CGRP. They are both vasodilatory neuropeptides, induce migraine in migraineurs [57,115], and both act on receptors that share an accessory subunit called receptor activity modifying protein-1 (RAMP-1) [116]. Infusion of PACAP38 in migraine patients does not increase blood levels of CGRP [117]. This suggests that PACAP38 has a role in producing migraine independent of CGRP.

Thus, there is hope that PACAP/PAC1 antibodies could offer a therapeutic advantage for patients who do not respond to CGRP antagonists.

Therefore, the lack of efficacy of AMG-301, a PAC 1 receptor is discouraging. However, it is possible that antagonism of VPAC1, or 2, or all three receptors is necessary to produce a clinical response. Direct inhibition of PACAP38 is also an alternative strategy. Further work needs to be done to disentangle this. A caveat to this approach is that due to the widespread distribution of PACAP and its involvement in various physiological functions [42–47]; nonselective inhibition of PACAP receptors or the peptide itself could increase the possibility of side effects.

With regards to orexin, dual orexin receptor antagonism was not successful [77]. However, given the differential effect of orexin-A vs B on trigeminal activation in preclinical studies [73]; selective receptor targeting may be a more viable strategy.

Based on the currently available data, mGluR5 may be the most promising target. ADX10059 showed efficacy in an acute therapy trial [94] but hepatotoxicity resulted in early termination of the preventive trial (NCT00820105). Fortunately, other negative allosteric modulators of mGluR5 have not been found to cause hepatotoxicity with prolonged use [98] meaning this strategy remains feasible. Lastly, selective nNOS inhibitors have great science from preclinical studies suggesting it as a viable target, but unfortunately, to date, there have been no clinical trials for the use of selective nNOS inhibitors in migraine prevention.

Overall, there is a need for more clinical trials to pinpoint which of these potential drug targets will be effective for migraine prevention.

Declaration of interest

PJ Goadsby reports personal fees from Aeon Biopharma, personal fees from Alder

Biopharmaceuticals, grants and personal fees from Amgen, personal fees from Allergan, personal fees from Biohaven Pharmaceuticals Inc., grants from Celgene, personal fees from Clexio, grants and personal fees from Eli Lilly and Company, from Electrocore LLC, personal fees from eNeura Inc, personal fees from Epalex, personal fees from GlaxoSmithKline, personal fees from Impel Neuropharma, personal fees from Lundbeck, personal fees from MundiPharma, personal fees from Novartis, personal fees from Pfizer, personal fees from Praxis, personal fees from Santara Therapeutics, personal fees from Sanofi, personal fees from Satsuma, personal fees from Teva

Pharmaceuticals, other from Trigemina Inc, personal fees from WL Gore, personal fees from Dr Reddy’s, outside the submitted work; In addition, PJ Goadsby has a patent Magnetic stimulation for headache licensed to eNeura without fee and fees for advice through Gerson Lehrman Group and Guidepoint, and fees for educational materials

from Medery, Medlink, PrimeEd, UptoDate, WebMD, and fees for publishing from Oxford University Press, Massachusetts Medical Society, and Wolters Kluwer, and for medicolegal advice in headache. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have received honoraria from Allergan, Eli-Lilly, Novartis, TEVA as a consultant and speaker. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Summary of clinical trials

Table

Molecular target	Drug name/ compound	Mechanism of action	Acute or preventive treatment	Trial phase	Status	Primary endpoint met?	Clinical trials.gov identifier
PACAP	AMG 301	PAC1 receptor Monoclonal antibody	Preventive	Phase 2	Completed in 2019	No	NCT03238781
	ALD 1910	Anti-PACAP monoclonal antibody	Preventive	Phase 1	Ongoing	No results available	NCT04197349
	LY3451838	Antibody for PACAP38 neuropeptide	Preventive	Phase 2	Ongoing	No results available	NCT04498910
Orexin	Filorexant	Dual orexin receptor antagonist	Preventive	Phase 2	Completed in 2012	No	NCT01513291
Metabotropic glutamate receptor	ADX10059	Negative allosteric modulator of mGluR5 receptor	Acute	Phase 2a	Completed	Yes
	ADX10059	Negative allosteric modulator of mGluR5 receptor	Preventive	Phase 2b	Terminated in 2009	Terminated due to hepatotoxicity	NCT00820105
Nitric oxide synthase	GW274150	iNOS inhibitor	Preventive	Phase 2	Completed in 2007	No	NCT00242866
	NXN-188	nNOS inhibitor +5HT1B/1D receptor agonist	Acute	Phase 2	Completed in 2010	No	NCT00959751
	NXN-188	nNOS inhibitor +5HT1B/1D receptor agonist	Acute	Phase 2	Completed in 2010	No	NCT00877838

Additional information

Funding

This paper was not funded.