The therapeutic potential of novel anti-migraine acute therapies

Abstract

Introduction: Migraine is a highly disabling neurovascular disorder. ‘The complex and multifactorial properties of migraine pathogenesis provide the opportunity to identify new therapeutic targets from a wide range of receptors.

Areas covered: In this editorial, the authors focus on future pharmacological interventions for acute migraine including: 5-HT receptors and their agonists, calcitonin gene-related peptide receptors and their antagonists, PAC1 receptors and their antagonists, glutamate receptors and some of their antagonists as well as transient receptor potential channels and their antagonists. The authors also discuss preventative treatments for migraine that are currently in development.

Expert opinion: Future pharmaceutical research that looks at the well-known mechanisms involved in the pathophysiology of migraine should aim to overcome the existing limitations of each pharmacological class and their side effects. There has lately been particular interest in the role of glutamate receptors, particularly metabotropic glutamate receptors, in the pathophysiology of migraine. These receptors may be potentially viable drug targets for migraine in the future.

Keywords:

• migraine
• new therapies
• pathophysiological targets
• receptor agonists
• receptor antagonists, receptors

1. Introduction

Migraine is a severe disabling neurovascular disorder, associated with a significant reduction of health-related quality of life and has an important impact on social functioning [1]. It is characterized by recurrent episodes of crippling headache, autonomic nervous system dysfunction and, in some patients, neurological aura symptoms. The exact mechanism of migraine pathophysiology has been debated since the 17th century but is still not fully clarified, even though scientists have made a lot of progress in understanding it. Triptans have a variety of potential effects on the migraine process and are vasoconstrictive. They are the first-line drugs for the acute treatment of migraine but the fact that calcitonin gene-related peptide (CGRP) receptor antagonists have no vasoconstrictive properties but are equally effective as triptans would imply that vasoconstriction is an not the only mechanism of action. This provides a wider context for the development of novel treatments for migraine, because migraine is considered a cortical and a brainstem disorder [2]. Actually, the complex and multifactorial properties of migraine pathogenesis provide the opportunity of using new drugs for its pharmacological treatment.

2. Migraine therapeutic access keys

2.1 5-HT receptors and 5-HT receptor agonists

The 5-HT receptors have been involved in pain transmission. A significant advance in migraine treatment has occurred with the introduction of selective serotonin receptor agonists, so-called triptans. The triptans are characterized by three main mechanisms of action, all contributing to their anti-migraine effect. These effects include: i) the peripheral inhibition of the vasoactive peptides release from trigeminal nociceptive afferents; ii) the cranial vasoconstriction; and iii) the inhibition of the second-order neurons transmission through the trigeminocervical complex [3]. There is also evidence that they may be acting in other brainstem nuclei and the thalamus [4,5]. Unfortunately, triptans could induce vasoconstriction of the coronary arteries; therefore, they are also contraindicated in patients affected by cardiovascular and cerebrovascular diseases and hypertension not pharmacologically controlled [3].

Nowadays, triptans are considered the first-line option in the acute treatment of moderate–severe migraine attacks. Cardiovascular and cerebrovascular diseases represent the main contraindication for the prescription of triptans, although the clinical significance of triptan vasoconstriction is unclear and still being debated. Therefore, innovative molecules have been developed to avoid the vasoconstrictor effects of the classical 5-HT receptor agonists and, at the same time, maintaining their well-known efficacy in migraine. Lasmiditan (COL-144), a novel serotonin receptor agonist, has been reported to penetrate the CNS and selectively targets 5-HT_1F receptors expressed in the trigeminal nerve pathway, without affecting the peripheral serotonin transmission and is now ready to advance to Phase III trials.

NXN-188 has a dual mechanism of action, such as the5-HT_1B/1D activation and the selective inhibition of neuronal nitric oxide (NO) synthase by blocking NO synthesis, a vasodilator that may activate trigeminovascular fibers to cause the release of CGRP [6]. NXN-188 was well tolerated in clinical trials with no serious adverse effects and no triptan-like adverse events reported. NXN-188 certainly represents an innovative approach by incorporating two mechanisms of action against two specific targets in migraine and is now in Phase II trial.

2.2 CGRP receptors and CGRP receptor antagonists

The CGRP has been implicated in migraine. CGRP is a potent vasoactive neuropeptide. In particular, CGRP is released from both the peripheral and the central arch of the trigeminal neurons; therefore, it could cause peripheral and central sensitization during the activation of the trigeminovascular system [7]. Thus, CGRP receptor antagonists, so-called gepants, have been discussed in the recent years as a novel, attractive approach for the pharmacological treatment of migraine. Several molecules have been developed as part of a non-vasoconstrictive approach for the acute treatment of migraine, but the clinical developmental programs for CGRP receptor antagonists, telcagepant and MK-3207 were discontinued because of liver toxicity, whereas the development of olcegepant was stopped because it could be administered only intravenously [8,9].

However, the BMS-927711 and BI44370TA were included in development programs and could represent the future of this class.

In a Phase II study, BMS927711 was tested in different doses. The purpose of the study was to identify a safe and clinically superior to placebo dose for the treatment of acute migraine (NCT 01430442). The purpose of the Phase I study was to evaluate the pharmacokinetics (PK) of BMS-927711 during migraine and non-migraine conditions (NCT 01445067).

Moreover, a Phase II clinical trial was performed to assess the safety, tolerability and efficacy of three doses of BI 44370 TA for the treatment of patients both with an acute migraine attack and with moderate/severe intensity headache pain. BI 44370 TA has been compared to placebo and eletriptan (NCT00751803). The Phase I clinical trial has been designed to evaluate the relative oral bioavailability of BI 44370 TA tablets as well as safety, tolerability and PK (NCT00743015) during and between migraine attacks.

2.3 PAC1 receptors and PAC1 receptor antagonists

Pituitary adenylate cyclase-activating peptide (PACAP) and its receptors (PAC1, VPAC1 and VPAC2) are present in sensory neurons and in vascular smooth muscle related to the trigeminovascular system, a key factor in migraine pain. Recent data point to an involvement of PACAP, in particular the PAC1 receptor, in the pathophysiology of migraine. Vasoactive intestinal peptide and PACAP mediate their effect via VPAC1 and VPAC2 receptors with almost equal affinity, whereas PACAP in addition has high affinity to the PAC1-receptor. Considering that PACAP-38 is a trigger of migraine attacks [10], the PAC1-receptor may therefore be a putative target for migraine treatment [11]. Furthermore, recent clinical studies have demonstrated that the intravenous administration of PACAP can induce middle meningeal artery vasodilation and headache in both migraineurs and healthy subjects [11].

Maxadilan is the only available PAC1 receptor agonist. A recent study by Banki et al. [12] showed that PAC1R activation by maxadilan could inhibit the acute neurogenic arterial vasodilation and the plasma protein release from the venules. Considering the findings that demonstrated the migraine attack induction by PACAP, the PAC1 receptor can represent a promising candidate as a therapeutic target [13].

2.4 Glutamate receptors and glutamate receptors antagonists

Glutamate is the most represented excitatory neurotransmitter in the central nervous system. Several studies have involved glutamate in the pathogenesis of migraine. In fact, elevated levels of glutamate in plasma and cerebrospinal fluid have been found in patients affected by migraine. The glutamate-induced excitability arises from both the ionotropic (iGluR) and the metabotropic glutamate receptors (mGluR). The iGluRs are ligand-gated ion channels and include several subunits: GluN1–GluN3B for N-methyl-D-aspartate (NMDA) receptors, GluA1–GluA4 for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid AMPA receptors and GluK1–GluK5 for kainite receptors. The mGlu receptors are G-protein coupled and include eight different subtypes (mGluR1–8). Thus, NMDA, AMPA and kainate receptor antagonists have been considered as potential therapeutic agents in migraine treatment. The NMDA receptor antagonist (MK-801, memantine, and ketamine) have been demonstrated to reduce c-fos expression within the trigeminal nucleus caudalis and increased blood flow in migraine animal models. Glutamate has also been involved in cortical spreading depression (CSD). In fact, it has been demonstrated that CSD is reduced by NMDA receptors antagonists but not by the non-NMDA ones [14]. AMPA receptor antagonists and γ-aminobutyric acid (GABA) receptor agonists also inhibit CSD and thus may be targets in migraine therapy [15]. Kainate receptors with the GluR5 subunit are present in the trigeminal ganglion and may be involved in nociception [16].

Tezampanel, an AMPA/kainate (AK) receptor antagonist, is considered a promising alternative to the existing treatments among the non-serotoninergic and non-vascular ones. AK receptors play a crucial role in the development of central sensitization phenomena involved in many pain syndromes, including migraine [17]. Due to their mechanism of action, not implying the interaction with serotonin receptors, AK antagonists carry a safety profile that might offer significant benefits with respect to the existing drugs for migraine management. The use of tezampanel as an antimigraine agent has been evaluated by a Phase II dose-ranging study. The study has been developed to evaluate the effects of a single subcutaneous administration of drug at three different dosage levels compared to placebo, in the treatment of a single episode of acute migraine (NCT00567086).

2.5 Transient receptor potential channels and transient receptor potential vanilloid receptor antagonists

Transient receptor potential (TRP) channels are expressed in dural afferents, even in those containing CGRP, and are involved in pain mechanisms. In particular, the TRP vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) channels have been reported to have an important role in different models of pain diseases. Recent studies highlighted the role of the nociceptive neurons TRP channels in the pathogenesis of migraine pain. Among this channel subset, the TRPA1 is a sensor of oxidative, nitrative and electrophilic stress, and is activated by several irritant and pain-provoking exogenous and endogenous agents. Several of the TRPA1 activators are also known as triggers of migraine attack. Moreover, antimigraine drugs have been shown to inhibit or desensitize TRPA1 channels. Thus TRP channels, particularly TRPA1, might be proposed as major contributing pathways in migraine pathophysiology and therefore represent new targets for its treatment [18,19].

SB-705498 is the first TRPV1 receptor antagonist. Preclinical data have already shown that the TRPV1 receptor is expressed both centrally and peripherally in the trigeminal system and the inhibition of TRPV1 with SB-705498 can both prevent and reverse central sensitization. Unfortunately, past trials of TRPV1 antagonists in animals and humans have not been fruitful [6]. However, SB-705498 is in Phase II study for the treatment of migraine pain (NCT00269022) even if trial final data has not been reported.

3. Conclusion

Future pharmaceutical research based on the well-known mechanisms involved in the pathophysiology of migraine should aim to overcome the existing limitations for each pharmacological class, mostly represented by specific side effects [20]. Efforts in research should be addressed to the development of a safe and effective treatment for an underdiagnosed, silent but omnipresent disease such as migraine [21] and for the reduction of both its direct and indirect costs [22].

4. Expert opinion

The multifactorial features of migraine physiopathology provide the chance of using new drugs for its pharmacological treatment. Lasmiditan could be considered a novel drug for the acute treatment of migraine. In fact, it overcomes the main side effects of triptans such as the peripheral vasoconstriction, maintaining a comparable efficacy. Nevertheless, its central nervous system-related side effects, such as vertigo, dizziness, paresthesia and fatigue may limit its use. More than lasmiditan, NXN-188 seems to be promising, given its dual mechanism of action. Because CGRP-R antagonists lack direct vasoconstrictor effect, this class of antimigraine drugs offers a favorable pharmacological approach. Although the other reported drug classes (i.e., glutamate receptor antagonists, PAC1 receptor agonists and TRPV antagonists) do not directly cause vasoconstriction, they might induce vascular effects as well. In fact, they inhibit the responses to endogenous vasoactive molecules with different mechanisms of action. For this reason, CGRP-R antagonists, BMS-927711 and BI 44370 TA, should be considered as the antimigraine molecules with the greatest therapeutic potential. On the other hand, there is a recent interest in the role of the mGluR in the pathophysiology of migraine that makes these receptors novel potential drug targets.

Declaration of interest

P Martelletti has received educational and research grants, honoraria for Advisory Boards, travel grants from ACRAF Angelini, Allergan, Pfizer Inc. 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.