Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iemd20 Expert Opinion on Emerging Drugs ISSN: 1472-8214 (Print) 1744-7623 (Online) Journal homepage: http://www.tandfonline.com/loi/iemd20 Emerging drugs for migraine treatment: an update Giorgio Lambru, Anna P. Andreou, Martina Guglielmetti & Paolo Martelletti To cite this article: Giorgio Lambru, Anna P. Andreou, Martina Guglielmetti & Paolo Martelletti (2018): Emerging drugs for migraine treatment: an update, Expert Opinion on Emerging Drugs, DOI: 10.1080/14728214.2018.1552939 To link to this article: https://doi.org/10.1080/14728214.2018.1552939 Accepted author version posted online: 28 Nov 2018. Published online: 30 Nov 2018. Submit your article to this journal Article views: 1 View Crossmark data
Transcript
Full Terms & Conditions of access and use can be found athttp://www.tandfonline.com/action/journalInformation?journalCode=iemd20
Giorgio Lambru, Anna P. Andreou, Martina Guglielmetti & Paolo Martelletti
To cite this article: Giorgio Lambru, Anna P. Andreou, Martina Guglielmetti & Paolo Martelletti(2018): Emerging drugs for migraine treatment: an update, Expert Opinion on Emerging Drugs,DOI: 10.1080/14728214.2018.1552939
To link to this article: https://doi.org/10.1080/14728214.2018.1552939
Accepted author version posted online: 28Nov 2018.Published online: 30 Nov 2018.
Emerging drugs for migraine treatment: an updateGiorgio Lambrua,b, Anna P. Andreoua,b, Martina Guglielmettic and Paolo Martelletti c
aThe Headache Centre, Pain Management and Neuromodulation, Guy’s and St Thomas NHS Foundation Trust, London, UK; bThe Wolfson CARD,Institute of Psychology, Psychiatry and Neuroscience, King’s College London, London, UK; cDepartment of Clinical and Molecular Medicine,Sapienza” University, “Sant’Andrea” Hospital, Regional Referral Headache Centre, Rome, Italy
ABSTRACTIntroduction: Migraine is a very frequent and disabling neurological disorder. The current treatmentoptions are old, generally poorly tolerated and not migraine-specific, reflecting the low priority ofmigraine research and highlighting the vast unmet need in its management.Areas covered: Advancement in the understanding of migraine pathophysiological mechanisms andidentification of novel potentially meaningful targets have resulted in a multitude of emerging acuteand preventive treatments. Here we review the known putative migraine pathophysiological mechan-isms in order to understand the rationale of the most promising novel treatments targeting theCalcitonin-Gene-Related Peptide receptor and ligand and the 5 hydroxytryptamine (5-HT)1F receptor.Key findings on the phase II and phase III clinical trials on these treatments will be summarized.Furthermore, a critical analysis on failed trials of potentially meaningful targets such the nitric oxideand the orexinergic pathways will be conducted. Future perspective will be outlined.Expert opinion: The recent approval of Erenumab and Fremanezumab is a major milestone in thetherapy of migraine since the approval of triptans. Several more studies are needed to fully understandthe clinical potential, long-term safety and cost-effectiveness of these therapies. This paramountachievement should stimulate the development of further research in the migraine field.
ARTICLE HISTORYReceived 27 September 2018Accepted 23 November 2018
Migraine is a brain disorder affecting globally about 12% ofthe general population [1,2]. The lifetime prevalence ofmigraine is 33% in women and 13% in men [3]. Migraine isassociated with a significant detrimental effect on health-related quality of life (HRQoL) and important socioeconomicimpact [4]. The World Health Organization (WHO) ranksmigraine as the most disabling condition amongst the dis-eases worldwide under the age of 50 [5]. Migraine is consid-ered a disturbance of sensory processing with wideimplications within the central nervous system [6]. It is char-acterized by a multiphasic process that includes a premonitoryphase, when systemic, psychological and neurological symp-toms, the commonest of which are fatigue, impaired concen-tration, irritability, yawning, nausea and craving for food canoccur; an aura phase, which occurs in about 20–30% of sub-jects with migraine and is characterized by reversible transientvisual, sensory, speech, motor, and/or brainstem disturbancesoccurring before, during, after the pain phase or in absence ofit. These symptoms usually last between 5 and 60 min beforethe headache begins; the migraine pain phase, often charac-terized by moderate to very severe throbbing uni-bilateralhead pain episodes lasting 4–72 hours and potentially accom-panied by various neurological symptoms, namely photopho-bia, phonophobia osmophobia, nausea, vomiting and/ordiarrhoea, dizziness, and vertigo. Over 70% of patients have
cutaneous allodynia, which is the perception of pain whennon-painful stimuli are applied to the painful skin area.Finally, the postdromal phase, is described as a period wherethe severe head pain has settled but other symptoms, namely,asthenia, fatigue, somnolence, impaired concentration, photo-phobia, and irritability continue for hours to few days [7].These multiphasic process of a broad constellation of signsand symptoms highlight the complexity and the diffuse invol-vement of multiple neural networks and anatomical brainregions.
According to the International Classification of HeadacheDisorders 3 (ICHD-3), subjects with at least 15 headache daysof which at least eight fulfill the criteria for migraine with orwithout aura per month for at least three consecutive monthshave chronic migraine (CM) [8]. CM affects around 2–4% of thegeneral population, with an annual incidence among peoplewith episodic migraine is 2 · 5–3 · 0% [9]. This type of migraineis related to a higher degree of headache-related disabilitythan episodic migraine and is commonly linked with medica-tion overuse headache (MOH) [10].
Refractorymigraine is still a debated definition. It refers to thosesubjects predominantly with CM who fail to tolerate and/orrespond to adequate trials of established acute and preventivetreatments. Up to 5% of themigraine population fulfills the criteriafor refractory CM. This group of patients suffers from tremendousdisruption of their quality of life because of the migraine [11].
CONTACT Giorgio Lambru [email protected] The Headache Centre, Pain Management and Neuromodulation, Guy’s and St Thomas NHSFoundation Trust, London SE1 7HE, UK
EXPERT OPINION ON EMERGING DRUGShttps://doi.org/10.1080/14728214.2018.1552939
The current management of migraine includes treatmentsaiming to abort a migraine episode when it occurs and treat-ments to prevent future migraine occurrence, along withreducing the severity of symptoms and/or duration of theepisode. The selection between abortive, preventive, or bothstrategies for a given patient, depends upon several factorsincluding the severity of the migraine pain and associatedsymptoms and the frequency of occurrence of the migrainesand disability associated. Broadly speaking, abortive strategiesshould be the main treatment for people with an episodicmigraine with infrequent attacks, whereas preventive treat-ments should be offered in people with episodic ‘high fre-quency’ migraine and CM. These later group of patientsshould also be educated upon the potential risk of MOH,a very common chronification factor in migraine sufferers,which often interferes with the full potential effect of conco-mitant prophylactic treatments [12].
Non-steroidal antinflammatory drugs (NSAIDs), triptans andprokinetics remain the mainstay of acute migraine treatment.Stepped-up and stepped-down approaches are adopted inmost Countries. In stepped-up care the patient is started onthe simplest treatment and increasingly efficacious medica-tions are prescribed until a satisfactory response is obtained.A caveat of this approach can be the delays until an effectivetreatment is found. A stepped-down care involves startingwith the most effective treatment or combination of treat-ments and subsequently reducing the dose or number ofabortive treatments taken to allow effective treatment withthe minimum amount and number of treatments. A stepped-down approach is recommended by National Institute forHealth and Care Excellence (NICE) guidelines in the UnitedKingdom (U.K.), in view of its cost-effectiveness. NICE suggestsa combination of a triptan, NSAID or paracetamol, and an anti-emetic taken as soon as possible after the start of the head-ache [13].
Over-the-counter medications, such as NSAIDs and acetami-nophen, are often chosen first drug-class for mild-to-moderatemigraine attacks. NSAIDs inhibit the activity of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) and, thereby, thesynthesis of prostaglandins and thromboxanes, exerting anunspecific antinflammatory effect. Potential gastrointestinaland renal side effects along with lack of efficacy ina significant proportion of patients, limit their use in themigraine population. Triptans are widely considered to be first-line drugs for patients with migraine attacks associated withmoderate or severe pain intensity [14]. This class of drug wasspecifically designed to abort migraine by agonizing the sub-types 1B/D 5-hydroxytryptamine (5-HT) receptors, althoughsome triptans also act at the 5-HT1F receptor site [15]. Thisreceptors binding leads to vasoconstriction, mediated throughactivation of the postsynaptic 5-HT1B receptors at the level ofthe vascular smooth muscle, and inhibition of neuronal trans-mission along the trigeminal system by acting on pre-junctional5-HT1B/D receptors, which can also result in inhibition of calci-tonin gene-related peptide (CGRP) release from perivascularsensory nerve terminals. Their pharmacological profile, as well
as more recent positron emission tomography (PET) studiessuggest that the site of action of triptans is outside the blood-brain barrier [16]. Interestingly, despite the perception thattriptans mechanisms of action tackle paramount migraine-specific pathways, a proportion of migraine patients find themineffective. Alongside with those who do not tolerate their sideeffects, about 30–40% of migraine subjects are consideredtriptan-non responders [14]. Furthermore, in view of their vaso-constrictive effect, their use is contraindicated in uncontrolledhypertension, coronary artery disease, peripheral vascular dis-ease, or stroke. Nausea and vomiting during migraine attacksare common symptoms that affect at least 60% of patientssuffering from migraines. These symptoms are often more dis-abling than the headache itself, causing a great burden on thepatient’s life. Antiemetics, such as metoclopramide or domper-idone, are often prescribed as a combined treatment to NSAIDSand triptans aiming to increase abortive treatment’s gastricabsorption and tackle the nausea and vomiting during theirmigraines [14].
Preventive pharmacological treatments are considered ifheadaches occur on four or more days per month; if abortivetreatment is contraindicated and/or ineffective and if abortivetreatments need to be used ten of more days per month everymonth. The preventive treatment of migraine include differentclasses of drugs, namely, b-blockers, tricyclic antidepressants,antiepileptics, calcium channel blockers or angiotensin-converting enzyme inhibitors. The choice of preventativetreatment depends upon the individual drug’s efficacy andside-effect profile, the presence of any comorbid conditionsand patient’s preferences. However very often migraine sub-jects fail to adhere to these oral medications long enough toobtain a migraine preventive effect [17].
The only two approved medications for CM are topiramateand more recently Onabotulinum toxin type A (BoNTA). Theintroduction of BoNTA has significantly advanced the manage-ment of CM in view of its favorable tolerability profile and highresponder rate found in clinical trials [18,19] and replicated inreal-world studies [20]. Caveats in the use of BoNTA in clinicalpractice include the three-monthly administration in a hospitalsetting and the multiple injection sides, which can put strainon headache services. Besides, about one-third of patients donot respond to BoNTA [20].
For pharmacological and injectable treatments non-responders, the label of refractory CM is used [21]. For thisseverely disabled group of patients, no pharmacologicaltreatment has hitherto been showed to be effective.Occipital nerve stimulation has gathered positive open-labelevidence, which were not confirmed in randomized con-trolled trials [22–26]. However these trials were criticized formethodological issues. The use of noninvasive neuromodula-tion techniques, including vagus nerve stimulation, single-pulse transcranial magnetic stimulation and transcutaneouselectrical nerve stimulation have recently emerged as alter-natives to pharmacological treatments as well as to invasiveneuromodulation approaches. Their different mechanisms ofaction [27,28] along with different patients selection mayaccount for the mixed efficacy outcomes observed in clinicalpractise [29–31].
2 G. LAMBRU ET AL.
3. Medical need
Despite the broad arsenal of treatments, there is still a vastunmet need for novel migraine treatments. This includes:
(1) Better tolerated abortive treatments, which could alsobe used in specific subgroup of migraine patients,namely, the pediatric population, pregnant women, sub-jects with comorbid cardiovascular and/or cerebrovas-cular diseases and the elderly migrainous population.
(2) More effective abortive treatments that may be bene-ficial in the triptan non-responder population.
(3) Preventive treatments with better tolerability profiles,long-term safety, and patient-friendly administrationroutes.
(5) Preventive treatments for CM refractory to establishedmedical treatments. At present no pharmacological treat-ments hold compelling evidence of efficacy in this chal-lenging-to-treat group of people. Furthermore, invasiveneurostimulation approaches, such as occipital nerve sti-mulation, have failed to demonstrate a meaningful ther-apeutic effect in clinical trials.
4. Scientific rationale
Current research directions aim to produce therapies that areable to tackle known migraine underlying putative pathophy-siological mechanisms. Based on current theories, migraine isconsidered a brain disorder where subcortical and potentiallycortical modulatory structures fail to modulate normal sensoryafferent trigemino-cervical inputs from the trigeminovascularsystem [6]. The consequence of activation of this system isthought to be responsible for the perception of head pain inmigraine.
During the premonitory phase of migraine, a number ofbrain imaging studies have demonstrated altered blood flowchanges in the hypothalamic region [32,33], and in somestudies also in the visual cortex [34,35]. How functionalchanges in the hypothalamus can eventually drive activationof the trigeminovascular system is not understood, but likely itinvolves alterations in descending pain pathways to the trige-minocervical complex (TCC) [36]. The trigeminovascular sys-tem consists of trigeminal nociceptive nonmyelinated andthinly myelinated fibers innervating the meninges and duralvasculature. These trigeminal afferents arrive predominantlyfrom the ophthalmic (V1) division of the trigeminal nerve,but also to a lesser extent, from the maxillary (V2) and man-dibular divisions (V3). Centrally, they project to the TCC, whichextends from the trigeminal nucleus caudalis to the uppercervical spinal cord, mainly C2-C3 [37].
Activation of the trigeminovascular system results in therelease of a number of vasoactive neuropeptides, includingCGRP and substance P [38]. The dural vascular tone is alsoregulated by sympathetic and parasympathetic fibers innerva-tion. Sympathetic fibers contain vasoconstrictive peptides,
including Neuropeptide Y and norepinephrine, while the para-sympathetic vasodilatory innervation is characterized mainlyby Vasoactive Intestinal Peptide (VIP) and pituitary adenylatecyclase-activating peptide (PACAP) [39]. The ascending trige-minothalamic pathway is modulated by a complex descendingnetwork of midbrain and brainstem nuclei, which communi-cate to one another via a plethora of neurotransmitters,including serotonin, glutamate, GABA, dopamine, and endo-cannabinoids [40].
At a cortical level, cortical spreading depression (CSD) isthought to be the physiological substrate of migraine aura[41]. It results from depolarization, followed by a sustainedhyperpolarization of cerebral cortical neurons and glial activa-tion, and it also induces an initial hyperemia, followed byoligoemia, resulting in profound disturbance of the corticalvascular tone [42]. CSD is driven by the release of glutamatewhich is modulated by calcium, potassium and sodium cur-rents [43,44]. It is not yet clear whether CSD can activate thetrigeminovascular system and, hence exacerbate pain inmigraine. Electrophysiological studies in animal models sug-gest that both peripheral and central mechanisms are possible[45,46]. Nevertheless, disease mechanisms involved inmigraine aura are of interest also for the migraine withoutaura prevention, since some of the treatments that can blockCSD, namely sodium valproate, topiramate, and sTMS, can alsoprevent migraine without aura episodes [47,48].
5. Current research goals
Targeting the peptides, or their receptors, found to bereleased during a migraine attack, or blocking activation ofthe trigeminovascular system along with the neurotransmit-ters’ receptors involved in the migraine process, have beenconsidered of pivotal relevance for the development of novelacute and preventive pharmacological migraine-specific treat-ments. In view of the pitfalls in the use of triptans, researchdevelopment programmes have had the objective to developnovel acute treatments as, or more effective and better toler-ated than triptans, with an exquisite neural, migraine-specificmechanism of action that when possible avoid modulation ofthe vascular tone. To this purpose two main pathways havebeen studied: the CGRP and the serotonin pathways, whichproduced two new family of drugs: the Gepants and theDitans. Targeting the CGRP pathway has also led to the devel-opment of therapies potentially effective as preventive treat-ments, the anti-CGRP monoclonal antibodies. These classes ofdrugs are in an advanced stage of development and some ofthese therapies will be on the market shortly.
6. Competitive environment
6.1. Calcitonin gene-related peptide
CGRP is one of the most potent vasodilators known. It exists in2 forms in humans: a-CGRP (37-amino acid peptide), mainlyexpressed in primary sensory neurons of the dorsal root gang-lia, trigeminal ganglia and vagal ganglia, and b-CGRP primarilyfound in intrinsic enteric neurons. CGRP is an ubiquitous pep-tide distributed within the cerebral and cerebellar cortex,
EXPERT OPINION ON EMERGING DRUGS 3
thalamus, hypothalamus inhibitory nociceptive nuclei of thebrainstem, the trigemino-cervical complex and the trigemino-vascular system [49]. Within the trigeminal ganglia CGRP isexpressed in cells that give rise to thinly myelinated A delta-fibers and in unmyelinated C-fibers [50]. CGRP receptors havebeen identified within the above-mentioned cortical and sub-cortical structures, while on trigeminal fibers CGRP receptorsfunction as autoreceptors, regulating CGRP release [51].
CGRP levels have been found to be elevated duringa migraine attack, although some studies also suggest other-wise [52,53]. Intravenous infusion of CGRP in migraine patientshas been also shown to induce a migraine attack in about 60%of the patients [54]. Of interest, patients with familial hemi-plegic migraine, a rare form of migraine with aura, are notsensitive to CGRP [55], potentially due to changes of CGRPlevels in their trigeminal system [56]. Experimental activationof trigeminal ganglion cells is known to result in the release ofCGRP, which is dose-dependently inhibited by 5-HT1B/D ago-nists, highlighting the trigeminal system as a key site that maybe targeted by CGRP receptor antagonists and triptans [57,58].In addition to its vascular effects, CGRP has emerged as a keymodulator of neuronal function, which has important effectson neurotransmitter systems such as the glutamatergic sys-tem [59].
Based on these findings, drugs directed at modulatingCGRP activity in migraine have emerged as particularly pro-mising future treatments. CGRP receptor antagonists, whichcompete with endogenous CGRP at the receptor binding sites,have been developed as novel anti-migraine drugs and foundto be effective in the treatment of acute migraine attacks.Other ways to modulate CGRP activity have been introducedrecently through the development of monoclonal antibodies(mAb) against CGRP and the CGRP receptor.
6.1.1. CGRP receptor antagonists (the Gepants)CGRP receptor antagonist are small compounds that competewith endogenous CGRP at the receptor binding sites. To date,it is not clear if the CGRP receptor antagonists cross the blood-brain barrier. The progress of the new emerging CGRP antago-nists has followed a previous successful development ofantagonists, named olcegepant (BIBN4096BS), telcagepant(MK-0974) and MK-3207, which had good efficacy as acutetreatments for migraine, however, their safety profile wasrather unfavorable.
In a proof of concept study in acute migraine treatment,intravenously administered Olcegepant 2.5 mg was signifi-cantly superior to placebo at 2 h response rate (66% versus27% of placebo-treated patients, p = 0.001), suggestinga potential role in acute migraine treatment [60].Subsequently, telcagepant, developed as an oral CGRP recep-tor antagonist, was tested in a phase II proof-of-concept studydemonstrating the efficacy of 300–600 mg dose [61]. A dose of150 mg, 300 mg were then tested in a randomized placebo-controlled, parallel-treatment trial compared with zolmitriptan5 mg in acute migraine. Telcagepant 300 mg was found to besuperior to placebo and similarly effective to zolmitriptan 5 min pain-freedom, pain relief, and other secondary outcomes.Side effects did not differ much from placebo [62]. However,when Telcagepant was tried on a daily basis as a preventive
migraine treatment, it caused liver enzymes derangement andthe trials were discontinued [63].
MK-3207 was the third oral CGRP receptor antagonistdeveloped and tested in migraine. A phase II multicenter,double-blind, randomized, placebo-controlled, parallel-groupstudy showed superiority to placebo above the dose of 10 mgin 2-h pain freedom, whether secondary outcomes of 2 hfreedom from photophobia/phonophobia/nausea and 2 to24 h sustained pain freedom were significant at a much higherdose (200 mg) only [64]. Similarly to other gepants however,MK-3207 development was discontinued because of liver toxi-city issues.
BI 44370 TA was another CGRP receptor antagonist used ina phase II study which assessed its safety, tolerability, andefficacy in the treatment of an acute migraine attack in episo-dic migraine sufferers. The doses of 50 mg, 200 mg, and400 mg were tested against placebo and eletriptan 40 mg.The dose of 50 mg and 200 mg did not meet the primaryendpoint pain-free at two hours. The 400 mg dose of BI 44370TA and eletriptan 40 mg were more effective than placebo. BI44370 TA 400 mg and eletriptan 40 mg were also superior toplacebo on the absence of photophobia, phonophobia andnausea as well as a reduction in functional disability at 2h [65]. Although outcomes from this study did not supporta concern for unfavorable side effects, studies on this agentare now discontinued.
6.1.1.1. Ubrogepant (MK-1602). Ubrogepant (MK-1602) isa novel oral CGRP receptor antagonist chemically distinctfrom telcagepant and MK-3207 (Figure 1). The safety andefficacy of Ubrogepant at different doses (1 mg, 10 mg,25 mg, 50 mg, 100 mg) was explored in a Phase IIb, multi-center, randomized, double-blind, placebo-controlled trial [66].Study primary efficacy endpoints were pain freedom at twohours post-dose (reduction in headache severity from grade 2or 3 at baseline to grade 0) and headache response at twohours post-dose (reduction in headache severity from grade 2or 3 at baseline to grade 1 or 0). Several other secondaryendpoints including safety endpoints were also analyzed.A total of 834 participants were randomized to 1 mg, 10 mg,25 mg, 50 mg, 100 mg of ubrogepant and placebo. The studyshowed a positive response trend across ubrogepant dosesregarding the 2-h pain freedom endpoint. Ubrogepant 100 mgwas statistically superior to placebo for 2-h pain freedom(25.5% vs 8.9%, P = 0.003), followed by ubrogepant 50 mg(21.0% vs 8.9%, p = 0.020) and ubrogepant 25 mg (21.4% vs8.9%, p = 0.013) However the two-hour headache responsedid not significantly differ between different ubrogepantdoses and placebo. Ubrogepant 100 mg showed significantimprovements vs placebo on all secondary endpoints exceptthe absence of nausea at 2 h. With regards to adverse events(AEs), their overall incidence were similar for ubrogepantgroups and placebo. The most common ubrogepant sideeffects were dry mouth, nausea, fatigue, dizziness, and som-nolence. The incidence of triptan-associated AEs in the ubro-gepant groups was comparable to that of placebo. There wereno serious AEs within 14 days post-dose. Importantly, therewere no observed post-treatment elevations of ALT >3 ULN
4 G. LAMBRU ET AL.
and no other abnormal laboratory values of clinical relevance,as found with the earlier CGRP antagonists. This promisingresults supported further progression into phase 3 clinicaltrials. Initial positive efficacy and safety results of two phaseIII multicenter randomised, double-blind, placebo-controlledclinical trials comparing ubrogepant 50 mg and 100 mg versusplacebo (Achieve 1) and ubrogepant 25 mg and 50 mg versusplacebo (Achieve 2) were recently presented at the AmericanHeadache Society (AHS) conference in San Francisco, California(28 June to 1 July 2018).
Overall the available data support the role of this newtreatment in the acute management of migraine, althoughdata on consistency of effect as well as safety data on subjectsin whom triptans are contraindicated are needed to confirmits role as an alternative treatment to triptans.
6.1.1.2. Rimegepant (BMS-927711). Rimegepant is alsoa novel CGRP-receptor antagonist chemically distinct fromtelcagepant (Figure 1). Rimegepant’s efficacy and safety inthe acute treatment of migraine were tested in a phase II,double-blind, randomized, placebo-controlled, dose-rangingtrial in 885 participants [67]. Patients were randomized toreceive one of six doses of BMS-927711 (10 mg, 25 mg,75 mg, 150 mg, 300 mg, or 600 mg), sumatriptan (100 mg),or placebo for the treatment of a moderate or severe migraineattack. The primary endpoint was pain freedom at two hourspost-dose. Secondary endpoints included a composite end-point consisting of freedom from headache pain coupledwith no symptoms of photophobia, phonophobia, and nausea,at 2 h post-dose. Other secondary efficacy and safety end-points were studied. The percentage of participants who metthe primary endpoint of pain-freedom at two hours washigher in the group taking Rimegepant 150 mg (32.9%) com-pared to the other Rimegepant doses (p < 0.001): 31.4% in the75 mg, 29.7% in the 300 mg dose, 15.3% in the placebo group.Sumatriptan 100 mg was superior to all dose of Rimegepant(35%). The dose of Rimegepant 75 mg was the most effectivein meeting the secondary efficacy endpoint of total migrainefreedom (28.2%) and it was statistically superior than placebo.Sumatriptan 100 mg was superior to each dose of Rimegepantat this secondary endpoint. The percentage of patients withheadache freedom up to 24 h post-dose was superior toplacebo for several doses of Rimegepant and for sumatriptan.Most of the AEs were mild to moderate in intensity. No
patients discontinued because of AEs. Two patients hadincreased hepatic enzymes reported as an adverse event, onin the Rimegepant group and one in the placebo group.
The findings of this study suggest that Rimegepant hassimilar efficacy to sumatriptan 100 mg in the treatment ofa migraine attack, with potentially less triptan-related sideeffects, namely paresthesia, and chest discomfort. A phase IIIstudy comparing the efficacy of Rimegepant 75 mg versusplacebo has been recently completed. Furthermorea prospective multicentre open-label long-term safety studyis underway and recruitment is anticipated to be completedby late 2019. The finding of these two studies will shed morelights on the consistency and safety of this molecule inmigraine therapy.
6.1.1.3. Atogepant (AGN-241689). Atogepant, a smallmolecule with distinct, but similar structure to that of ubroge-pant (Figure 1) is currently the only CGRP receptor antagonistused in a study for the prevention of migraine. It has a higherpotency and longer half-life than ubrogepant, making it sui-table for preventive treatment. A phase II/III, multicentre ran-domized, double-blind, placebo controlled, parallel-groupstudy evaluated the efficacy, safety, and tolerability of multipledosing regimens of oral atogepant in episodic migraine pre-vention (NCT02848326). Adult patients were randomized toplacebo, 10-mg QD, 30-mg QD, 30-mg BID, 60-mg QD, and 60-mg BID, respectively, and treated under double-blind condi-tions 12 weeks for the prevention of episodic migraine. Theprimary efficacy endpoint was the change from baseline inmean monthly migraine/probable migraine headache daysacross the 12-week treatment period. All active treatmentgroups demonstrated a statistically significant reduction frombaseline in the primary efficacy parameter (10 mg QD vsplacebo, Δ −1.15, p = 0.0236; 30 mg QD vs placebo, Δ −0.91,p = 0.0390; 60 mg QD vs placebo, Δ −0.70, p = 0.0390; 30 mgBID vs placebo; Δ −1.39, p = 0.0034, 60 mg BID vs placebo, Δ−1.29, p = 0.0031). Atogepant appeared to be well toleratedwith the most common adverse events being nausea, fatigue,constipation, nasopharyngitis, and urinary tract infection. Theliver safety profile for atogepant was similar when comparedto placebo, with no indications of hepatotoxicity with the dailyadministration over 12 weeks. The development program ofthis treatment is going to be moving to the next stage.
a b c
Figure 1. Chemical structures of (a) ubrogepant. (b) rimegepant. (c) atogepant.
EXPERT OPINION ON EMERGING DRUGS 5
6.1.2. Anti-CGRP and anti-CGRP receptor monoclonalantibodiesThe CGRP pathway has been targeted also via antibodiesagainst CGRP and the CGRP receptor. This is the first timeengineered antibodies are used in the field of migraine andinitially their development was faced with some skepticism.Three monoclonal antibodies (mAbs) target the ligand pre-venting the binding of CGRP to its receptor. These are: galca-nezumab (LY2951742), a fully humanized mAb anti CGRP,fremanezumab (TEV-48125), a fully humanized mAb anti-CGRP and eptinezumab, a genetically engineered humanizedanti-CGRP antibody. Erenumab (AMG 334), is a fully huma-nized mAb targeting the CGRP receptor.
The favorable pharmacological profile of these compoundsincludes their long half-life, the lack of a vasoconstrictive effect orother relevant hemodynamic changes [68]. Given their highmolecular weight, these compounds do not cross the blood-brain barrier, indicating a reduced likelihood of central nervoussystem-related side effects, which are commonly observed withpharmacological prophylaxis treatments currently used inmigraine. Furthermore, their administration route, which is eithersubcutaneously (sc) or intravenously (IV) at different rates ran-ging between once every three months to twice a monthdepending on the compound, may improve long-term patients’treatment compliance compared to oral treatments.
Methodologically similar randomized, double-blind, pla-cebo-controlled Phase II and III clinical trials explored theefficacy and safety of these novel treatments in the preventionof episodic and CM.
6.1.2.1. Erenumab (AMG334). In a phase II trials in partici-pants with episodic migraine, erenumab 70 mg given monthlyfor three months was found to significantly reduce the num-ber of migraine days per month by 3.4 days compared toplacebo (−2.3 days) at 12 weeks [69].
Subsequently, the STRIVE study, a multicenter, randomized,double-blind, placebo-controlled, parallel-group, phase III trial,
assessed the efficacy and safety or subcutaneous (sc) injectionof either erenumab, at a dose of 70 mg or 140 mg, or placeboin episodic migraine prevention monthly for 6 months. Theprimary end point was the change from baseline to months 4through 6 in the mean number of migraine days per month.Secondary endpoints included the proportion of participantswith ≥50% reduction in mean migraine days per month.Amongst other secondary endpoints the study evaluatedchanges in scores on the physical-impairment and every day-activities domains of the Migraine Physical Function ImpactDiary (scale transformed to 0 to 100, with higher scores repre-senting greater migraine burden on functioning) [70]. Theoverall mean number of migraine days/month was 8.3 atbaseline. Table 1 showed the main efficacy outcomes of thestudy, highlighting the superiority of both doses of erenumabcompared to placebo in reduction of migraine days andresponder rate. The study showed also a significant improve-ment of the disability questionnaires for both doses ofErenumab compared to placebo (p < 0.001).
The ARISE trial consisted in a randomized, double-blind,placebo-controlled, phase III study assessing the efficacy andsafety of erenumab 70 mg only vs placebo in episodicmigraine participants [71]. The primary endpoint was changedin monthly migraine days. Secondary endpoints included≥50% reduction in monthly migraine days and changes inmigraine disability scores. The efficacy outcomes of the studywere superior to placebo and interestingly similar to theSTRIVE study ones as summarised in Table 1. However thisstudy, unlike the STRIVE study, did not show significantimprovement in the migraine disability scores. Both theSTRIVE and ARISE trials indicate a favorable safety and toler-ability profile of erenumab. Most frequent adverse eventswere upper respiratory tract infection, injection site pain, andnasopharyngitis.
The interim analysis of the planned 5-year long open-labelextension of the phase II clinical trial [69] with Erenumab70 mg included 383 episodic migraine participants who had
Table 1. Efficacy outcomes in phase II and phase III clinical trials using mAbs anti-CGRP for the prevention of episodic migraine.
(<0.001)Eptinezumab IV −5.6 −4.6 −1.0 Active: 75.0%*
(1000 mg) (p = 0.030) Placebo: 54.0%
*Statistically significant difference compared to placebo**One single injection quarterly
6 G. LAMBRU ET AL.
failed up to two previous preventive treatments [72]. Thisstudy looked at 1-year changes in migraine days, percentageof participants achieving ≥50%, ≥75% and 100% reduction inmonthly migraine days, change in disability score using HIT-6, MIDAS and MSQ and safety profile. From an average base-line of 8.8 migraine days/month of those who took part inthe open-label trial, at week 64, 28% of participants discon-tinued the treatments for various reasons. Of the remainingparticipants, a mean reduction of 5 migraine days was found.Looking at participants who were treated with erenumab70 mg since month 1 of the randomized controlled phase,from month 3 to month 64 the mean number of migrainedays diminished from −3.4 to – 5 days/month, with anestimate gain of −1.6 migraine days less after 52 months.At week 64, 65%, 42%, and 26% achieved, respectively, 50%,75%, and 100% reduction in migraine days. Disability andquality of life scores displayed a meaningful improved atweek 64. No safety concerns emerged during the open-label extension.
The safety and efficacy of Erenumab in the preventionof CM were evaluated in a randomized, double-blind, placebo-controlled phase II clinical trial [73]. Patients were randomlyassigned (3:2:2) to subcutaneous placebo, erenumab 70 mg, orerenumab 140 mg, given every 4 weeks for 12 weeks. Theprimary endpoint was the change in monthly migraine daysfrom baseline to the last 4 weeks of double-blind treatment(weeks 9−12). Secondary endpoints included the percentageof participants achieving 50% reduction in monthly migrainedays, change in the use of monthly acute migraine treatmentsand change in cumulative headache hours from baseline.Safety endpoints were also analyzed. At baseline the meanmonthly migraine days ranges between 17.8 and 18.2 days.Table 2 outlines the reduction in migraine days compared toplacebo with erenumab 70 mg and 140 mg and the 50%response rate. There was a significant reduction in monthlyacute medicines intake in both erenumab groups, but nosignificant reduction in cumulative monthly headache hours.No safety issues emerged during the trial.
Erenumab (Aimovig) obtained FDA approval in May 2018for the prevention of migraine in adults.
6.1.2.2. Galcanezumab (LY2951742). Galcanezumab isa humanized monoclonal antibody that blocks CGRP activityby blocking the ligand and not the receptor. Phase II proof-of-concept trials conducted in episodic migraine participants.LY2951742 (150 mg) or placebo were given as a sc onceevery 2 weeks for 12 weeks. The primary endpoint was themean change in number of migraine headache days [74].Safety outcomes were also assessed. The primary endpointwas met with a mean reduction of 4.2 monthly migrainedays compared to a reduction of 3.0 days in the placeboarm (p = 0.003). Erythema, upper respiratory tract infections,and abdominal pain were the most frequently adverse eventsreported in the trial. No serious adverse events were reportedin the active arm.
A recently published phase IIb clinical trial ofGalcanezumab and placebo in episodic migraine sufferersaimed to assess the superiority of galcanezumab administeredsc monthly at different doses (5, 50, 120, 300 mg) for threemonths compared to placebo. The primary efficacy outcomewas mean change from baseline in migraine days from week 9to 12 post-randomization. Galcanezumab 120 mg significantlyreduced migraine headache days compared with placebo(−4.8 days vs −3.7 days) [75].
These initial findings led to the development of two phaseIII randomized, multicenter, double-blind, placebo-controlledtrials in episodic migraine patients (EVOLVE-1 and EVOLVE-2)[76,77]. In the both trials, the efficacy and safety of monthly scinjections of galcanezumab 120 and 240 mg versus placebofor 6 months were assessed. Participants were subsequentlyfollowed-up for 5 months after the last injection. Primary end-point was overall mean change from baseline in monthlymigraine headache days. Secondary outcomes included≥50%, ≥75%, and 100% reduction in monthly migraine head-ache days. Disability, quality of life, and safety measures werealso analyzed. Both studies met the primary and secondaryefficacy endpoints for both doses at 6 months as shown inTable 1. There was no significant difference in migraineimprovement between 120 mg and 240 mg. Migraine disabil-ity outcomes were significantly improved compared to pla-cebo. Injection site pain was the most common AE.
Table 2. Efficacy outcomes in phase II and phase III clinical trials using mAbs anti-CGRP for the prevention of chronic migraine.
Change in migraine days
active placeboΔ
(p-value) % of participants achieving 50% migraine days reduction
Erenumab (Phase II)(70, 140 mg)
−6.6 −4.2 −2.4 Active 70 mg: 40%*(<0.0001) Active 140 mg: 41%*
Placebo: 23%Galcanezumab (Phase III)(120, 240 mg)
−4.8 −2.7 −2.1 Not reported but superior to placebo–4.6 –1.9
*Statistically significant difference compared to placebo**One single injection quarterly
EXPERT OPINION ON EMERGING DRUGS 7
The REGAIN study (NCT02614261) is a double-blind, rando-mized, placebo-controlled, 3-month study with a 9-monthopen-label extension for the prevention of a migraine in par-ticipants in CM. The study preliminary results were presentedas a poster at the AHS 2018. Participants were randomized2:1:1 to sc placebo, galcanezumab 120 mg or 240 mg givenmonthly for three months. The primary endpoint was theoverall mean change from baseline in the number of monthlymigraine days during the 3-month double-blind treatmentphase. Secondary efficacy outcomes included the percentageof patients with 50%, 75%, and 100% reduction in monthlymigraine days, along with migraine-related disability and qual-ity of life scores. The study met the primary endpoint at3 months as it is shown in Table 2. Compared to placebothere was a higher incidence of injection site reaction,erythema, and sinusitis in the galcanezumab arms.
6.1.2.3. Fremanezumab (TEV48125). Fremanezumab isa fully humanized monoclonal antibody targeting CGRP.Similarly to the other monoclonal CGRP antibodies, favorablePhase I studies encouraged the development of phase II stu-dies in the prevention of migraine. The efficacy and safety ofsc TEV-48125 (225 mg and 675 mg) versus placebo was stu-died in a multicentre, randomized, double-blind, placebo-controlled, phase 2b study in episodic migraine. Participantswere randomized to receive either TEV-48125 225 mg or675 mg or placebo every 28 days for 3 months. The primaryefficacy endpoint was the mean decrease from baseline in thenumber of days migraine days during the third treatmentcycle (weeks 9–12). Primary safety parameters were also ana-lyzed. In post-hoc analyses, the proportion of participantsobtaining at least 50% and 75% decrease in the number ofmigraine-days compared to baseline was evaluated. The studymet the primary efficacy outcome with both doses of TEV-48125 (Table 1). No safety or tolerability issues were identified.The most common treatment-related adverse events weremild injection-site pain or erythema [78].
Subsequently, the preventive effect of TEV-48125 (frema-nezumab) in episodic migraine was studied in a randomized,double-blind, placebo-controlled, parallel-group phase III trial[79]. The design of the trial implied the injection of monthly scfremanezumab 225 mg, or 675 mg following a quarterly doseregimen, or placebo. The primary study endpoint was meanchange in number of monthly migraine days/month at the 12-week period. Secondary efficacy end points included the pro-portion of patients obtaining at least a 50% reduction in themean number of monthly migraine days from baseline toweek 12 as well as changes in migraine-related disabilityscores. The mean number of monthly migraine days at base-line ranged between 8.9 and 9.3 days in the three study arms.The study met the primary efficacy endpoint for both monthlyand quarterly regimens, showing superiority to placebo inreduction of mean migraine days. No significant differencewas noticed between the two different fremanezumab regi-mens. The most common AEs were injection site reactions.Similar low proportion of participants in the different armsdiscontinue because of AEs (2%).
The main strength of this study includes for the first timethe outcomes of a single dose therapy given quarterly. Giventhe similar results compared to monthly injections, this strat-egy may open interesting avenues on potentially effectivemultiple injection regimens in migraine prevention.
The safety, tolerability, and efficacy of TEV-48125 (fremane-zumab) were also tested in CM in a multicentre, randomized,double-blind, placebo-controlled, phase IIb study [80]. Thedose of the active treatment differ from the episodic migrainetrials. TEV-48125 was administered at the dose of 675 mg inthe first treatment cycle and 225 mg in the second and thirdtreatment cycles, or at the dose of 900 mg monthly for threemonths versus placebo. The efficacy endpoints also differedfrom the episodic migraine studies. For this trial, change frombaseline in the number of headache-hours during the thirdtreatment cycle (weeks 9–12) was set as primary outcome. Thechange in the number of moderate or severe headache-dayswas considered a secondary endpoint. At baseline, partici-pants had a mean of 162 headache-hours/month, 21.1 head-ache-days of any duration and 16.8 migraine days/month. Themajority of participants had not tried any preventive treat-ment at baseline. During weeks 9–12, a significant reductionin a number of headache-hours was demonstrated for bothdoses compared to placebo (675/225: – 59.84; 900 mg: –67.51 h; placebo: – 37.10 h, p = 0 · 0386 and p = 0.0057).Similarly, a significantly greater reduction in mean number ofheadache days was found for both doses compared to pla-cebo (Table 2). The higher fremanezumab doses were fairlywell tolerated and no serious concerns emerged in terms ofAEs from this trial.
On the basis of the promising results of the phase II study,a randomized, double-blind, placebo-controlled, parallel-group trial was subsequently conducted to confirm the effi-cacy of fremanezumab for the prevention of CM [81].Participants with CM were randomized in a 1:1:1 ratio toreceive fremanezumab quarterly (a single dose of 675 mg atbaseline and placebo at weeks 4 and 8), fremanezumabmonthly (675 mg at baseline and 225 mg at weeks 4 and 8)or placebo. The primary end point was the mean change frombaseline in the average number of headache days, definedaccording to the International Headache Society (IHS) criteria.Interestingly the mean number of monthly migraine days atbaseline was higher than the number of headache days butlower than the number of days of any severity and duration.Furthermore, the majority of participants did not use topira-mate or BoNTA at baseline. The study met the primary end-point for both doses and showed a significantly greaterpercentage of participants obtaining at least 50% reductionin headache days with fremanezumab compared to placebo(Table 2). Discontinuation of the trial due to adverse eventswas infrequent. Similarly to other trials, fremanezumab wasassociated with a higher incidence of injection-site reactionsthan placebo, though the severity of such reactions did notdiffer significantly among the trial arms.
Fremanezumab (Ajovy) was granted FDA approval on the 14thof September 2018, making it the second anti-CGRP monoclonalantibodies approved for the preventive treatment of migraine inadults and the first onewith quarterly andmonthly dosingoptions.
8 G. LAMBRU ET AL.
6.1.2.4. Eptinezumab (ALD403). ALD403 (Eptinezumab) isa genetically engineered, humanized antibody targeting bothforms of human CGRP. Its efficacy, safety, and tolerability havebeen evaluated in a phase II proof-of-concept study in parti-cipants with an episodic migraine [82]. The primary aim of thestudy was to assess the safety of a single dose of 1000 mg ofALD403 administered intravenously compared with placebo.Secondary outcomes included efficacy and migraine-relateddisability measures at 12 weeks post infusion. In particularchange from baseline to weeks 5–8 in migraine days wasevaluated. The frequency of migraine days at baseline was8.8 in the placebo and 8.4 in the active group. Adverse eventswere experienced by 52% participants in the placebo groupand 57% in the ALD403 group. The most frequent AEs wereupper respiratory tract infection, urinary tract infection, fati-gue, back pain, nausea and vomiting, and arthralgia. Most ofthem were mild or moderate in severity. None of the infre-quent serious adverse events were considered related to theactive drug. In terms of the efficacy endpoints, there wasa significant reduction in the mean number of migraine daysbetween baseline and weeks 5–8 for ALD403 compared toplacebo (Table 1). Interestingly a very high proportion ofparticipants obtained 50% reduction of migraine days atweeks 5–8. It was also noted that the placebo response ratesin this trial were remarkably high compared to the previoustrials using anti-CGRP monoclonal antibodies, possiblybecause of the intravenous administration of the drug.
These preliminary findings led to the development of a phaseIII randomized, double-blind, placebo-controlled study to evalu-ate the efficacy and safety of different doses of eptinezumab inepisodic migraine (PROMISE 1) (NCT02559895). The primary end-point was the mean change in migraine days over weeks 1–12compared to a 28-day baseline. Baseline migraine days averaged8.5 days/month across groups. Participants were randomized toreceive eptinezumab 300 mg, 100 mg, 30 mg, or placebo byintravenous infusion every 12 weeks. The study met the primaryefficacy endpoint. A significantly greater reduction of migrainedays was achieved at all eptinezumab doses compared to pla-cebo (−4.3, −3.9, −4.0 vs −3.2). Furthermore, a significantlygreater proportion of participants given eptinezumab hada 50% reduction in migraine days (49.8%-56.3% vs placebo:37.4%). No AEs issues emerged in this trial. In most of the anti-CGRP monoclonal antibodies trials have emerged the remark-able fast response compared to placebo normally within the firstmonth for active drug administration. Eptinezumab was shownto be able to reduce migraine from day 1 and to maintainedsimilar improvement at four and 12 weeks post-infusion. Thepreliminary findings of this study were presented at theAmerican Academy of Neurology 2018 (AAN) Conference, LosAngeles, California.
The efficacy, safety, and tolerability of eptinezumab in CMwere assessed in a phase II and a phase III trial. A randomized,double-blind, placebo-controlled phase II study tested variousdoses of ALD403 versus placebo. Participants were rando-mized to receive a single intravenous dose of ALD403300 mg, 100 mg, 30 mg, 10 mg, or placebo. Unlike other anti-CGRP monoclonal antibodies trials, the primary endpoint herewas the percentage of patients achieving a 75% reduction in
migraine days per month from baseline to week 12. Thepercentage of participants achieving 75% reduction inmigraine days with ALD403 300 mg and 100 mg was signifi-cantly greater than the one receiving placebo (33% and 31%vs 21%). These results were presented at the AAN 2018 con-ference Los Angeles, California.
The PROMISE 2 (PRevention Of Migraine via IntravenousALD403 Safety and Efficacy 2) is a Phase III, randomized,double-blind, placebo-controlled trial evaluating the safety,and efficacy of eptinezumab for the prevention of CM.Patients were randomized to receive eptinezumab (300 mgor 100 mg), or placebo administered by infusion once every12 weeks (NCT02974153). The primary endpoint was the meanchange from baseline in monthly migraine days over the12 week, double-blind treatment period. Secondary efficacy,migraine-related disability, and safety outcomes were alsoanalyzed, including the percentage of participants showingreduction in migraine prevalence at day 1 post-infusion. Thebaseline mean frequency of migraine days was 16.1 across thegroups. Both eptinezumab doses met the primary endpointwith mean migraine reduction of 7.7 days (dose 100 mg), –8.2 days (dose 300 mg) versus placebo (−5.6 days) (p < 0.0001)(Table 2). Interestingly, 51% who received 100 mg and 52%who received 300 mg of the active drug compared to 27% ofthose who received placebo, showed a reduction in migrainerisk beginning at day one post-infusion, which was then sus-tained through day 28. The safety profile of eptinezumab inthis study was comparable to the one of previous studies.These preliminary results were presented at the AAN 2018Conference, Los Angeles, California.
6.2. 5-HT1F receptor and 5-HT1F receptor agonists (theDITANS)
The 5-hydroxytryptamine (serotonin) receptor 1F, also knownas 5-HT1F receptor, is a member of the 5-HT1 subfamily of the5-HT serotonin receptors that bind to the endogenous neuro-transmitter serotonin. Like other 5-HT1 receptors, 5-HT1F isa protein coupled to Gi/Go and mediates inhibitory neuro-transmission. Interestingly, this receptor is found at the pre-junctional site of the trigeminal fibers but is lacking from thevascular smooth muscles. Centrally is found in the TCC, cere-bellum, and cortex [83].
Triptans, mediate part of their effect through modulation of5-HT1F receptors on trigeminal sensory neurons; hence, 5-HT1Fagonist compounds were postulated to have an abortive anti-migraine effect without the vasoconstrictive effect [84]. Thisled to the development of the first 5HT1F agonist LY334370which was investigated in a small randomized, double-blind,placebo-controlled, parallel-design clinical trial, and proved tobe effective for the acute treatment of migraine attacks at60 mg and 200 mg. Unfortunately, frequent adverse eventssuch as asthenia, dizziness, and somnolence, as well as, com-pound-specific safety concerns stopped further clinical devel-opments [85].
Following this, lasmitidan (COL-144, LY573144), a more spe-cific 5-HT1F receptor agonist with a novel pyridinoyl-piperidinestructure, was developed. Lasmitidan showed promising
EXPERT OPINION ON EMERGING DRUGS 9
results in a proof-of-concept study where doses above 20 mginfused intravenously, produced pain relief at 2 h in a signifi-cantly higher percentage of cases than placebo during anacute migraine attack. The efficacy became evident at 20–-40 min after administration, in the absence of serious adverseevents [86]. Subsequently, a phase II study with oral lasmitidantested at the doses of 50, 100, 200 and 400 mg for the acutemigraine attack, showed superiority with respect to placebo at2 h. Also, migraine-associated symptoms improved with alldoses. Fifty percent of treated subjects reported a return ofheadache within 24 h after treatment. The most severeadverse events included dizziness [87].
Two Phase III randomized, double-blind, placebo-controlledstudies have been tested lasmitidan in an episodic migraineacute treatment. In the SAMURAI trial (NCT02439320), partici-pants were randomized to lasmitidan 200 mg, 100 mg or pla-cebo. In the SPARTAN study (NCT02605174) participants wererandomized to lasmitidan 200, 100, 50 mg or placebo. Key stu-dies endpoints were the proportion of participants who becomeheadache-free at 2 h post-dose and the proportion of partici-pants who free from the most bothersome symptom at 2 h post-dose. Secondary outcomes including headache recurrence,changes in pain-killers utilization and freedom from migraine-associated symptoms. A statistically significant proportion ofparticipants using Lasmitidan 50 mg, 100 mg, and 200 mgwere headache-free and most bothersome symptom-free com-pared to placebo at 2 h post-dose. In particular 32.2% in theSAMURAI study and 38.8% of the participant in the SPARTANstudy receiving lasmiditan 200 mg compared to 15.3% and21.3%, respectively, in the placebo group, became headache-free and 40.7% in the SAMURAI and 48.7% in the SPARTAN studywere free from the most bothersome symptom compared to29.5% and 33.5%, respectively, in the placebo group.Lasmiditan 50, 100 and 200 mg was also superior to placebo inproportion of participants with headache relief, percentage ofparticipants needing to use rescue medication, percentage ofparticipants reporting photophobia and phonophobia-freedomat two hours, but not in nausea-freedom. Themost common sideeffects with lasmiditan were dizziness, paresthesia, somnolence,fatigue, nausea, and lethargy. These data were presented at theAAN 2018 Conference, Los Angeles, California.
An open-label Phase III study, called GLADIATOR aiming toevaluate the long-term safety of lasmiditan for the acutetreatment of migraine is underway. Furthermore, a global,multicenter, double-blind, modified parallel, placebo-controlled study has been planned to assess the safety, effi-cacy, and consistency of lasmiditan in the acute treatment ofmultiple migraine attacks with or without aura. The results ofthese studies will confirm the long-term efficacy and consis-tency of response of this novel medication for the acutetreatment of migraine.
6.3. Pituitary adenylate cyclase-activating polypeptide(PACAP) and pituitary adenylate cyclase-activatingpolypeptide type 1 receptor (PAC1)
Pituitary adenylate cyclase-activating polypeptide (PACAP) isanother neuropeptide that has been implicated in migrainepathophysiology [88]. PACAP is closely related to VIP and is
found in two isoforms, PACAP-38 and PACAP-27 with PACAP-38 to be more abundant. In neuronal tissues, the isoformPACAP-38 predominates [89]. It is known to play hypophysio-tropic, neuromodulatory, and neurotransmitter roles, and hasbeen associated with differentiation- and proliferation-inducing effects in the developing nervous system, as well aswith cytoprotective, anti-apoptotic, and anti-inflammatory fea-tures within various target organs [90]. Within the trigeminalganglia, PACAP is localized in small neurons which in additionstore CGRP [91]. Other structures relevant to the pathogenesisof migraine, such as in trigeminal afferents in the dura mater,the cerebral vessels, the TCC, brainstem nuclei, as well as thesphenopalatine and otic ganglia also express PACAP [92–94].In a recent preclinical study, it was found that both VIP andPACAP similarly cause transient vasodilation of meningealarteries, yet only PACAP was able to trigger a delayed sensiti-zation of second order trigeminocervical neurons [95,96]. Inmigraine patients, elevated levels of plasma PACAP-38 wererevealed in the ictal migraine period but not during interictalphase in migraineurs [97,98]. Stimulation of the trigeminalganglion was shown to increase PACAP expression in thetrigeminal nucleus caudalis, a phenomenon blocked bykynurenic acid analogues and NMDA receptor antagonists[99]. be Additionally, intravenous infusion of PACAP-38, butnot VIP, was shown to trigger migraine-like headaches inmigraine patients [100,101].
The pituitary adenylate cyclase-activating polypeptide type1 receptor (PAc1) has been identified as a receptor whichbinds the PACAP molecule with high affinity [90]. A novelmolecule, AMG 301, is a PAc1 receptor selective monoclonalantibody which has been developed for the prevention ofmigraine, potentially by inhibition of trigeminal autonomicsignaling. A phase IIa randomized double-blind placebo-controlled study that aims to evaluate the efficacy and safetyof AMG 301 in migraine prevention is currently underway(NCT03238781).
6.4. Unresolved questions from previous clinical trials
6.4.1. Nitric oxide synthaseNitric oxide synthases (NOS) are a family of enzymes catalyzingthe production of nitric oxide (NO) from L-arginine. Nitricoxide is a gaseous molecule which involved in a variety offunctions including endothelial-dependent vasodilation,neural signaling, and development. Nitric oxide is producedin mammals by the endothelial (eNOS) and neuronal (nNOS),while the inducible isoform, iNOS produces NO as an immuneresponse. NO donors are known to induce a delayed migraineattack in a portion of migraine patients and are used for theexperimental induction of migraines [102]. NO donors arewidely used in animal models of migraine and have beenshown to induce fos activation in many migraine-relatedareas, including the TCC, brainstem, and hypothalamus [103].Hence, the development of selective NOS inhibitors has beensuggested as an emerging therapy for migraine [104].
Research has focused on other specific NOS inhibitors, withthe initial study of a specific iNOS inhibitor GW274150 failingto reach its clinical end point in both an acute and preventive
10 G. LAMBRU ET AL.
study [105]. A mixed triptan and nNOS inhibitor NXN-188 wasalso found to be ineffective in both migraine without aura andspecifically in the aura phase [106]. The question abouta possible effect of a specific nNOS inhibitor remainsunresolved.
On the other hands the role of peripherally produced NO asa therapeutic agent is currently investigated in a clinical trialusing B244- ammonia-oxidizing bacteria (AOB). AOB isa naturally occurring type of nitrifying bacteria that metabolizethe ammonia found in sweat, creating nitrite and nitric oxide[107]. In an ongoing a randomized, vehicle-controlled, double-blind, phase II study the safety, tolerability, and efficacy ofB244 delivered as an intranasal spray is tested for preventivetreatment in subjects with an episodic migraine(NCT03488563). The hypothesis that is being tested is thatby increasing local and systemic NO levels, this bacteria exertan anti-inflammatory effect that may have a potential thera-peutic effect in migraine.
6.4.2. Orexin receptorsOrexin A and B are neuropeptides that are synthesized in thehypothalamus and thought to play a role in nociception. Theyexhibit their action by activating their receptors orexin 1 (OX1)and orexin 2 (OX2). In an animal models of trigeminovascularactivation, activation of the OX1 and OX2 receptor in theposterior hypothalamus has been shown to differentially mod-ulate nociceptive dural input to the TNC [108]. Activation ofthe OX1 receptor was found to elicit an anti-nociceptive effectwhereas OX2 receptor activation elicits a pro-nociceptiveeffect. Filorexant, is a dual OX1 and OX2 receptor antagonistwhich was originally developed to treat insomnia [109] andwas found to have some effect in animal models of migraine[110]. In a phase IIa trial for the prophylaxis of migraine,Filorexant was found to be ineffective [111]. It remains to beevaluated though if a more specific OX2 receptor antagonist ora specific OX1 agonist will have different outcomes in migraineprevention.
6.4.3. Glutamate receptor antagonistsGlutamate is the main excitatory neurotransmitter of the ner-vous system and the neurotransmitter that manifest transmis-sion from primary trigeminal neurons to second-order neuronsin the TCC, along the ascending trigeminothalamic pathwayand from third order thalamic neurons to the cortex. Glutamateis implicated in many aspects of migraine pathophysiology,including trigeminovascular activation, central sensitization,and CSD [112]. Glutamate exhibits it actions on ionotropicglutamate receptors, namely: N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA),and kainite, and metabotrobic glutamate receptors (mGLuR),namely: mGluR1-8. Antagonizing glutamate transmission alongthe ascending trigeminovascular-trigeminothalamic pathwayswould have been an ideal treatment for migraine. However,blockade of central glutamatergic transmission can have tre-mendous results for the brain.
Small clinical trials using specific glutamate receptorantagonists, that do not antagonise the main ionotropicreceptors NMDA and AMPA, aimed to investigate their efficacyin an acute migraine. Such treatments could offer a non-
narcotic, non-vascular approach to the management of head-ache pain and represent a potentially promising alternative tocurrent migraine treatments. Tezampanel (LY293558) wasa small molecule initially developed against the GluK5 subunitof the kainite receptor, although further studies demonstratedan additional competitive action for the AMPA receptor [113].Preclinical studies have demonstrated a role for kainate recep-tor in migraine pathophysiology and selective antagonists inthe trigeminovascular model were shown to suppress trigemi-novascular stimulation [114]. In a placebo and active-controlled phase II trial in patients with acute migraine, thecompound, administered intravenously, achieved statisticalsignificance in all primary and secondary endpoints whichincluded pain relief at two hours and relief of nausea, photo-phobia, and phonophobia. Tezampanel demonstrated anattractive safety and pharmacokinetic profile [113].Unfortunately, no further developments were carried on withthis molecule or other kainite receptor-specific antagonists,although this is an avenue worth exploring further.
ADX10059 was an mGluR5 negative allosteric modulatorused in a small clinical trial for the acute treatment ofa migraine. The primary efficacy endpoint for the clinicaltrial, 2 h pain-free, demonstrated a significant effect ofADX10059 375 mg, 17%, versus placebo, 5%, with transientdizziness being the most common treatment-emergent eventin about half the patients [115]. ADX10059 was also used ina phase II randomized, double-blind, placebo-controlled studyfor the prevention of a migraine. However, the study wasterminated early following the emergence of a higher thanexpected rate of liver enzyme abnormalities [116]. TargetingmGluRs was thought to be a more safe approach to blockingglutamate in the CNS. Although mGluR5 did not meet thisexpectation, positive allosteric modulators against othermGluRs may have a therapeutic value for migraine thatremains to be investigated [117].
6.5. Future targets for emerging treatments
6.5.1. The tryptophan-kynurenic pathwayAn increasing number of preclinical studies highlight theimportance of the kynurenine pathway in the pathophysiol-ogy of migraine [118]. The tryptophan-kynurenic pathway isthe second most prevalent metabolic pathway of tryptophanand accounts for approximately 90% of tryptophan catabo-lism, with the synthesis of the synthesis of 5HT to account forthe metabolism of ~3% or less of non-protein tryptophan[119]. Major components of the pathway – quinolinic acidand kynurenic acid – were shown to act on NMDA receptors,with quinolinic acid having an excitatory action and kynurenicacid being an antagonist of ionotropic glutamate recep-tors [120].
A number of preclinical studies implicated the kynurenicpathway in the nociceptive activation of the trigeminal sys-tem. Administration of nitroglycerine, which induces migraineto patients, sensitizes the trigeminal system of animal and wasshown to downregulate a number of enzymes of the kynure-nic pathway, with a potential influence on the glutamatergicsystem [121]. Pre-treatment with kynurenic acid was shown toprevent the nitroglycerine-induced neuronal activation and
EXPERT OPINION ON EMERGING DRUGS 11
sensitization in the TCC in rodents [122]. In the same model,the kynurenic acid analog 1 was shown to suppress nitrogly-cerine-induce hyperalgesia and to suppress the increasedlevels of CGRP, nNOS, and cytokines in the trigeminal system[123,124]. Kynurenic acid and its derivatives have been alsoshown to suppress nociceptive activation of the trigeminalpathway [125–128], and to reduce the release of glutamate,the excitatory neurotransmitter that drives activation of theascending trigeminothalamic pathway [125].
Recent studies in CM patients found altered serum levels ofall kynurenine metabolites [129]. Of interest, altered serumlevels of kynurenine metabolites were also found in clusterheadache patients [130]. Further studies for the potentialutilization of the kynurenine pathway in the treatment ofmigraine may open new therapeutic perspectives.
6.5.2. CannabinoidsCannabinoids may have therapeutic use in pain and may alsohave a role in the treatment of migraine. There are two clonedcannabinoid receptors the cannabinoid receptor 1 (CB1) ispresent on neurons in the peripheral and central nervoussystem, while the CB2 receptor is found predominantly inimmune cells [131,132]. CB1-immunoreactive neurons arefound in the trigeminal ganglia and TCC [133]. In animalmodels of migraine endogenous cannabinoids and cannabi-noid agonists have an inhibitory effect on trigeminovascularactivation through the cannabinoid receptor 1 (CB1) [134].
Very few studies exist on the potential role for the canna-binoid system in migraine. CB1 binding was shown to beincreased interictally in female migraine patients [135], whilevariations in the CB1 CNR1 gene were suggested to predis-pose to migraine [136]. Despite the lack of solid evidence forthe potential role of CB1 in migraine pathophysiology, manyindividuals are currently using cannabis for the treatment ofmigraine with positive results [137]. Currently, there is notenough evidence from well-designed clinical trials to supportthe use of cannabis for headache, but there are sufficientanecdotal and preliminary results, as well as plausible neuro-biological mechanisms, to warrant properly designed clinicaltrials. Such trials are needed to determine short- and long-term efficacy for specific headache types, compatibility withexisting treatments, optimal administration practices, as wellas potential risks.
6.5.3. Advanced botulinum toxin moleculesBoNTA is an approved treatment with established efficacy inmigraine prevention [138–140]. Its limitations include its toxi-city and the unwanted muscle paralysis that limit a potentiallyhigher dose-effect. Finding a potentially better injections-paradigm has been suggested as a new way forward in advan-cing its clinical outcomes and currently a clinical trial is under-way to investigate the effect of 90U of BoNTA injected alongthe skull sutures (NCT03543254), where trigeminal fibers maybe exiting the skull [141].
However, the field of BoNT engineering has progressedsignificantly in recent years. A number of approaches havebeen used in the engineering of novel BoNT molecules. Such
approaches include among others, recombining of the BoNTAprotein domains, creating of BoNTA/E chimeras, chimera pro-teins that incorporate the endopeptidase and translocationdomains of BoNTA combined with targeting binding ligand[142,143].
Senrebotase (AGN-214868) was a retargeted endopepti-dase with a synthetic nociceptin receptor-binding BoNT mole-cule which was used in clinical trials for painful overactivebladder and post-herpetic neuropathy. The trials ended earlierdue to the lack of statistically significant differences in thelong-term observations. Although no attempts have beenmade in studying advanced BoNT molecules in clinical trialsof migraine, an increasing number of data now suggests anemerging role for such molecules in migraine treatment.
BiTox is the first synthetic recombinant BoNTA chimera thatappears to lack paralytic effects, while it suppresses trigeminalactivation in animal models of migraine [144,145]. BiTox hasbeen also shown to attenuate inflammatory mediators in ani-mal models of inflammatory pain [146]. In the pain field otheradvanced BoNT molecules have been tested with significantoutputs. Using the BoNTA binding domain as a delivery vehi-cle to selected cell populations has very recently shown to bean exciting new avenue in the field of pain. A dermorphin-botulinum and a SP-botulinum constructs have been shown totarget pain-processing neurons in the dorsal horn uponintrathecal application and to suppress chronic pain in animalmodels [147]. Dolly et all, produced a recombinant BoNTA/Echimera by attaching the BoNTE protease moiety to an enzy-matically inactive mutant of BoNTA. The resultant molecule isa long-acting superior inhibitor of motor neuron and C-fibre-mediated transmission. In vivo, local injection of this recombi-nant BoNTA/E molecule resulted in extended amelioration ofinflammatory pain [142].
7. Conclusion
There is a vast unmet need in the current migraine treat-ment options that can be summarised into efficacy, toler-ability issues and lack of migraine-specific treatmentsbesides the triptans. This review summarises the currentunderstanding of the pathophysiological mechanismsknown to be relevant targets for the development ofnovel migraine treatments. A multitude of abortive andpreventive migraine-specific treatments are currently inadvanced stages of their development. The positive phaseIII trials results for CGRP receptor antagonist Ubrogepantand 5-HT1F receptor agonist lasmiditan, suggest that thesetreatments may be available in the near future in triptansnonresponders or in those category of patients in whomtriptans are contraindicated. Some of the anti-CGRP mono-clonal antibodies have already been approved by the FDAand the EMA and currently used in some Countries asmigraine preventive treatments (Tables 3 and 4). Thesetreatments could dramatically improve the way migrainehas been managed so far, besides promoting new researchin the development of further antibodies against otherrelevant targets such as PACAP.
12 G. LAMBRU ET AL.
8. Expert opinion
The migraine field has recently been experiencing an explo-sion of novel, specifically-designed acute and preventive treat-ments, reflecting advances in the understanding of thisdisorder and better acknowledgement of its global detrimen-tal impact on sufferers’ quality of lives.
The chemically modified CGRP receptor antagonistUbrogepant seems to overcome the disappointing safety issuesthat stopped this class of medication from further develop-ment. Along with selective 5-HT1F agonist Lasmitidan, boththese novel compound could play a role in the future of acutemigraine treatments as an alternative to triptans in triptansnon-responders or in those in whom triptans are contraindi-cated or not tolerated. Future studies in patients with cardio-
vascular comorbidities are necessary to determine the benefitof the lack of arterial tone modulation, mechanism, that distin-guishes these novel medications from the triptans.
Themost promisingdata come from the anti-CGRPmonoclonalantibodies. All phase II and III trials performed have shown con-sistent superiority to placebo. Beside remarkable efficacy out-comes, this class of medication seems to offer a fast onset ofmigraine frequency reduction, along with potentially cumulativebenefit overtime, at least according to some initial evidence.Further meaningful findings that emerged from published trialshighlight the high adherence to treatment, alongwith the efficacyof different injections regimens. No particular issues in terms ofsafety and tolerability have emerged as confirmed by the very lowdropout rates shown across the clinical trials. Their excellent
tolerability profiles seem to be one of the major advantages com-pared to the established oral preventive treatments currently usedinmigraine. One of the problemswith the use ofmAbsmay be thelong-term risk effect in women of childbearing age, given theirlonger half-life. The use of an oral CGRP receptor antagonist likeatogepant may overcome this issue.
Future studies should concentrate on long-term preventiveefficacy and safety of these treatments. Indeed the risk of long-term blockade of CGRP signaling is unknown [148]. Furthermorestudies in challenging-to-treat migraine patients are needed toestablish whether the promising results showed in clinical trialenvironment, will be replicated in real-life patients.
Although, the anti-CGRP treatments are not the cure formigraine, they have undoubtedly stimulated further researchinto different migraine targets that could be inhibited by specifi-cally designed antibodies. This will hopefully facilitate the devel-opment of treatments for those patients who currently do notrespond to treatments targeting the CGRP pathway.
Funding
This paper was not funded.
Declaration of interest
P Martelletti has received research and educational funds, travel grants orfees for advisory board participation from: Teva, Allergan, Novartis,
ElectroCore, Springer, Amgen and Daiichi Sankyo. G Lambru has receivedresearch and educational funds, travel grants or fees for advisory boardparticipation from: Allergan, Novartis and Autonomic Technologies.A P Andreou has received honoraria from Allergan for consultanciesadvisory board participation and delivering education presentations. Shehas also received a research grant from eNeuro. The authors have no otherrelevant affiliations or financial involvement with any organization orentity with a financial interest in or financial conflict with the subjectmatter or materials discussed in the manuscript apart from thosedisclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or otherrelationships to disclose.
ORCID
Paolo Martelletti http://orcid.org/0000-0002-6556-4128
References
Papers of special note have been highlighted as either of interest (•) or ofconsiderable interest (••) to readers.
1. Robbins MS, Lipton RB. The epidemiology of primary headachedisorders. Semin Neurol. 2010;30(2):107–119.
2. Lipton RB, Bigal ME, Diamond M, et al. Migraine prevalence, diseaseburden, and the need for preventive therapy. Neurology. 2007;68(5):343–349.
10. Evers S, Marziniak M. Clinical features, pathophysiology, and treat-ment of medication-overuse headache. Lancet Neurol. 2010;9(4):391–401.
11. Lionetto L, Negro A, Palmisani S, et al. Emerging treatment forchronic migraine and refractory chronic migraine. Expert OpinEmerg Drugs. 2012;17(3):393–406.
12. Zeeberg P, Olesen J, Jensen R. Discontinuation of medication over-use in headache patients: recovery of therapeutic responsiveness.Cephalalgia. 2006;26(10):1192–1198.
14. Diener HC, Limmroth V. Advances in pharmacological treatment ofmigraine. Expert Opin Investig Drugs. 2001;10(10):1831–1845.
15. Loder E. Triptan therapy in migraine. N Engl J Med. 2010;363(1):63–70.
16. Amin FM, Hougaard A, Cramer SP, et al. Increased brainstem perfu-sion, but no blood-brain barrier disruption, during attacks withoutaura. A 3T DCE. Eur J Neurol. 2017;24(9):1116–1124.
17. Hepp Z, Dodick DW, Varon SF, et al. Adherence to oralmigraine-preventive medications among patients with chronicmigraine. Cephalalgia. 2015;35(6):478–488.
18. Aurora SK, Dodick DW, Turkel CC, et al. OnabotulinumtoxinA fortreatment of chronic migraine: results from the double-blind, ran-domized, placebo-controlled phase of the PREEMPT 1 trial.Cephalalgia. 2010;30(7):804–814.
19. Diener HC, Dodick DW, Aurora SK, et al. OnabotulinumtoxinA fortreatment of chronic migraine: results from the double-blind, ran-domized, placebo-controlled phase of the PREEMPT 2 trial.Cephalalgia. 2010;30(7):793–803.
20. Andreou AP, Trimboli M, Al-Kaisy A, et al. Prospective real-worldanalysis of OnabotulinumtoxinA in chronic migraine post-NationalInstitute for Health and Care Excellence UK technology appraisal.Eur J Neurol. 2018;25(8):1069–e1083.
21. Martelletti P, Katsarava Z, Lampl C, et al. Refractory chronicmigraine: a consensus statement on clinical definition from theEuropean Headache Federation. J Headache Pain. 2014 Aug;28(15):47.
22. Palmisani S, Al-Kaisy A, Arcioni R, et al. A six year retrospectivereview of occipital nerve stimulation practice-controversies andchallenges of an emerging technique for treating refractory head-ache syndromes. J Headache Pain. 2013;6:14–67.
23. Miller S, Watkins L, Matharu M. Long-term outcomes of occipitalnerve stimulation for chronic migraine: a cohort of 53 patients.J Headache Pain. 2016;17(1):68.
24. Lipton R, Goadsby PJ, Cady R, et al. PRISM study: occipital nervestimulation for treatment-refractory migraine. Cephalalgia. 2009;29(Suppl 1):30.
25. Saper JR, Dodick DW, Silberstein SD, et al. Occipital nerve stimula-tion for the treatment of intractable chronic migraine headache:ONSTIM feasibility study. Cephalalgia. 2011;31(3):271–285.
26. Silberstein SD, Dodick DW, Saper J, et al. Safety and efficacy ofperipheral nerve stimulation of the occipital nerves for the man-agement of chronic migraine: results from a randomized, multi-center, double-blinded, controlled study. Cephalalgia. 2012;32(11):1165–1179.
27. Oshinsky ML, Murphy AL, Hekierski H, et al. Noninvasive vagusnerve stimulation as treatment for trigeminal allodynia. Pain.2014;155(5):1037–1042.
28. Andreou AP, Holland PR, Akerman S, et al. Transcranial magneticstimulation and potential cortical and trigeminothalamic mechan-isms in migraine. Brain. 2016;139(Pt 7):2002–2014.
30. Trimboli M, Al-Kaisy A, Andreou AP, et al. Non-invasive vagus nervestimulation for the management of refractory primary chronicheadaches: a real-world experience. Cephalalgia. 2018;38(7):1276–1285.
31. Starling AJ, Tepper SJ, Marmura MJ, et al. A multicenter, prospec-tive, single arm, open label, observational study of sTMS formigraine prevention (ESPOUSE Study). Cephalalgia. 2018;38(6):1038–1048.
32. Denuelle M, Fabre N, Payoux P, et al. Hypothalamic activation inspontaneous migraine attacks. Headache. 2007;47(10):1418–1426.
33. Maniyar FH, Sprenger T, Monteith T, et al. Brain activations in thepremonitory phase of nitroglycerin-triggered migraine attacks.Brain. 2014;137(Pt 1):232–241.
34. Schulte LH, Allers A, May A. Visual stimulation leads to activation ofthe nociceptive trigeminal nucleus in chronic migraine. Neurology.2018;90(22):e1973–e1978.
35. Schulte LH, May A. The migraine generator revisited: continuousscanning of the migraine cycle over 30 days and three sponta-neous attacks. Brain. 2016;139(Pt 7):1987–1993.
36. Schulte LH, May A. Of generators, networks and migraine attacks.Curr Opin Neurol. 2017;30(3):241–245.
37. Bartsch T, Goadsby PJ. Stimulation of the greater occipital nerveinduces increased central excitability of dural afferent input. Brain.2002;125(Pt 7):1496–1509.
38. Edvinsson L, Goadsby PJ. Neuropeptides in the cerebral circulation:relevance to headache. Cephalalgia. 1995;15(4):272–276.
39. Goadsby P, Charbit A, Andreou AP, et al. Neurobiology of migraine.Neuroscience. 2009;161(2):327–341.
40. Akerman S, Holland PR, Goadsby PJ. Diencephalic and brainstemmechanisms in migraine. Nat Rev Neurosci. 2011;12(10):570–584.
41. Olesen J, Larsen B, Lauritzen M. Focal hyperemia followed byspreading oligemia and impaired activation of rCBF in classicmigraine. Ann Neurol. 1981;9(4):344–352.
42. Leão AA. Pial circulation and spreading depression of activity in thecerebral cortex. J Neurophysiol. 1944;7:391–396.
43. Do Carmo RJ, Martins-Ferreira H. Glutamate-K+ interactions withrelation to spreading cortical depression [proceedings]. An AcadBras Cienc. 1979;51(3):579.
44. Lauritzen M, Hansen AJ. The effect of glutamate receptor blockadeon anoxic depolarization and cortical spreading depression.J Cereb Blood Flow Metab. 1992;12(2):223–229.
45. Zhang X, Levy D, Kainz V, et al. Activation of central trigeminovas-cular neurons by cortical spreading depression. Ann Neurol.2011;69(5):855–865.
46. Andreou AP, Sprenger T, Goadsby PJ. Cortical modulation of tha-lamic function during cortical spreading depression- Unravelinga new central mechanism involved in migraine aura. J HeadachePain. 2013;14:16.
47. Freitag FG. Divalproex in the treatment of migraine.Psychopharmacol Bull. 2003;37(Suppl 2):98–115.
48. Palermo A, Fierro B, Giglia G, et al. Modulation of visual cortexexcitability in migraine with aura: effects of valproate therapy.Neurosci Lett. 2009;467(1):26–29.
49. Inaba M, Nishizawa Y, Morii H. Tissue distribution and physiologicrole of calcitonin and CGRP. Nihon Rinsho. 1990;48(5):1011–1015.
50. Lawson SN, Crepps B, Perl ER. Calcitonin gene-related peptideimmunoreactivity and afferent receptive properties of dorsal rootganglion neurones in guinea-pigs. J Physiol. 2002;540(Pt3):989–1002.
51. Moreno MJ, Cohen Z, Stanimirovic DB, et al. Functional calcitoningene-related peptide type 1 and adrenomedullin receptors in
human trigeminal ganglia, brain vessels, and cerebromicrovascularor astroglial cells in culture. J Cereb Blood Flow Metab. 1990;19(11):1270–1278.
52. Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release inthe extracerebral circulation of humans during migraine headache.Ann Neurol. 1990;28:183±187.
53. Tvedskov JF, Lipka K, Ashina M, et al. No increase of calcitoningene-related peptide in jugular blood during migraine. Ann Neurol.2005;58(4):561–568.
54. Hansen JM, Hauge AW, Olesen J, et al. Calcitonin gene-relatedpeptide triggers migraine-like attacks in patients with migrainewith aura. Cephalalgia. 2010;30(10):1179–1186.
55. Hansen JM, Thomsen LL, Olesen J, et al. Calcitonin gene-relatedpeptide does not cause the familial hemiplegic migrainephenotype. Neurology. 2008;71(11):841–847.
56. Mathew R, Andreou AP, Chami LA, et al. Immunohistochemicalcharacterization of calcitonin gene-related peptide in the trigem-inal system of the familial hemiplegic migraine 1 knock-in mouse.Cephalalgia. 2011;31(13):1368–1380.
57. Williamson DJ, Shepheard SL, Hill RG, et al. The novel anti-migraineagent rizatriptan inhibits neurogenic dural vasodilation andextravasation. Eur J Pharmacol. 1997;328(1):61–64.
58. Durham PL, Russo AF. Regulation of calcitonin gene-related pep-tide secretion by a serotonergic antimigraine drug. J Neurosci.1999;19(9):3423–3429.
59. Biella G, Panara C, Pecile A, et al. Facilitatory role of calcitoningene-related peptide (CGRP) on excitation induced by substanceP (SP) and noxious stimuli in rat spinal dorsal horn neurons. Aniontophoretic study in vivo. Brain Res. 1991;559(2):352–356.
60. Olesen J, Diener HC, Husstedt IW, et al. Calcitonin gene--relatedpeptide receptor antagonist BIBN 4096 BS for the acute treatmentof migraine. N Engl J Med. 2004;350:1104–1110.
61. Ho TW, Mannix LK, Fan X, et al. Randomized controlled trial of anoral CGRP receptor antagonist, MK-0974, in acute treatment ofmigraine. Neurology. 2008;70:1304–1312.
62. Ho TW, Ferrari MD, Dodick DW, et al. Efficacy and tolerability ofMK-0974 (telcagepant), a new oral antagonist of calcitoningene-related peptide receptor, compared with zolmitriptan foracute migraine: a randomised, placebo-controlled,parallel-treatment trial. Lancet. 2008;372:2115–2123.
63. Ho TW, Connor KM, Zhang Y, et al. Randomized controlled trial ofthe CGRP receptor antagonist telcagepant for migraine prevention.Neurology. 2014;83:958–966.
64. Hewitt DJ, Aurora SK, Dodick DW, et al. Randomized controlled trialof the CGRP receptor antagonist MK-3207 in the acute treatment ofmigraine. Cephalalgia. 2011;31:712–722.
65. Diener HC, Barbanti P, Dahlöf C, et al. BI 44370 TA, an oral CGRPantagonist for the treatment of acute migraine attacks: results froma phase II study. Cephalalgia. 2011;31:573–584.
66. Voss T, Lipton RB, Dodick DW. A phase IIb randomized,double-blind, placebo-controlled trial of ubrogepant for the acutetreatment of migraine. Cephalalgia. 2016;36(9):887–898.
67. Marcus R, Goadsby PJ, Dodick D, et al. BMS-927711 for the acutetreatment of migraine: a double-blind, randomized, placebo con-trolled, dose-ranging trial. Cephalalgia. 2014;34:114–125.
68. Zeller J, Poulsen KT, Sutton JE, et al. CGRP function-blocking anti-bodies inhibit neurogenic vasodilatation without affecting heartrate or arterial blood pressure in the rat. Br J Pharmacol. 2008;155(7):1093–1103.
69. Sun H, Dodick DW, Silberstein S, et al. Safety and efficacy of AMG334 for prevention of episodic migraine: a randomised,double-blind, placebo controlled, phase 2 trial. Lancet Neurol.2016;15(4):382–390.
70. Goadsby PJ, Reuter U, Hallstrom Y, et al. A controlled trial of erenumabfor episodic migraine. N Engl J Med. 2017;377(22):2123–2132.
• One of the pivotal studies demonstrating efficacy of Erenumabin episodic migraine.
71. Dodick DW, Ashina M, Brandes JL, et al. ARISE: a Phase III rando-mized trial of erenumab for episodic migraine. Cephalalgia. 2018;38(6):1026–1037.
72. Ashina M, Dodick D, Goadsby PJ, et al. Erenumab (AMG 334) inepisodic migraine: interim analysis of an ongoing open-label study.Neurology. 2017;89(12):1237–1243.
73. Tepper S, Ashina M, Reuter U, et al. Safety and efficacy of erenu-mab for preventive treatment of chronic migraine: a randomised,double-blind, placebo-controlled phase II trial. Lancet Neurol.2017;16(6):425–434.
74. Dodick DW, Goadsby PJ, Spierings EL, et al. Safety and efficacy ofLY2951742, a monoclonal antibody to calcitonin gene-related peptide,for the prevention of migraine: a phase 2, randomised, double-blind,placebo-controlled study. Lancet Neurol. 2014;13(9):885–892.
• Important study demonstrating efficacy of LY2951742 in epi-sodic migraine.
75. Skljarevski V, Oakes TM, Zhang Q. Effect of different doses ofGalcanezumab vs Placebo for episodic migraine prevention:a randomized clinical trial. JAMA Neurol. 2018;75(2):187–193.
76. Stauffer VL, Dodick DW, Zhang Q, et al. Evaluation of Galcanezumabfor the prevention of episodic migraine: the EVOLVE-1 randomizedclinical trial. JAMA Neurol. 2018;75(9):1080–1088.
77. Skljarevski V, Matharu M, Millen BA, et al. Efficacy and safety ofgalcanezumab for the prevention of episodic migraine: results ofthe EVOLVE-2 phase 3 randomized controlled clinical trial.Cephalalgia. 2018;38(8):1442–1454.
78. Bigal ME, Dodick DW, Rapoport AM, et al. Safety, tolerability, andefficacy of TEV-48125 for preventive treatment of high-frequency epi-sodic migraine: a multicentre, randomised, double-blind, placebo- con-trolled, phase 2b study. Lancet Neurol. 2015;14:1081–1090.
• Study demonstrating efficacy of Fremanezumab in episodicmigraine.
79. Dodick DW, Silberstein SD, Bigal ME. Effect of fremanezumab com-pared with placebo for prevention of episodic migraine:a randomized clinical trial. JAMA. 2018 15;319(19):1999–2008.
80. Bigal ME, Dodick DW, Krymchantowski AV, et al. TEV-48125 for thepreventive treatment of chronic migraine: efficacy at early timepoints. Neurology. 2016 5;87(1):41–48.
81. Silberstein SD, Dodick DW, Bigal ME, et al. Fremanezumab for thepreventive treatment of chronic migraine. N Engl J Med. 201730;377(22):2113–2212.
• Study demonstrating efficacy of Fremanezumab in chronicmigraine.
82. Dodick DW, Goadsby PJ, Silberstein SD, et al. Safety and efficacy ofALD403, an antibody to calcitonin gene-related peptide, for theprevention of frequent episodic migraine: a randomised,double-blind, placebo- controlled, exploratory phase 2 trial.Lancet Neurol. 2014;13:1100–1107.
• Study demonstrating the safety and efficacy of the only anti-CGRP monoclonal Ab administered intravenously.
83. Bruinvels AT, Landwehrmeyer B, Gustafson EL, et al. Localization of5-HT1B, 5-HT1D alpha, 5-HT1E and 5-HT1F receptor messengerRNA in rodent and primate brain. Neuropharmacology. 1994;33(3–4):367–386.
84. Johnson KW, Schaus JM, Durkin MM. 5-HT1F receptor agonists inhibitneurogenic dural inflammation in guinea pigs. Neuroreport.1997;8:2237–2240.
85. Goldstein DJ, Roon KI, Offen WW, et al. Selective serotonin 1F (5-HT(1F)) receptor agonist LY334370 for acute migraine: a randomisedcontrolled trial. Lancet. 2001;358:1230–1234.
86. Ferrari MD, Färkkilä M, Reuter U, et al. Acute treatment of migrainewith the selective 5-HT1F receptor agonist lasmiditan–a rando-mised proof-of-concept trial. Cephalalgia. 2010;30:1170–1178.
87. Färkkilä M, Diener HC, Géraud G, et al. Efficacy and tolerability oflasmiditan, an oral 5-HT(1F) receptor agonist, for the acute treatmentof migraine: a phase 2 randomised, placebo-controlled,parallel-group, dose-ranging study. Lancet Neurol. 2012;11:405–413.
88. Tuka B, Helyes Z, Markovics A, et al. Alterations in PACAP-38-likeimmunoreactivity in the plasma during ictal and interictal periodsof migraine patients. Cephalalgia. 2013;33(13):1085–1095.
89. Edvinsson L. PACAP and its receptors in migraine pathophysiology:commentary on Walker et al., Br J Pharmacol 171: 1521-1533. BrJ Pharmacol. 2015;172(19):4782–4784.
16 G. LAMBRU ET AL.
90. Edvinsson L, Tajti J, Szalardy L, et al. PACAP and its role in primaryheadaches. J Headache Pain. 2018;19(1):21.
• Important paper summarising the potential therapeutic role oftreatment targeting PACAP in primary headaches.
91. Eftekhari S, Salvatore CA, Johansson S, et al. Localization of CGRP,CGRP receptor, PACAP and glutamate in trigeminal ganglion.Relation to the blood-brain barrier. Brain Res. 2015;1600:93–109.
92. Eftekhari S, Warfvinge K, Blixt FW, et al. Differentiation of nervefibers storing CGRP and CGRP receptors in the peripheral trigemi-novascular system. J Pain. 2013;14(11):1289–1303.
93. Palkovits M, Somogyvari-Vigh A, Arimura A. Concentrations ofpituitary adenylate cyclase activating polypeptide (PACAP) inhuman brain nuclei. Brain Res. 1995;699(1):116–120.
94. Uddman R, Tajti J, Moller S, et al. Neuronal messengers and peptidereceptors in the human sphenopalatine and otic ganglia. Brain Res.1999;826(2):193–199.
95. Markovics A, Kormos V, Gaszner B, et al. Pituitary adenylatecyclase-activating polypeptide plays a key role in nitroglycerol-induced trigeminovascular activation in mice. Neurobiol Dis. 2012;45(1):633–644.
97. Gazerani P, Cairns BE. New insight in migraine pathogenesis:vasoactive intestinal peptide (VIP) and pituitary adenylatecyclase-activating polypeptide (PACAP) in the circulation aftersumatriptan. Scand J Pain. 2013;4(4):208–210.
98. Cernuda-Morollon E, Riesco N, Martinez-Camblor P, et al. Nochange in interictal PACAP levels in peripheral blood in womenwith chronic migraine. Headache. 2016;56(9):1448–1454.
99. Körtési T, Tuka B, Tajti J, et al. Kynurenic acid inhibits the electricalstimulation induced elevated pituitary adenylate cyclase-activatingpolypeptide expression in the TNC. Front Neurol. 2018;16(8):745.
100. Guo S, Vollesen AL, Hansen RD, et al. Part I: pituitary adenylatecyclase-activating polypeptide-38 induced migraine-like attacks inpatients with and without familial aggregation of migraine.Cephalalgia. 2017;37(2):125–135.
101. Hansen JM, Sitarz J, Birk S, et al. Vasoactive intestinal polypeptideevokes only a minimal headache in healthy volunteers.Cephalalgia. 2006;26(8):992–1003.
102. Iversen HK, Olesen J, Tfelt-Hansen P. Intravenous nitroglycerin asan experimental model of vascular headache. Basic characteristics.Pain. 1989;38(1):17–24.
103. Andreou AP, Summ O, Charbit AR, et al. Animal models of head-ache: from bedside to bench and back to bedside. Expert RevNeurother. 2010;10(3):389–411.
104. Lassen LH, Ashina M, Christiansen I, et al. Nitric oxide synthaseinhibition in migraine. Lancet. 1997;349(9049):401–402.
105. Hoivik HO, Laurijssens BE, Harnisch LO, et al. Lack of efficacy of theselective iNOS inhibitor GW274150 in prophylaxis of migraineheadache. Cephalalgia. 2010;30(12):1458–1467.
106. Hougaard A, Hauge AW, Guo S, et al. The nitric oxide synthaseinhibitor and serotonin-receptor agonist NXN-188 during the auraphase of migraine with aura: a randomized, double-blind,placebo-controlled cross-over study. Scand J Pain. 2013;4(1):48–52.
107. Jones ML, Ganopolsky JG, Labbe A, et al. Antimicrobial propertiesof nitric oxide and its application in antimicrobial formulations andmedical devices. Appl Microbiol Biotechnol. 2010;88(2):401–407.
108. Bartsch T, Levy MJ, Knight YE, et al. Differential modulation of noci-ceptive dural input to [hypocretin] orexin A and B receptor activationin the posterior hypothalamic area. Pain. 2004;109(3):367–378.
109. Connor KM, Mahoney E, Jackson S, et al. A phase II dose-rangingstudy evaluating the efficacy and safety of the orexin receptorantagonist filorexant (MK-6096) in patients with primaryinsomnia. Int J Neuropsychopharmacol. 2016;19:8.
110. Hoffmann J, Supronsinchai W, Akerman S, et al. Evidence for orex-inergic mechanisms in migraine. Neurobiol Dis. 2015;74:137–143.
111. Chabi A, Zhang Y, Jackson S, et al. Randomized controlled trial ofthe orexin receptor antagonist filorexant for migraine prophylaxis.Cephalalgia. 2015;35(5):379–388.
112. Andreou AP, Goadsby PJ. Therapeutic potential of novel glutamatereceptor antagonists in migraine. Expert Opin Investig Drugs.2009;18(6):789–803.
113. Sang CN, Ramadan NM, Wallihan RG, et al. LY293558, a novelAMPA/GluR5 antagonist, is efficacious and well-tolerated in acutemigraine. Cephalalgia. 2004;24(7):596–602.
114. Andreou AP, Holland PR, Goadsby PJ. Activation of iGluR5 kainatereceptors inhibits neurogenic dural vasodilatation in an animalmodel of trigeminovascular activation. Br J Pharmacol. 2009;157(3):464–473.
115. Waung MW, Akerman S, Wakefield M, et al. Metabotropic gluta-mate receptor 5: a target for migraine therapy. Ann Clin TranslNeurol. 2016;3(8):560–571.
116. Chan K, MaassenVanDenBrink A. Glutamate receptor antagonists inthe management of migraine. Drugs. 2014;74(11):1165–1176.
117. Blanco MJ, Benesh DR, Knobelsdorf JA, et al. Discovery of dualpositive allosteric modulators (PAMs) of the metabotropic gluta-mate 2 receptor and CysLT1 antagonists for treating migraineheadache. Bioorg Med Chem Lett. 2017;27(2):323–328.
118. Curto M, Lionetto L, Fazio F, et al. Fathoming the kynureninepathway in migraine: why understanding the enzymatic cascadesis still critically important. Intern Emerg Med. 2015;10(4):413–421.
119. Stone TW, Darlington LG. Endogenous kynurenines as targets fordrug discovery and development. Nat Rev Drug Discov. 2002;1(8):609–620.
120. Stone TW, Perkins MN. Quinolinic acid: a potent endogenous exci-tant at amino acid receptors in CNS. Eur J Pharmacol. 1981;72(4):411–412.
121. Nagy-Grócz G, Laborc KF, Veres G, et al. The effect of systemicnitroglycerin administration on the kynurenine pathway in the rat.Front Neurol. 2017;14(8):278.
122. Fejes-Szabó A, Bohár Z, Vámos E, et al. Pre-treatment with newkynurenic acid amide dose-dependently prevents thenitroglycerine-induced neuronal activation and sensitization in cer-vical part of trigemino-cervical complex. J Neural Transm (Vienna).2014;121(7):725–738.
123. Greco R, Demartini C, Zanaboni AM, et al. Effects of kynurenic acidanalogue 1 (KYNA-A1) in nitroglycerin-induced hyperalgesia: tar-gets and anti-migraine mechanisms. Cephalalgia. 2017;37(13):1272–1284.
124. Vámos E, Fejes A, Koch J, et al. Kynurenate derivative attenuatesthe nitroglycerin-induced CamKIIα and CGRP expression changes.Headache. 2010;50(5):834–843.
125. Lukács M, Warfvinge K, Tajti J, et al. Topical dura mater applicationof CFA induces enhanced expression of c-fos and glutamate in rattrigeminal nucleus caudalis: attenuated by KYNA derivate (SZR72).J Headache Pain. 2017;18(1):39.
126. Veres G, Fejes-Szabó A, Zádori D, et al. A comparative assessmentof two kynurenic acid analogs in the formalin model of trigemina-lactivation: a behavioral, immunohistochemical and pharmacoki-netic study. J Neural Transm (Vienna). 2017;124(1):99–112.
127. Csáti A, Edvinsson L, Vécsei L, et al. Kynurenic acid modulatesexperimentally induced inflammation in the trigeminal ganglion.J Headache Pain. 2015;16:99.
128. Lukács M, Warfvinge K, Kruse LS, et al. KYNA analogue SZR72modifies CFA-induced dural inflammation- regarding expressionof pERK1/2 and IL-1β in the rat trigeminal ganglion. J HeadachePain. 2016;17(1):64.
129. Curto M, Lionetto L, Negro A, et al. Altered kynurenine pathwaymetabolites in serum of chronic migraine patients. J HeadachePain. 2015;17:47.
130. Curto M, Lionetto L, Negro A, et al. Altered serum levels of kynur-enine metabolites in patients affected by cluster headache.J Headache Pain. 2015;17:27.
131. Matsuda LA, Lolait SJ, Brownstein MJ, et al. Structure ofa cannabinoid receptor and functional expression of the clonedcDNA. Nature. 1990;346(6284):561–564.
132. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization ofa peripheral receptor for cannabinoids. Nature. 1993;365(6441):61–65.
EXPERT OPINION ON EMERGING DRUGS 17
133. Tsou K, Brown S, Sanudo-Pena MC, et al. Immunohistochemicaldistribution of cannabinoid CB1 receptors in the rat central nervoussystem. Neuroscience. 1998;83(2):393–411.
135. Van der Schueren B. J., K. Van Laere, Gérard N., et al. Interictal type1 cannabinoid receptor binding is increased in female migrainepatients. Headache. 2012;52(3):433–440.
136. Juhasz G, Lazary J, Chase D, et al. Variations in the cannabinoid receptor1 gene predispose to migraine. Neurosci Lett. 2009;461(2):116–120.
137. Lochte BC, Beletsky A, Samuel NK, et al. The use of cannabis forheadache disorders. Cannabis Cannabinoid Res. 2017;2(1):61–71.
138. Dodick DW, Turkel CC, DeGryse RE, et al. PREEMPT chronic migrainestudy group. OnabotulinumtoxinA for treatment of chronicmigraine: pooled results from the double-blind, randomized,placebo-controlled phases of the PREEMPT clinical program.Headache. 2010;50(6):921–936.
139. Negro A, Curto M, Lionetto L, et al. A two years open-label pro-spective study of OnabotulinumtoxinA 195 U in medication over-use headache: a real-world experience. J Headache Pain. 2015;17:1.
140. Andreou AP, Trimboli M, Al-Kaisy A, et al. Prospective real-worldanalysis of OnabotulinumtoxinA in chronic migraine post-NationalInstitute for Health and Care Excellence UK technology appraisal.Eur J Neurol. 2018;25(8):1069–e83.
141. Zhang X, Strassman AM, Novack V, et al. Extracranial injections ofbotulinum neurotoxin type A inhibit intracranial meningeal noci-ceptors’ responses to stimulation of TRPV1 and TRPA1 channels:are we getting closer to solving this puzzle? Cephalalgia. 2016;36(9):875–886.
142. Dolly JO, Wang J, Zurawski TH, et al. Novel therapeutics based onrecombinant botulinum neurotoxins to normalize the release oftransmitters and pain mediators. FEBS J. 2011;278(23):4454–4466.
143. Wang J, Zurawski TH, Meng J, et al. A dileucine in the protease ofbotulinum toxin A underlies its long-lived neuroparalysis: transferof longevity to a novel potential therapeutic. J Biol Chem. 2011;286(8):6375–6385.
144. Torres-Perez JV, Chamberlain J, Miedzik AA. Non-paralytic botuli-num chimeras increase the activation threshold of the trigemino-vascular system in migraine models. Cephalalgia. 2015;35:4.
145. Paraskevopoulou M, Perez JT, Miedzik A, et al. Non-paralytic botu-linum molecules for the control of migraine. Cephalalgia.2016;36:135.
146. Mangione AS, Obara I, Maiaru M, et al. Nonparalytic botulinummolecules for the control of pain. Pain. 2016;157(5):1045–1055.
147. Maiaru M, Leese C, Certo M, et al. Selective neuronal silencing usingsynthetic botulinum molecules alleviates chronic pain in mice. SciTransl Med. 2018;10(450):eaar7384.
148. Edvinsson L. The trigeminovascular pathway: role of CGRP andCGRP receptors in migraine. Headache. 2017;57(Suppl 2):47–55.
