HT1F Receptors for the Acute Therapy of Migraine: a Literature Review

Review Articles

Targeting CGRP and 5-HT1F Receptors for the Acute Therapy of Migraine: A Literature Review

David Moreno-Ajona, MD ; Calvin Chan, MD; María Dolores Villar-Martínez, MD; Peter J. Goadsby, MD, PhD

Objective.—To review and highlight current literature on emerging acute migraine treatments, focusing on CGRP receptor antagonists, gepants, and 5-HT1F receptor agonists (ditans). Background.—Current acute migraine therapy consists of nonspecific analgesia and triptans. Limitations to these medicines, including lack of efficacy in many patients, side effects and the contraindication of triptans in patients with cardiovascular disease, suggest that there is an unmet need for new treatments. Studies of serotonin pharmacology led to the development of triptans, 5-HT1B/1D receptor agonists, some of which have actions at the 5-HT1F receptor. Exploration of the role of calcitonin gene-related peptide (CGRP) has resulted in the development of CGRP receptor antagonists. Method.—The authors performed a literature search of Pubmed and Cochrane databases as well as reviewed abstracts presented at meetings: American Headache Society, American Academy of Neurology, European Headache Federation and the Migraine Trust International Symposium, as well as on-line sources. The authors briefly detail the relevant migraine pathophysiology pertaining to 5-HT1F receptor and the CGRP pathway relevant to acute therapies. Recent clinical trials of acute therapies in which 5-HT1F receptor agonists or CGRP receptor antagonists were studied are summarized. Results.—Two 5-HT1F receptor agonists have reached phase II clinical trials. One, lasmiditan, has completed 2 phase III clinical trials, demonstrating a significant effect for pain freedom and most bothersome symptom at 2 hours. Among the 6 gepants tested for the acute treatment of migraine to date, after issues for some of hepatic safety or efficacy, 2 CGRP receptor antagonists, rimegepant and ubrogepant, have completed phase III trials showing efficacy and safety. Conclusion.—Current available therapies have either been nonspecific or had important limitations, including in patients with cardiovascular risk factors. Phase III clinical trials of lasmiditan, rimegepant and ubrogepant all met their primary endpoints, so the options for migraine-targeted acute therapy will likely soon increase.

Key words: calcitonin gene-related peptide, 5-HT1F, acute medications, migraine, acute therapy

(Headache 2019;59:3-19)

From the Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK (D. Moreno-Ajona, C. Chan, M.D. Villar-Martinez, and P.J. Goadsby); NIHR-Wellcome Trust King’s Clinical Research Facility/SLaM Biomedical Research Centre, King’s College Hospital, London, UK (D. Moreno-Ajona, C. Chan, M.D. Villar-Martinez, and P.J. Goadsby).

Address all correspondence to P.J. Goadsby, NIHR-Wellcome Trust King’s Clinical Research Facility/SLaM Biomedical Research Centre, King’s College Hospital, Wellcome Foundation Building, London SE5 9PJ, UK, email: [email protected]

Accepted for publication June 7, 2019.

Conflict of Interest: PJG reports grants and personal fees from Amgen and Eli-Lilly and Company, and personal fees from Alder Biopharmaceuticals, Allergan, Autonomic Technologies Inc., Biohaven Pharmaceuticals Inc., Dr Reddy’s Laboratories, Electrocore LLC, eNeura, Novartis, Teva Pharmaceuticals, and Trigemina Inc., and personal fees from MedicoLegal work, Massachusetts Medical Society, Up-to-Date, Oxford University Press, and Wolters Kluwer; and a patent Magnetic stimulation for headache assigned to eNeura without fee. The other authors have no conflict of interest.

3 4 July 2019

INTRODUCTION targeting different molecules. Awareness of migraine Migraine is a clinically complex, disabling neuro- pathophysiology offers the possibility to under- logical disease that principally affects adult females stand the symptoms and target these molecules with 11 during the years of greatest productivity.1 It disabil- appropriate therapies. Among the possible targets, ity has probably been underestimated.2,3 Recent data 2 have the largest body of evidence. Studies of sero- suggest that migraine is the most common cause tonin pharmacology have led to the development of of neurological disability, the sixth leading cause 5-HT1F receptor agonists, whereas exploration of of global disability and has jumped from the sixth the role of calcitonin gene-related peptide (CGRP) position to the second leading cause of years lived has resulted in the development of CGRP receptor with disability, outstripped only by back pain.4 antagonists. Why are New Acute Medications Necessary?— Literature Review Strategy.—We performed a The use of inadequate acute treatment may result literature search of the Pubmed and Cochrane data in a significant socioeconomic burden. While up to bases on January 2019, utilizing the keywords: “CGRP 34% of patients in the United States are treated with receptor blockers”, “CGRP receptor antagonists”, barbiturates or opioids for chronic migraine, only about “gepants”, “5-HT1F receptor agonists” and a fifth are treated with a migraine-specific treatment.5 “ditans”. Articles addressing the pathophysiology In fact, ineffective acute treatment is associated with and translational research that has led to our under 6 2-fold increased risk of new onset chronic migraine standing of CGRP and 5-HT1F receptors in migraine as which leads to substantial direct and indirect costs7 due well as phase II to phase IIIb randomized-controlled to loss of productivity.8 trials of acute treatment targeting the aforementioned, The basic measures of the utility of any treat- were included. Individual case reports were excluded. ment are efficacy, tolerability and patient preference. The search included publications in English and Currently, we have a wide range of options for the Spanish. In total, 26 published clinical trials were acute and preventive treatment of migraine.9 The ma- included. The reference lists of relevant and recent jority of available preventive and acute drugs were not articles focusing on acute medications targeting specifically designed to treat migraine. Around 40% of CGRP and/or 5-HT1F receptors were also reviewed and patients are unsatisfied with the degree of relief or the added if considered appropriate. Reviewed articles speed of effect of their acute treatment.10 Practically included peer-reviewed publications from inception half of patients will either need a second dose or will to date. Additional information was obtained from have recurrence of pain. Therefore, it is not surprising abstracts presented at the American Headache Society that almost 80% of patients refer to be willing to try American Academy of Neurology, the Migraine Trust another acute medication.10 International Symposium meetings, as well as press Current acute migraine therapy consists of non- releases from the latest trials when full peer-reviewed publications were not yet available. specific analgesia and triptans, 5-HT1B/1D receptor agonists. Limitations to these medicines, including lack What is the Current Migraine Model?—Several of efficacy in many patients, side effects and the con- hypotheses about the mechanisms of action of treatments traindication of triptans in patients with cardiovascu- in migraine have been proposed. Lars Edvinsson lar disease, suggest that there is an unmet need for new suggested in 1985 that CGRP, along with other 12 treatments. Due to vasoactive properties, triptans are molecules, may play a role in cerebral circulation. contraindicated in populations with uncontrolled hy- In the last decades, pharmacological development pertension, history of cerebrovascular accidents, myo- has targeted pathways related to migraine and their cardial infarction or ischemic heart disease. transmitters, such as CGRP and 5-HT, released during 13 Choosing the correct drug, taking into account trigeminovascular activation. Cranial arterial the clinical features, patient’s comorbidities and pref- vasodilatation, the basis of the vascular theory of 14 erences becomes a challenge. The need for new acute migraine, was initially interpreted as the cause of pain. medications has led to the development of therapies The vasodilation observed has since been considered an Headache 5 epiphenomenon in migraine,15,16 and itself is insuffici vasoactive and perivascular changes.13 The TCC has ent11 to describe the multiple facets of migraine. This projections to the rostral ventromedial medulla, locus conclusion is supported by three main findings. The first coeruleus, periaqueductal gray, hypothalamus, thal- one is the inability of some vasodilators, such as VIP, amus and cortical regions central to somatosensory to trigger reliably a migraine attack, despite inducing processing giving the sensation of pain.32 Descending cranial arterial vasodilatation.17 The second is the fact projections from the hypothalamus, ie, the A11 that nitroglycerine-induced migraine attacks are not nucleus,33 and the described brainstem structures11 associated with arterial vasodilatation.18 Finally, no are thought to modulate nociceptive firing from the significant extra cranial arterial vasodilatation and TCC. The TCC shares a reflex connection with the minimal intracranial arterial vasodilatation are superior salivary nucleus where parasympathetic observed in migraine attacks when investigated with signaling occurs via the sphenopalatine ganglion to MR angiography, intraictally.19 Plasma protein intracranial and intracranial structures producing extraversion (PPE) leading to sterile dural inflammation cranial autonomic symptoms such as lacrimation, has been observed with electrical stimulation of the ptosis, flushing and facial sweating.34 trigeminal ganglion.20 This observation, among others, CGRP and Migraine.—CGRP has been associated formed the peripheral neurogenic theory of mig with sensitization and pain generation.35 Properties of raine. The effect is observed when migraine effective this molecule in the meningeal arteries may lead to medications, such as ergotamine and dihydroergota neurogenic vasodilation and sterile inflammation.26,36 mine,21 aspirin,22 indomethacin22 and valproate23 are In the afferent nerves of the vessels, transient- infused in pre-clinical models. The inhibition of sterile receptor potential and acid-sensing channels detect dural inflammation through PPE from trigemi pH changes and the presence of irritant substances. nal ganglion stimulation20 may be mediated via At this level and in the trigeminal nucleus caudalis, 24 5-HT1B/1D receptors; triptans block PPE and sterile CGRP may also induce neural plasticity, ultimately dural inflammation.25 However, action on PPE has leading to sensitization.37 This phenomenon has also been found not to be predictive of drug efficacy in been related to CGRP signaling in the trigeminal treatment of migraine,26 as detailed bellow. Our under ganglion.38 Furthermore, in the TCC, CGRP may standing of the pathophysiology of migraine has facilitate nociceptive transmission39 and, peripherally, progressed from a vascular to the neurogenic to the augment plasma extravasation associated with sub neurovascular model. stance P release.40 CGRP may be able to enhance Migraine is currently considered a neurological glutamatergic signaling.39 In fact, high brain glutamate disorder that leads to an altered brain sensory process- levels and altered glutamate metabolism have been ing influenced by genetics and environment, in which reported in migraine patients, leading to the con the trigeminal durovascular afferent pathway plays a sideration of glutamate as a possible target for future crucial role.11 The trigeminocervical complex (TCC) therapies.41 has been proposed as a significant structure in cranial Stimulation of the trigeminovascular system has nociceptive processing.27 In brief; the dura and the in- resulted in the increased levels of CGRP and pituitary tracranial blood vessels are innervated by unmyelin- adenylate cyclase-activating peptide when measured ated C fiber and A delta fibers from the trigeminal in the jugular veins of cats and humans.42,43 Moreover, ganglion.28,29 The dura mater is also innervated by af- interictal levels of CGRP in peripheral blood have ferent nerves from the upper cervical dorsal root gan- been found consistently elevated in chronic compared glion.30,31 Stimulation mechanically, chemically and to episodic migraine patients.44 Ultimately, the intra- electrically produces pain and an increases in firing venous injection of CGRP has been able to induce mi- from the trigeminal ganglion. CGRP and pituitary graine-like headache in migraine patients.45 adenylate cyclase-activating peptide are found within In the brain, the distribution of the CGRP and its the axon terminals of these nerves and are released receptor involve both the central and peripheral ner- when the trigeminal ganglion is stimulated leading to vous system including the trigeminal sensory nerve 6 July 2019 fibers.46 Mechanistically, CGRP binds to its receptor, been shown to reduce plasma CGRP levels in patients leading to an activation of adenylyl cyclase-producing treated with sumatriptan for a migraine attack with cyclic AMP which, in turn, increases protein-kinase A concurrent improvement in pain72 and, in healthy in- and phosphorylates glutamate N-Methyl-D-aspartate dividuals, inhibit capsaicin-induced CGRP release.73 (NMDA) receptor. NMDA has shown to commence This suggests agonism of one or a combination of the cortical spreading depression, the preclinical model 5-HT1B, 5-HT1D and 5-HT1F receptors, results in inhi- of migraine aura.47 bition of CGRP release and therefore efficacy in pain

CGRP and Vasodilation.—Another important relief in migraine. Selective 5-HT1B agonists reduce the role of CGRP, in almost all vasculatures, is vasodilation. vasodepressor effects of CGRP,74 although currently it Smooth muscles cells containing CGRP-positive- is unclear at which structure or structures their action fibers are both in the cranial and coronary arteries. In is instigated.75 contrast with the endothelial cells, smooth muscle cells Targeting 5-HT1D receptors in treatment has express the 2 CGRP receptor components, calcitonin been explored but without success. PNU-142633F is receptor-like receptor (CLR) and receptor activity- a specific 5-HT1D agonist that was shown to strongly modifying protein 1 (RAMP1), necessary for its inhibit PPE.76 PNU-142633F was also used to assess 48 functioning. There is evidence suggesting that CGRP the role of 5-HT1D receptors in the release of CGRP may have a protective role against the development of with conflicting results. One study has shown PNU- hypertension, cerebral ischemia in animal models and 142633 reduced the inducible release of CGRP from coronary artery disease in humans.49 Nevertheless, trigeminal nucleus caudalis,75 whereas in the presence inhibiting the release of CGRP in animal models has of a specific 5-HT1D antagonist, the vasodepressor been associated with longevity50 and lower rates of age- effects of CGRP was still observed.74 Further devel- 51 related diseases including cardiovascular diseases. opment of 5-HT1D agonists was not pursued after the What is the Role of 5-HT Receptors in Migraine?— unfortunate finding, in clinical studies, that PNU- Serotonin has long been noted to be involved in the 142633F was ineffective as an acute treatment.77 pathophysiology of migraine. Evidence supportive of All triptans act on the 5-HT1F receptor except for this includes: rizatriptan, which may act on the receptor but only on higher doses than clinically standard.25,70,78,79 Another 1. An Increased urinary excretion of 5-hydroxyin- example of this would be naratriptan, which has high

doleacetic acid, the major metabolite of serotonin affinity for 5-HT1B, 1D and 1F receptors. Naratriptan is observed with migraine attacks.52,53 has been shown to continue to exert inhibitory effects

2. Precipitous depletion of platelet serotonin, a marker on TCC firing in the presence of 5-HT1B and 5-HT1D 80 of plasma serotonin, is observed during a migraine receptor antagonists, suggesting 5-HT1F receptor attack.52,54 agonism may be producing this observed effect. In

3. Intravenous serotonin aborts induced spontaneous human brain studies, the 5-HT1F receptor can be migraine attacks.55,56 found in the globus pallidus, putamen, hippocampus, substantia nigra, spinal trigeminal nucleus, nucleus There are 7 classes of serotonin receptors; the triptans tractus solitarius, substantia gelatinosa and periaque- 81,82 act predominantly on the 5-HT1B and 5-HT1D recep- ductal gray. 5-HT1F receptor activation does not 57 tors. Activation of the 5-HT1B receptor produces result in the vasoconstrictor effects seen with 5-HT1B 58-66 83 vasoconstriction of intra and extracranial arteries receptor activation. 5-HT1F receptor agonists were 60,63-69 and coronary arteries. Sumatriptan is a 5-HT1B, developed during the period where inhibition of PPE 70 5-HT1D and 5-HT1F agonist that is unable to cross the was thought to be predictive of drug efficacy. 5-HT1F blood–brain barrier71 suggesting its action in reducing receptor agonists have been shown to inhibit PPE in migraine pain is via structures such as the trigeminal animal models.84,85 With the shift from inhibition ganglion. However, the true site or sites of action of of PPE as a marker of efficacy to the inhibition of sumatriptan is yet to be determined. Sumatriptan has TCC firing it is reassuring that, in the rodent model, Headache 7

91 agonists to 5-HT1F receptor have an inhibitory effect trigeminal nucleus caudalis. Importantly, lasmiditan 86 92 on the TCC. Specific 5-HT1F agonists, developed does not induce coronary artery vasoconstriction. prior to lasmiditan, have been shown to reduce the Lasmitidan was assessed in 2 phase II trials where it inducible CGRP release from the peripheral termi- was administered intravenously93 and orally.94 The nals of neurons at the dura mater75 and inhibit CGRP results of the randomized double-blind multicenter, vasodepressor effect. phase III trial, SAMURAI95 have recently been

Ditans – 5-HT1F Receptor Agonists – The Clinical published. The SAMURAI study was the first phase Evidence.—Several 5-HT1F receptor agonists have three clinical trial to announce results. Patients were been developed with only 2 assessed in clinical trials assigned to receive 100, 200 mg or placebo. The (Table 1). Only lasmiditan has proceeded into phase primary outcome measures of pain freedom and

III clinical trials. The first 5-HT1F receptor agonist to freedom of most bothersome symptoms at 2 hours were be trialed clinically was LY334370.87 This agonist inhi met for both doses. The SPARTAN study compared bits PPE more potently than naratriptan, zolmitriptan, 50, 100 and 200 mg doses of lasmiditan.96 The study sumatriptan and dihydroergotamine with negligible was completed in June 2017. The primary outcome effect of the diameter of the rabbit saphenous vein,85 a measures of pain freedom and freedom of most surrogate of vasoconstriction of the coronary arteries.88 bothersome symptoms at 2 hours were met with 50, Although the dose of LY334370 required to inhibit 100 and 200 mg doses. The most common side effects PPE was lower than the dose to produce pain relief,87 reported were dizziness, paresthesia, somnolence, suggestive of an alternate mode of action of the 5-HT1F fatigue, nausea, and lethargy. Three patients (0.5%) receptor. As discussed above, the current proposed who received 200 mg of lasmiditan and two patients mechanism of migraine pain is not through PPE who received 100 mg lasmiditan (0.3%) experienced but through activation of the trigeminal complex. palpitations. One patient (0.2%) who received 100 LY334370 inhibits nociceptive firing of second-order mg of lasmiditan experienced bradycardia. neurons within the TCC and therefore, the likely Lasmitidan is currently assessed in a prospective mechanism of action in acute treatment of migraine randomized open label study which included patients is central.89 A phase II trial of LY334370 involved who have completed SPARTAN or SAMURAI for 73 subjects as acute therapy for moderate to severe further evaluation of safety, tolerability and efficacy. migraine. Phase III trials were halted due to unpublished The study is named GLADIATOR.97 From a total data reporting liver toxicity in beagle dogs,79 which of 814 patients who completed the study over a me- was not detected in the preclinical rat model. Liver dian duration of 288 days, the most frequent AE was enzyme derangement was not a side effect noted in the dizziness (18.6%) followed by somnolence (8.5%) par- phase II clinical trial. Despite this, the drug did not aesthesia (6.8%), fatigue (5.5%), nausea (4.7%) and proceed into phase III trials. asthenia (2%). Lasmiditan.—Lasmiditan (COL-144 or LY57314), Gepants – CGRP Receptor Antagonists.—Small is a 5-HT1F receptor agonist, structurally different from molecule CGRP receptor antagonists or ‘gepants’ 98,99 LY334370. Lasmiditan has lower affinity to 1HT1A,1B,1D have been developed since 1999. Over the last 2 receptors than LY334730 and negligible to 5-HT2 and decades, 6 different gepants have been tested for the 5-HT7. This molecule was found also to have minimal acute treatment of migraine in humans (Table 2). adrenergic, dopaminergic, histaminergic and mus The first of these was olcegepant (BIBN4096BS),100 carinic affinity,78 with no measurable effect on rabbit’s which phase II, double-blind proof of concept trial saphenous vein contraction.78 Lasmiditan significantly in 2004, showed that it was effective in treating reduces dural PPE and c-fos expression in the acute migraine attacks.101 Currently, according cells of the trigeminal nucleus caudalis after electrical to the latest guidelines for controlled trials of stimulation of the trigeminal nerve of rodents,78 and drugs in migraine,102,103 the important endpoints to inhibits nociceptive firing from the TCC90 and CGRP determine effectiveness should include pain freedom release from the dura mater, trigeminal ganglion and at 2 hours, along with no headache recurrence within 8 July 2019 - - - - - Results ing pain or providing pain freedom at 2 hours. AEs included paresthesia and dizziness,asthenia, somnolence, 2019 < .001) were superiorP < .001) headache for vs placebo (15.3%) freedom at 2 hours. Relief of most bothersome symptoms at 2 hours was found vs placebo with mg 100 lasmiditan (40.9%, and 200P < .001) mg lasmiditan (40.7%, There were P < .001). significant results improvement for of headache pain and 200 at 2 hours mg mg (59%) 100 (59%) for vs placebo most (42.2%, P < .005).The common AE were diz lethargy and nausea, fatigue, somnolence, ziness, paresthesia, of most bothersome symptoms at two hours were met with 50, and100, 200 mg doses. Secondary outcomes, including im provement of headache pain, use of rescue medication within 2 hours, photophobia and phonophobia were also met all for doses. The most common AEs were dizziness, paresthesia, somnolence, fatigue, nausea, and lethargy rior with lasmiditan. The most common AEs reported were dizziness, fatigue, vertigo, paresthesia, and somnolence patients with improvement in headache at 2 hours’ vs placebo With 50 mg, mg 100 64%, P = .022; 43%, (25.9%). and with P = .0018 200P < .0001; 400 mg 51%, mg 65% ClinicalP < .0001. disability score at 2 hours, patient’s global impression and improvement in photophobia were also supe tan had pain relief with vs 45.2% placebo. minutes, 180 At had60.3% pain relief on placebo. vs 33.3% AEs included dizziness, paresthesia, fatigue, sensation of heaviness, and feeling of relaxation 60 and 200 mg doses significantly superior to placebo at reduc Recruitment closed. Estimated trial completion date September < .001), and 200 mg mg P < .001), 100 (28.2% lasmiditan (32.2% The primary outcome measures of pain freedom and freedom Effective IV dose was found to be 20 mg. 2 hours,At 64.3% of participants treated with 20 mg of lasmidi With all doses, there was a significant difference in number of Number of either 20, 60 or 200 mg 100 or 200100 mg orally lasmiditan or50, 200 100, mg orally IV Lasmitidan. Doses of 10, 2.5, 5, 20, 30 and mg 45 assessed were receiving either 50, 200,100, 400 mg Trial Drug) and Dose 73 patients73 received 100 or 200100 mg orally 2231 patients2231 received 3005 patients received 88 patients received total86 patients Participants (Received - Table 1.—Ditans-Table 5HT1F Receptor Agonists Study Type double-blind, parallel design pleted or COL 301 MIG COL 302MIG blind, placebo-controlled study placebo-controlled blind, study placebo-controlled blind, blind, open labelled study including patient who have com double-blind, group-sequential, adaptive treatment assignment intravenous dose finding study blind, parallel-group oral dose finding study Randomized, placebo-controlled, Prospective, randomized, double- Prospective, randomized, double Prospective, randomized, double Randomized, multicenter, Randomized, multicenter, double- Study Phase MIG-301 SAMURAI MIG-302 SPARTAN MIG-303 GLADIATOR MIG-201 MIG-202 Phase III COL Phase III COL Phase III COL Phase II Phase II COL Phase II COL 93 87 LY57314) LY334370 Trial Drug (Reference) Trial 94 95 96 97 Lasmiditan (COL-144

Headache 9 - - Results < .001) with sustained P < .001) effect vs at 24 hours (39.6% < .05). Most common P < .05). AEs were nausea, dizziness and telcagepant compared to rizatriptan (difference: −6.2% respectively). andP < .001 −15.6%, More patients discontinued telcagepant than 300 mg (38.2%) rizatriptan mg (30.9%) 10 patients 27% with (vs placebo, 44% pain P < .001), freedom at 2 hours vs 2% with placebo and pain 19% recurrence vs 46% with placebo. The most common AE was paresthesia in 8% Similardom P < .0001). 27% vs 10% efficacy to zolmitriptan, both more effective than telcagepant mg. Less 150 AEs with telcagepant vs zolmitriptan (dry mouth, somnolence, dizziness, nausea and fatigue) freedom at 2 hours were and 23.2% compared 23.8% to 10.7% with placebo Both doses P < .001). provided sustained pain freedom P < vs 5.8% .001) at 24 15.7% hours (13.5%, ischemia (ECG). placebo 300 mg was effective pain freedom (45.2% with at 2h vs 14.3% placebo, 11% with 600 placebo, mg led11% to pain P < .01). freedom at 2 hours and sustained pain and freedom 32%, respec (32.1% tively somnolence free rate with was 35.2% ibuprofen, with 38.3% acetaminophen alone), beingand 31.2% all significantly effective vs placebo Combined drugs(10.9%). led to more reported side effects, mainly nausea, fatigue, and somnolence Fewer triptan related and drug-related AEs were reported for Telcagepant 300 mg was more effective than placebo (pain free Olcegepant 2.5 mg provided pain relief at 2 hours in 66% of Telcagepant and 150 300 mg were efficacious vs placebo (pain Telcagepant well tolerated by CAD patients. doses of 300mgTwo telcagepant did not exacerbate myocardial differencesNo in treadmill exercise time with telcagepant vs Doses under 300 mg were discontinued due to lack of efficacy. No significantNo differences in efficacy vs telcagepant alone (pain - - - - Number of Participants triptan mild mg for 10 to severe migraine attacks telcagepant 280/300 or riza triptan 5 mg or placebo to treat migraine attacks IV 2.5, doses 5 1, 0.5, (0.25, mg) over a periodor 10 of 10 minutes pant mg, 300 150 mg, zolmi to severe attack with 50, 150, 300 mg telcagepant or placebo 280/300 mg. 28 CAD telcagepant received patients or placebo (24-hours ECG). 64 patients with stable angina received 600 mg telcagepant attack with telcagepant orally 20, 200, 100, (25, 300, 400 or 600 rizatriptan mg), mg or 10 placebo attack with oral telcagepant 280 mg, combined with ibupro fen 400 mg or acetaminophen 1000 mg or placebo (Received Trial Drug) and Dose 1068 patients1068 received 2:1 126 patients126 received different patients1380 received telcage patients1294 treated a moderate 165 CAD patients165 received 420 participants420 to treat an 683 participants683 to treat an - - - -

Table 2.—Gepants-Table CGRP Receptor Antagonists. Study Type center, randomized, double-blind, active- parallel-controlled group, 18-month trial center, double-blind, randomized clinical trial center, randomized, parallel-treatment, placebo-controlled, double-blind trial center, randomized, double-blind, placebo- parallel- controlled, group, outpatient trial blind, placebo- and active-controlled, studies crossover blind, parallel group, clinical trial with a two-stage, adaptive, dose-ranging design placebo- blind, controlled, parallel- controlled, group clinical trial International, multi International, Randomized, double- International, multi International, Randomized, double- Randomized, double multi International, multi International, Study Phase Phase III Phase II-III Phase II Phase II Phase II Phase III Phase III 101 104 (MK-0974) (BIBN4096BS) 109 110-112 Trial Drug (Reference) Trial 108 108 107 Telcagepant Telcagepant Olcegepant Olcegepant 10 July 2019 - - - - Results at 2-hours (21.2% with 100 mg, 19.2% with 50 mg vs 11.8% with withat with 2-hours mg, 100 50 19.2% mg vs (21.2% 11.8% placebo Absence P < .01). of photophobia, photophobia or nausea at 2 hours, was significant mg 100 and for 50 mg and 38.6%, respectively, with(37.7% vs placebo 27.8% P < .01). AEs were nausea, somnolence and dry mouth, being infre Elevationsquent and in (5%). AST were ALT registered in 6 patients < .05). Absence P < .05). placebo vs 14.3%; of most 21.8% (20.7%, bothersome symptoms was significant with vs 50 mg (38.9% with placebo;27.4% AEs P < .05). were nausea and dizziness, infrequent (<2.5%) cebo in achieving pain freedom at 2 hours with (36.2% 200 mg was well tolerated placebo) for MK-3207 vs 9.8% P < .001. and had similar AEs to its predecessors. One patient on 20 mg had more than 7 daysAST, after 3xULN receiving the drug vs placebo (27.4% vs 8.6 %) andvs placebo vs %) similar 8.6 (27.4% to eletriptan 40 mg (34.8%) Sustained P < .05. pain freedom at 24 hours was simi lar to eletriptan and superior to placebo BI44370TA, for (20.5% with eletriptan with21.7% placebo, and 7.1% P < .0005). AEs** fatigue, diarrhoea(9.6%), and influenza-like, were less frequent than with eletriptan (17.4%) measured by pain freedom at 2 hours vs P < .01), 8.9% (25.5% sustained pain and freedom vs 6.2% P < .01) at 24 hours (21.6% absence of photophobia at two hours vs 30.4% (54.9% AEs were nausea,P < .001). dizziness, dry mouth, somnolence and fatigue drug. A usual care arm was included in the study showing a similar profile of AE which were nasopharyngitis, upper res piratory tract infection, sinusitis, urinary tract infection and influenza. Drug-induced hepatotoxicity was not found Both doses were effective vs placebo in achieving pain freedom 25 and25 50 mg showed significant pain freedom at 2 hours vs All doses mg were above 10 significantly more effective vs pla Pain freedom with the 400-mg dose at 2 hours was superior Ubrogepant mg 100 was the most effective dose vs placebo, as In attacks total, 21,454 were treated doses with of 31,968 the - - Number of Participants Table 2.—(Continued) Table 100 mg100 ubrogepant or placebo to treat a single migraine at tack at home 50 mg or placebo to treat a single migraine attack 20, 50 or 100 mg MK-3207 20, 50 mg or 100 MK-3207 (200 mg dose was added after an interim analysis) or placebo 200 vs and 400 mg BI44370TA placebo and eletriptan 40 mg to treat one attack with 10, 1, mg 50, 100 ubrogepant25, or placebo pleted either ACHIEVE I or ACHIEVE II. Over weeks’ a 52 period, patients took 50 or mg100 ubrogepant tablets to treat up to 8 migraine attacks a month (Received Trial Drug) and Dose 1327 patients1327 received oral 50 or 1355 patients1355 received oral 25, 676 patients676 randomized to 10, 5, 161 patients161 received oral 50, patients834 were randomised 1254 patients1254 who have com Study Type double-blind, placebo- parallel- controlled, group study double-blind-placebo- parallel- controlled, group study double-blind, placebo- parallel- controlled, group study blind, double-dummy, placebo and active- parallel- controlled, group, outpatient study double-blind, placebo- trialcontrolled open-label extension extension open-label study Multicenter, randomized, Multicenter, randomized, Multicenter, randomized, Randomized, double- Multicenter, randomized, Multicenter, randomized, Study Phase Phase III ACHIEVE 1 Phase III ACHIEVE 2 Phase II Phase II Phase IIb Phase III UBR-MD-04 117 115 116 * * * (MK-1602) 119 120 Trial Drug (Reference) Trial 118

BI44370TA Ubrogepant Ubrogepant MK-3207 Headache 11 - - < .001). AEs < .001). < .002 rimegepant for and Results < .01). SustainedP < .01). pain freedom hours at 2-24 was achieved in was achieved and freedom P < .0001) vs 10.9%, (21.2% from most bothersome vs 26.8%, P = .0009). No symptom (35.1% occurred AE severe placebo in achieving pain freedom su for at 2 hours (35% matriptan, P 32.9%, 29.7%, 31.5%, with placebo).15.3% Sustained response was significant at 24 withhours placebo; ranging 7.4% (vs P 26.2-28.1% were nausea, dizziness and vomiting, especially with 600 mg*** 19.2% and 19.6% response and 19.6% 19.2% rates and with vs 12% 14.2% placebo ( withboth placebo studies vs 8.1% in (14% vs 12.3% study 301; with placebo7.1% in study 302; P < .01). the most bothersome symptom, rimege in for both (36.6% 301 pant vs 27.7% with wiht placebo)pant vs 27.7% rimegepant and 302 (37.6% vs with 25.2% placebo). major No were AEs**** registered. Nausea, dizziness and urinary tract infection were the most common AEs, similar to placebo nasopharyngitis with no hepatotoxicity (>5%), Rimegepant was superior to placebo. Pain freedom at 2 hours Sumatriptan and rimegepant 300 were 150 mg), superior (75, to 2-hours post-dose pain freedom was met in both studies with Rimegepant was significantly superior to placebo in treatment of Most common AEs included headache, oropharyngeal pain and - Number of Participants Table 2.—(Continued) Table orally dissolving rimegepant or placebo to treat a single moderate to severe migraine attack migraine attack and were eval uated 300 150, after 75, 25, 10, or 600 mg rimegepant, placebo mgor 100 sumatriptan 75 mg rimegepant75 or placebo to treat a single moderate to severe migraine attack intermittent ubrogepant 100 mg alternating with placebo 2 days each)(for over an 8 weeks’ period (Received Trial Drug) and Dose 1375 patients1375 received mg 75 799 patients799 treated a single 1162 and 1186 patients and received 1186 1162 516 healthy volunteers516 received

Study Type double-blind, single- dose, placebo- controlled outpatient study double-blind, single- dose, placebo- controlled outpatient study omized, placebo- trialscontrolled placebo-controlled trial Multicenter, randomized, Multicenter, randomized, Double-blind, rand Multicenter, randomized, 303 Studies 301 and 302 31110-105-002 Study Phase Phase III Study Phase II Phase III Phase II Study 121 * * * (BMS-927711) Trial Drug (Reference) Trial 120 122 123 *Unpublished. **One patient was five-fold found ALT> upper limit normal (ULN), AST> three-fold ULN and GGT> five-fold ULN, five days after 400 mgadministration. BI44370TA This patient, however, was found to be a protocol inclusion violation. Prior to inclusion a sub two-fold of ULNamitriptyline, elevation was in detected, ALT propranolol was taking and acetaminophen and was later diagnosed with cholecystitisbeing during patients one of them follow-up. had ***Two asymptomatic on active treatment mg) and mild the (75 other increase on placebo. Liver in enzyme liver enzymes, elevation spontaneously resolved withinelevations 2 months. enzymes above the ****Liver ULN were noted and in (AST ALT) patients 24 out of 1089 with rimegepant with and out of 1092 32 placebo with only one case of more than three-foldthe active ULN increase and one on the placebo on group; CAD: coronary artery disease. Rimegepant Rimegepant 12 July 2019

24 hours and no adverse events (AEs). In this context, developed to be a hepatotoxicity-free alternative to 2.5 mg olcegepant showed 44% pain freedom after its predecessors.117 Currently, 2 phase III, multicenter, 2 hours compared to 2% with placebo as well as double-blind, placebo-controlled trials have been 19% pain recurrence compared to 46% for placebo. completed (ACHIEVE I and ACHIEVE II) with all Despite these data, the poor oral bioavailability of the results yet to be published; however, they have been drug prevented its progress to further development. documented in company press releases. ACHIEVE Oral Gepants.—After the promising results of I included 1327 migraine patients randomized to olcegepant, the first oral gepant to be developed was placebo, ubrogepant 50 mg or ubrogepant 100 mg, to telcagepant (MK-0974). The first phase II trial treat a single migraine attack at home.118 Both doses compared multiple doses ranging from 25 to 600 mg.104 were found significantly effective in achieving pain Phase III trials confirmed positive results compared to freedom at 2-hours (21.2% for ubrogepant 100 mg, placebo, as well as non-inferiority of telcagepant 300 19.2% for ubrogepant 50 mg vs 11.8% for placebo mg compared to rizatriptan 10 mg and zolmitriptan 5 P < .01). According to the available data, AE were mg.105-108 The largest of these trials,105 showed less side infrequent (5%). The most common AE were nausea, effects in the telcagepant group. Long-term studies somnolence and dry mouth. Elevations in ALT and (12–18 months) showed similar results.109 No major AST were not thought to be drug related. ACHIEVE side effects were noted, including no cardiovascular II119 was performed in 1355 patients with similar effects. Cardiovascular safety was confirmed by results (see Table 2). In order to evaluate the long- testing high doses of telcagepant in patients with term safety and tolerability of the drug, an open concomitant coronary artery disease and stable label, multicenter, phase III trial (UBR-MD-04) angina.110-112 Telcagepant was considered a safe was conducted in 1254 patients who have completed drug until it was tested as a migraine preventive by either ACHIEVE I or ACHIEVE II. Over a 52-week administrating twice daily 140 or 280 mg. Liver period, patients took 50 or 100 mg ubrogepant tablets toxicity, alanine aminotransferase (ALT) and to treat up to 8 migraine attacks a month. A standard aspartate aminotransferase (AST) elevation, which care arm was included in the study showing a similar was symptomatic in in 2 patients, led to the study profile of adverse events which, for ubrogepant, were termination.113 Similarly, telcagepant 140 mg nasopharyngitis, upper respiratory tract infection, administered daily for 7 days for peri-menstrual sinusitis, urinary tract infection and influenza. Most migraine prevention, was found to cause ALT importantly, drug-induced hepatotoxicity was not elevations, which were more than 8-fold normal found. These results, along with those from a multi- values in 3 patients.114 These results led to the drug center, randomized, placebo-controlled safety trial development discontinuation, even if it was found to (study 31110-105-002), seem to have opened the be effective and safe as an intermittent acute therapy. doors for a new era in acute migraine treatment with In contrast with telcagepant, BI44370TA had gepants.120 only 1 phase II proof-of-concept trial.115 Side effects Rimegepant.—Rimegepant (BMS-927711), an oral were fatigue, diarrhea and influenza-like symptoms. CGRP receptor antagonist, underwent a phase II, The drug was not developed further. At the same time, dose-ranging trial with 10-600 mg doses of rimegepant the second developed oral CGRP receptor antago- compared to placebo and 100 mg sumatriptan as active nist, MK-3207, went through a multicenter phase II, comparator.121 Participants were asked to treat one dose-defining trial.116 Both had a dose-response trend. moderate to severe attack. Sumatriptan (100 mg) and All doses above 10mg were significantly more effective rimegepant (75, 150 and 300 mg), were superior to than placebo in achieving pain freedom at 2 hours. The placebo in achieving pain freedom at 2 hours (35% drug was not developed further due to hepatotoxicity. for sumatriptan, 31.5%, 32.9%, 29.7%, P < .002, for Ubrogepant.—Ubrogepant (MK-1602), is an orally rimegepant at respective doses and 15.3% for placebo). bioavailable CGRP receptor antagonist chemically The drug was well tolerated with side effects being distinct to both telcagepant and MK-3207, which was nausea, dizziness and vomiting, especially with the Headache 13

600 mg dose. Nausea/vomiting was reported with both CONCLUSION sumatriptan and rimegepant and chest discomfort The advent of acute treatment of migraine has was reported only with sumatriptan. Two phase III been possible with the translation of preclinical trials with 75 mg rimegepant to treat a single migraine observations. Current available therapies have either attack have been completed recently. The primary been nonspecific or limited to a population without endpoint of 2-hours post-dose pain freedom was met cardiovascular risk factors. However, with phase III in both studies with 19.2% and 19.6% response rates vs clinical trials of lasmiditan, ubrogepant and rimegepant 14.2% and 12% in the placebo groups (P < .01).122 No all meeting primary endpoints, the options of targeted major AE related to the drug were registered. In line acute therapy will likely soon increase. An application with these results, another pivotal trial on rimegepant for a FDA new drug approval has been sent for lasmidi- 75 mg, orally dissolving tablet, showed pain freedom tan129 and ubrogepant.130 At the time of writing, the at 2 hours compared to placebo (21.2% vs 10.9%, pharmaceutical company intends to submit a FDA new P < .0001). Freedom from most bothersome symptom drug approval applications in early 2019 for rimege- at 2 hours was also statistically significant compared pant.123 With the approval of these medications and fu- to placebo. This type of formulation could bring a ture acute therapies we will be better able to bring relief more rapid onset of pain relief. The available data to patients who are limited due to pre-existing cardio- suggest this could be in 15 minutes. Pooled hepatic vascular disease and we may be able to bring relief to function tests across all three studies showed similar those who found current therapies unsuccessful. results to placebo.123 BHV-3500.—Another third generation CGRP STATEMENT OF AUTHORSHIP receptor antagonist has been developed with a different type of formulation. BHV-3500 would be the Category 1 first available intranasal gepant. This is currently (a) Conception and Design investigated on a phase II trial.124 Peter J. Goadsby What Are the Benefits of these New Acute (b) Acquisition of Data Medications?—Both, ditans and gepants, have David Moreno-Ajona, Calvin Chan, María shown efficacy compared to placebo as well as good Dolores Villar-Martínez tolerability, and safety. In contrast with triptans, the (c) Analysis and Interpretation of Data presence or history of cardiovascular disease is not a Peter J. Goadsby, David Moreno-Ajona, Calvin contraindication. Gepants have been tested on patients Chan, María Dolores Villar-Martínez with coronary artery disease showing good Category 2 110-112 tolerability and no changes on 24-hour-ECG. (a) Drafting the Manuscript Indeed, there were no cardiovascular side effects Peter J. Goadsby, David Moreno-Ajona, Calvin 87,93-96,101,104,105,107,108,112,115-117,121,125 in the clinical trials Chan, María Dolores Villar-Martínez 83,92 as 5-HT1F receptor activation or CGRP receptor (b) Revising It for Intellectual Content 126 inhibition does not result in vasoconstrictor effects. Peter J. Goadsby, David Moreno-Ajona These new options may represent an alternative for Category 3 migraine patients who do not tolerate triptans’ associated (a) Final Approval of the Completed Manuscript side effects. The available data suggest gepants may lead Peter J. Goadsby, David Moreno-Ajona, Calvin to less side effects, although they may not be as effective as 104,105,115,121 Chan, María Dolores Villar-Martínez triptans. Furthermore, the available evidence suggests patients will not develop medication overuse headache as a result of gepants use. In line with this idea, there are ongoing clinical trials for atogepant127 and REFERENCES rimegepant128 as migraine preventives. No study to date 1. Buse DC, Manack A, Serrano D, Turkel C, Lipton has directly compared triptans with ditans in humans. RB. Sociodemographic and comorbidity profiles of 14 July 2019

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