CNS Drugs (2014) 28:11–17 DOI 10.1007/s40263-013-0126-2
REVIEW ARTICLE
Emerging Targets in Migraine Jan Hoffmann • Peter J. Goadsby
Published online: 8 December 2013 Ó Springer International Publishing Switzerland 2013
Abstract Migraine is a common and highly disabling neurological disorder. Despite the complexity of its pathophysiology, substantial advances have been achieved over the past 20 years in its understanding, as well as the development of pharmacological treatment options. The development of serotonin 5-HT1B/1D receptor agonists (‘‘triptans’’) substantially improved the acute treatment of migraine attacks. However, many migraineurs do not respond satisfactorily to triptans and cardiovascular comorbidities limit their use in a significant number of patients. As migraine is increasingly considered to be a disorder of the brain, and preclinical and clinical data indicate that the observed vasodilation is merely an epiphenomenon, research has recently focused on the development of neurally acting compounds that lack vasoconstrictor properties. This review highlights the most important pharmacological targets for which compounds have been developed that are highly likely to enter or have already advanced into clinical trials for the acute and preventive treatment of migraine. In this context, preclinical and clinical data on compounds acting on calcitonin gene-related peptide or its receptor, the 5-HT1F receptor, nitric oxide synthase, and acid-sensing ion channel blockers are discussed.
1 Introduction Migraine is one of the most common and disabling neurological disorders and its economic impact ranges among the highest of all neurological diseases [1–5]. Still, public awareness of this socioeconomic burden is small and research funding is limited compared to other neurological research areas. However, significant advances in the acute and prophylactic treatment of migraine have been achieved over the past 20 years. The serotonin 5-HT1B/1D agonists (‘‘triptans’’) have revolutionized the acute treatment of migraine attacks and changed the lives of millions of migraineurs worldwide [6]. Preventive treatment options for episodic and chronic migraine have also been substantially expanded with new drugs such as topiramate [7–9] and onabotulinum toxin A [10–12]. Nevertheless, none of the preventive drugs available are migraine specific and all available pharmacological approaches, acute or preventive, are only effective in a limited number of migraineurs. In addition, the lack of individual predictability for the efficacy of a specific compound complicates treatment and patient compliance. Therefore, despite multiple available pharmacological treatment options, there is a significant need for novel therapeutic drugs for the acute and preventive treatment of migraine [13]. This review focuses on the most relevant new pharmacological targets.
2 Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonists (‘‘Gepants’’) J. Hoffmann P. J. Goadsby (&) Headache Group, Department of Neurology, University of California, San Francisco, 1701 Divisadero St, San Francisco, CA 94115, USA e-mail: [email protected]
Calcitonin gene-related peptide (CGRP) is a vasoactive neuropeptide located on unmyelinated C-fibers and thinly myelinated Ad-fibers of the trigeminal nerve system. It can be found in peripheral parts of the trigeminal system, such
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as the trigeminal ganglion [14, 15] or the perivascular nerve fibers surrounding meningeal blood vessels [16], as well as on its central parts such as the trigeminovascular complex (TCC), thalamus, and hypothalamus [17, 18]. Interestingly, it is also located on inhibitory structures such as the periaqueductal gray (PAG) [17]. Due to its potent vasodilator properties [19], it was initially postulated that this effect was relevant for its role in migraine pathophysiology [20]. However, it became clear that migraine is mainly a disorder of the brain rather than of peripheral structures, such as the meninges or its blood vessels [21– 23], and preclinical studies have been conducted that demonstrated the ability of CGRP to modulate neuronal activity in the TCC [24]. Further experimental data indicate its involvement in the transmission of pain signals from the TCC to higher brain regions such as the thalamus and cortex [23]. From a clinical perspective, the causal relationship between migraine and CGRP became evident after a series of clinical studies demonstrated that CGRP concentrations are elevated during spontaneous migraine attacks and return to baseline levels after sumatriptan treatment [25– 27]. Further studies showed that CGRP infusion in migraineurs is able to trigger migraine without aura [28]. The relevance of CGRP was finally confirmed in a proof-ofconcept trial that demonstrated clinical efficacy of the CGRP receptor antagonist BIBN4096BS (olcegepant) in the acute treatment of migraine [29]. However, its exact site of action, peripheral or central, has not yet been elucidated. In this context, it also remains to be clarified to what extent CGRP receptor antagonists are able to cross the blood–brain barrier, and whether the blood–brain barrier remains intact during a migraine attack. Research efforts then focused on the development of compounds that allow oral administration. As a result several ‘‘gepants’’ were developed and multiple clinical trials tested their efficacy. The first orally available CGRP receptor antagonist, telcagepant (MK-0974), was proven to be effective in the acute treatment of migraine [30–32]. Clinical trials demonstrated efficacy for 2-h pain relief, 2-h pain freedom, as well as sustained pain freedom for 2–24 and 2–48 h [31, 32]. In addition to being effective in pain relief, it was effective in alleviating associated symptoms such as nausea, photophobia, and phonophobia. BI44370TA is another orally available CGRP receptor antagonist that was found to be effective when tested in a phase II trial [33]. Unfortunately, despite being generally well-tolerated, these promising results were hampered after some patients in a trial investigating the potential of telcagepant as a preventive showed significant increases in liver transaminases [34]. Although these patients had received telcagepant twice daily and the enzyme elevations were not observed in the trials for the acute treatment of
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migraine, further research on the compound was terminated [34]. Research efforts on a second CGRP receptor antagonist, MK-3207, that was characterized by a higher bioavailability and potency was also terminated [35, 36]. Although it is not clear if the observed liver toxicity is a class effect or specifically tied to both MK-compounds, Boehringer Ingelheim also stopped further development on BI44370TA. However, Bristol-Myers Squibb initially developed the CGRP receptor antagonist BMS846372, which was further modified to increase aqueous solubility leading to the development of BMS-927711, and has now been demonstrated to be effective in acute migraine [37].
3 Monoclonal Antibodies Against CGRP or its Receptor Targeting CGRP [38] or elements of its receptor [39] with monoclonal antibodies has drawn much attention as a potential new pharmacological approach for the acute and prophylactic treatment of migraine. In principle, disruption of CGRP function in this way may have a similar beneficial effect on migraine as that observed with CGRP receptor antagonists. Compared with CGRP receptor antagonists, preclinical studies revealed a slower onset of action and a far longer half-life, which in theory suggest utility in prevention [38]. Initial preclinical studies addressing safety concerns for the use of monoclonal CGRP antibodies indicate that these molecules do not seem to affect heart rate and arterial blood pressure [38]. However, based on these data, a clear statement on its safety in patients with significant vascular pathology is currently not possible. Therefore, despite these promising results, further studies are needed to clarify the safety of these compounds. Preclinical studies using a monoclonal antibody against a C-terminal epitope of human a-CGRP (muMab7E9) were conducted on two established in vivo rat blood flow models known to be predictive of clinical efficacy to elucidate a potential effect in the treatment of migraine [40]. Intravenous administration of the anti-CGRP antibody inhibited electrically induced vasodilation of the skin or the middle meningeal artery (MMA), a mechanism that is mainly based on the neurogenic release of CGRP from sensory afferents [38]. The extent of the observed inhibition was similar to that observed in preclinical studies using CGRP receptor antagonists. The antibody was characterized by a slow onset as treatment effect after a single dose of antiCGRP antibody was achieved 1–2 h after administration and lasted for at least 7 days. Another potent selective human monoclonal antibody against CGRP developed by Eli Lilly and Company, LY2951742, impedes CGRP from binding to its receptor. Preclinical studies with subcutaneously administered
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LY2951742 demonstrated its ability to prevent capsaicininduced increase of dermal blood flow in rats, non-human primates, and healthy human volunteers [41]. The results of a safety, tolerability, and pharmacokinetic study of single, escalating subcutaneous doses of LY2951742 have not yet become available (NCT01337596). Currently, a phase II randomized, double-blind, placebo-controlled trial in migraineurs with or without aura is in progress to assess the efficacy and safety of LY2951742 (150 mg) in the prevention of migraine during 3 months of treatment (NCT01625988). Amgen developed a selective human monoclonal antibody, AA95, against the human CGRP receptor which was tested in a preclinical study using an in vivo model of capsaicin-induced increase of dermal blood flow in cynomolgus monkey. Intravenous administration of AA95 induced a dose-dependent inhibition of capsaicin-induced increase of dermal blood flow that lasted up to 7 days [39]. Taken together, interfering in CGRP function with selective monoclonal antibodies appears to be a promising pharmacological approach for the treatment of migraine. However, further studies on efficacy and safety are needed to clarify its potential for clinical use.
4 Serotonin 5-HT1F Receptor Agonists (‘‘Ditans’’) The effect of triptans is based on agonism at the 5-HT1B/1D receptors, and certainly some triptans act at the 5-HT1F receptor. The 5-HT1B and 5-HT1D receptors are located on meningeal arteries and peripheral trigeminal neurons, respectively [42]. However, in a migraine context, 5-HT1F receptors are found in the trigeminocervical complex (TCC), as are the 5-HT1B and 5-HT1D receptors, and in the trigeminal ganglion [42]. In experimental in vivo models of migraine, activation of 5-HT1F receptors inhibits neuronal activity in the TCC of the rat [43]. Initially, the peripheral component of triptans’ action was believed to be the crucial element of their mechanism. However, as experimental and clinical evidence indicates more and more that migraine is mainly a disorder of the brain [21], research efforts have expanded to the central 5-HT effects. The vascular component is now considered to be more an accompanying epiphenomenon than a causal mechanism of migraine [21, 22], with therapeutic indications coming from non-steroidal anti-inflammatory drugs (NSAIDs) [44–46] and CGRP receptor antagonists [29, 30, 32, 33], which are effective in migraine treatment and do not significantly constrict meningeal blood vessels. This is further supported by the fact that sumatriptan-induced pain relief does not correlate with the induced vasoconstriction [47]. Moreover, sildenafil is able to induce migraine without any change in the diameter of the middle cerebral artery [48]. As a result,
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5-HT1F receptor antagonists (‘‘ditans’’) were developed as they have no vasoconstrictor actions. The first neurally active, indole-based, selective 5-HT1F receptor agonist that was investigated in a randomized, double-blind, placebo-controlled, parallel-design clinical trial, LY334370, proved to be effective for the acute treatment of migraine attacks [49]. The primary endpoint, sustained response rate at 2 h, which was defined as a reduction in migraine headache from moderate or severe to mild or none at 2 h after dosing, without worsening within 24 h or the use of rescue medication, was reached by the group taking 60 mg (n = 30) and 200 mg (n = 21) [49]. Unfortunately, adverse events were frequent, with asthenia, dizziness, and somnolence being the most common ones reported [49]. Due to compound-specific safety concerns in animals, clinical development was stopped [50]. However, based on these results the centrally acting 5-HT1F receptor agonist lasmiditan (COL-144, LY573144), with a novel pyridinoyl-piperidine structure that is characterized by a higher receptor selectivity, has been developed [51]. In a clinical trial using a prospective, randomized, double-blind, placebo-controlled design with group-sequential adaptivetreatment assignment, intravenously administered lasmiditan proved to be effective for the acute treatment of migraine attacks at doses above 20 mg [50]. Adverse events were reported by 65 % of the subjects treated with lasmiditan (n = 88) compared with 45 % in the placebo group (n = 42) [50]. Efficacy of an oral formulation of lasmiditan was demonstrated in a phase II randomized, double-blind, parallel-group, dose-ranging study involving 391 patients. The primary endpoint, dose response for headache relief at 2 h, was achieved for 50, 100, 200, and 400 mg [52]. The efficacy in comparison with triptans and its safety in patient groups that cannot use triptans due to their vasoconstrictive properties, such as patients with a history of stroke or myocardial infarction, will finally define the future of this pharmacological mechanism in the treatment of acute migraine attacks.
5 Nitric Oxide Synthase Inhibitors Nitric oxide (NO) is involved in many physiological processes. Its most important property is the ability to induce vasodilation including cerebral and extracerebral arteries. Beside its vascular properties, NO is able to modulate neuronal activity in several regions of the CNS, including the PAG [53] as well as neurons of the TCC that receive meningeal input [54]. Furthermore, experimental data indicate an involvement of NO in the establishment of central sensitization [55], which is believed to be the pathophysiological correlate of migraine-associated allodynia [56, 57]. Interestingly, in animal models the systemic
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[54, 58] as well as the microiontophoretic administration of NO synthase (NOS) inhibitors [59] into the TCC reduce neuronal activity in the TCC. From a clinical perspective, the relationship between NO and migraine has a long history. The observation that workers in explosives factories had a significantly higher incidence of migraine led to the suspicion that glyceryl trinitrate (GTN), an NO-donor, was the responsible molecule for the attack induction. This idea was confirmed by a clinical study demonstrating that intravenous administration of GTN in migraineurs reliably induces migraine attacks without aura [60, 61]. Years later, Afridi et al. [62] showed that GTN not only induces the migraine attack itself, but also the preceding premonitory symptoms, which were identical to those reported in spontaneous migraine attacks [63] thereby highlighting the neuronal effects of NO. Based on these observations, several NOS inhibitors were developed and investigated in clinical trials. In principle, all three NOS isoforms, the neuronal (nNOS), endothelial (eNOS), and inducible (iNOS) NOS isoforms, could represent a potential pharmacological target. However, since in the context of migraine pathophysiology the neuronal effects of NO appear to prevail, the search for therapeutic compounds quickly shifted from non-specific NOS inhibitors to those that target only specific isoforms that have more influence on NO production at the neuronal level, namely nNOS and iNOS. However, the first compound tested for the treatment of acute migraine attacks was the non-specific NOS inhibitor L-NG methylarginine hydrochloride (L-NMMA) [64]. Despite encouraging response rates of 67 % in the L-NMMA group compared with 14 % in the placebo group, the results have to be interpreted with caution as the study suffered from some methodological shortcomings [65]. Poor oral absorption and an associated increase in systemic blood pressure as a result of eNOS inhibition made this compound unsuitable for clinical use [66]. More recently, the iNOS inhibitor GW274150 was tested for the acute [67] and preventive [68, 69] treatment of migraine. Despite the high efficacy of GW274150 in iNOS inhibition [70, 71], both well-designed trials were negative. Initial results with a novel nNOStriptan combination drug NXN-188 suggest that more needs to be understood to exploit this direction. However, preclinical results are encouraging as in experimental migraine models NXN-188 inhibits CGRP release [72].
6 Acid-Sensing Ion Channel Blockers Acid-Sensing Ion Channels (ASICs) are a family of cation channels gated by extracellular protons [73]. They are located in the peripheral and central nervous system and are expressed on sensory neurons of the cranial meninges
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as well as the trigeminal, vagal, and dorsal root ganglion [73]. The ASIC1a subunit is mainly found in the CNS and the ASIC3 subunit is largely located in the peripheral nervous system [73]. ASICs act as a sensor to decreased extracellular pH, which occurs during inflammatory pain in the periphery or central electrical events, such as cortical spreading depression (CSD), which is believed to be the pathophysiological correlate of migraine aura [74]. Therefore, they act as chemo-electric transducers. Due to their function and anatomical location, ASICs are of increasing interest as a potential therapeutic target for the treatment of migraine. In a series of preclinical in vivo studies and a small sample of patients with refractory migraine with prolonged aura, Holland et al. [75] investigated the effect of the potassium-sparing diuretic amiloride, the first blocker of ASICs to be described. In the experimental in vivo models of migraine, the authors demonstrated that intravenous amiloride 10 mg/kg significantly inhibited needle prickinduced CSDs. In transgenic mice with a deletion of the ASIC1-producing ACCN2 gene, the effect of amiloride was not observed. Taken together, the data suggest a potential therapeutic effect on migraine aura. Furthermore, amiloride inhibited neurogenic vasodilation of the MMA and stimulus-induced neuronal activity in the TCC, indicating an inhibitory effect on nociceptive processing within the trigeminal system and suggesting a pain-relieving effect in migraine. In the small open-label pilot study on seven migraineurs suffering from refractory migraine with persistent aura, the intravenous administration of amiloride 10–20 mg/kg/day significantly reduced headache severity and the frequency of aura in four patients during the observation period of 6–24 months [75]. In conclusion, preclinical and clinical data strongly suggest a possible therapeutic effect on migraine and migraine aura, highlighting the need for randomized placebo-controlled clinical trials.
7 Conclusions Despite the evident relief and increase in quality of life that triptans have brought to many migraineurs, there is still a substantial need for novel pharmacological strategies for the treatment of migraine. Among the broad range of pharmacological targets currently under investigation, CGRP and its receptor, the 5-HT1F receptor, NOS, and ASICs are among the targets that have the potential for clinical efficacy and are likely to enter or have already entered clinical trials. While clinical trials on CGRP receptor antagonists demonstrated their clinical efficacy, two advanced compounds have been hampered by liver toxicity issues. In contrast, antibodies against CGRP or its
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receptor may offer similar beneficial effects combined with a long-lasting effect that may reduce the risk of recurrence headache. Trials on 5-HT1F receptor agonists have shown clinical efficacy and their development is awaited with interest. Clinical efficacy could not be demonstrated for the acute and prophylactic treatment of migraine by iNOS inhibitors, and nNOS is now likely to be explored. In contrast, ASIC blockers may offer a completely novel pharmacological approach and initial positive results from preclinical studies have been complemented by the promising results of a small open-label study that suggests clinical efficacy for migraine and migraine aura. However, placebo-controlled randomized trials are needed to confirm these preliminary results. Acknowledgments JH has received honoraria for editorial work from Journal Watch Neurology and travel support from Allergan. PJG is on Advisory Boards for Allergan, Colucid, MAP pharmaceuticals, Merck, Sharpe and Dohme, eNeura, Neuraxon, Autonomic Technologies Inc., Boston Scientific, Electrocore, Eli-Lilly, Medtronic, Linde Industrial Gases, Arteaus, AlderBio, and Bristol-Myers Squibb. He has consulted for Pfizer, Nevrocorp, Lundbeck, Zogenix, Impax, and Dr.Reddy’s, and has been compensated for expert legal testimony. He has grant support from Allergan, Amgen, MAP pharmaceuticals, and Merck, Sharpe and Dohme. He has received honoraria for editorial work from Journal Watch Neurology and for developing educational materials and teaching for the American Headache Society. JH and PJG have received no funding for writing this review.
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J. Hoffmann, P. J. Goadsby 46. Weatherall MW, Telzerow AJ, Cittadini E, Kaube H, Goadsby PJ. Intravenous aspirin (lysine acetylsalicylate) in the inpatient management of headache. Neurology. 2010;75(12):1098–103. 47. Limmroth V, May A, Auerbach P, Wosnitza G, Eppe T, Diener HC. Changes in cerebral blood flow velocity after treatment with sumatriptan or placebo and implications for the pathophysiology of migraine. J Neurol Sci. 1996;138(1–2):60–5. 48. Kruuse C, Thomsen LL, Birk S, Olesen J. Migraine can be induced by sildenafil without changes in middle cerebral artery diameter. Brain. 2003;126(Pt 1):241–7. 49. Goldstein DJ, Roon KI, Offen WW, Ramadan NM, Phebus LA, Johnson KW, et al. Selective serotonin 1F (5-HT1F) receptor agonist LY334370 for acute migraine: a randomised controlled trial. Lancet. 2001;358(9289):1230–4. 50. Ferrari MD, Farkkila M, Reuter U, Pilgrim A, Davis C, Krauss M, et al. Acute treatment of migraine with the selective 5-HT1F receptor agonist lasmiditan—a randomised proof-of-concept trial. Cephalalgia. 2010;30(10):1170–8. 51. Nelson DL, Phebus LA, Johnson KW, Wainscott DB, Cohen ML, Calligaro DO, et al. Preclinical pharmacological profile of the selective 5-HT1F receptor agonist lasmiditan. Cephalalgia. 2010;30(10):1159–69. 52. Farkkila M, Diener HC, Geraud G, Lainez M, Schoenen J, Harner N, et al. Efficacy and tolerability of lasmiditan, an oral 5-HT(1F) receptor agonist, for the acute treatment of migraine: a phase 2 randomised, placebo-controlled, parallel-group, dose-ranging study. Lancet Neurol. 2012;11:405–13. 53. Tassorelli C, Joseph SA. Systemic nitroglycerin induces Fos immunoreactivity in brainstem and forebrain structures of the rat. Brain Res. 1995;682(1–2):167–81. 54. De Col R, Koulchitsky SV, Messlinger KB. Nitric oxide synthase inhibition lowers activity of neurons with meningeal input in the rat spinal trigeminal nucleus. Neuroreport. 2003;14(2):229–32. 55. Lin Q, Palecek J, Paleckova V, Peng YB, Wu J, Cui M, et al. Nitric oxide mediates the central sensitization of primate spinothalamic tract neurons. J Neurophysiol. 1999;81(3):1075–85. 56. Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An association between migraine and cutaneous allodynia. Ann Neurol. 2000;47(5):614–24. 57. Burstein R, Cutrer MF, Yarnitsky D. The development of cutaneous allodynia during a migraine attack clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. Brain. 2000;123(Pt 8):1703–9. 58. Hoskin KL, Bulmer DC, Goadsby PJ. Fos expression in the trigeminocervical complex of the cat after stimulation of the superior sagittal sinus is reduced by L-NAME. Neurosci Lett. 1999;266(3):173–6. 59. Lambert GA, Hoskin KL, Zagami AS. Nitrergic and glutamatergic neuronal mechanisms at the trigeminovascular first-order synapse. Neuropharmacology. 2004;47(1):92–105. 60. Olesen J, Thomsen LL, Iversen H. Nitric oxide is a key molecule in migraine and other vascular headaches. Trends Pharmacol Sci. 1994;15(5):149–53. 61. Olesen J, Iversen HK, Thomsen LL. Nitric oxide supersensitivity: a possible molecular mechanism of migraine pain. Neuroreport. 1993;4(8):1027–30. 62. Afridi SK, Kaube H, Goadsby PJ. Glyceryl trinitrate triggers premonitory symptoms in migraineurs. Pain. 2004;110(3):675–80. 63. Giffin NJ, Ruggiero L, Lipton RB, Silberstein SD, Tvedskov JF, Olesen J, et al. Premonitory symptoms in migraine: an electronic diary study. Neurology. 2003;60(6):935–40. 64. Lassen LH, Ashina M, Christiansen I, Ulrich V, Olesen J. Nitric oxide synthase inhibition in migraine. Lancet. 1997;349(9049):401–2. 65. Hoffmann J, Goadsby PJ. New agents for acute treatment of migraine: CGRP receptor antagonists, iNOS inhibitors. Curr Treat Options Neurol. 2011;14:50–9.
Emerging Targets in Migraine 66. Olesen J. Nitric oxide-related drug targets in headache. Neurotherapeutics. 2010;7(2):183–90. 67. Palmer JE, Guillard FL, Laurijssens BE, Wentz AL, Dixon RM, Williams PM. A randomised, single-blind, placebo-controlled, adaptive clinical trial of GW274150, a selective iNOS inhibitor, in the treatment of acute migraine. Cephalalgia. 2009;29:124. 68. Hoivik HO, Laurijssens BE, Harnisch LO, Twomey CK, Dixon RM, Kirkham AJ, et al. Lack of efficacy of the selective iNOS inhibitor GW274150 in prophylaxis of migraine headache. Cephalalgia. 2010;30(12):1458–67. 69. Høye KLB, Harnisch LO, Twomey CK, Dixon RM, Kirkham A, Williams PM, Wentz AL. Efficacy and tolerability of the iNOS inhibitor GW274150 administered up to 120 mg daily for 12 weeks in the prophylactic treatment of migraine. Cephalalgia. 2009;29:132. 70. Alderton WK, Angell ADR, Craig C, Dawson J, Garvey E, Moncada S, et al. GW274150 and GW273629 are potent and highly selective inhibitors of inducible nitric oxide synthase in vitro and in vivo. Br J Pharmacol. 2005;145(3):301–12.
17 71. De Alba J, Clayton NM, Collins SD, Colthup P, Chessell L, Knowles RG. GW274150, a novel and highly selective inhibitor of the inducible isoform of nitric oxide synthase (NOS), shows analgesic effects in rat models of inflammatory and neuropathic pain. Pain. 2006;120(1–2):170–81. 72. Bhatt DK, Gupta S, Jansen-Olesen I, Andrews JS, Olesen J. NXN-188, a selective nNOS inhibitor and a 5-HT1B/1D receptor agonist, inhibits CGRP release in preclinical migraine models. Cephalalgia. 2013;33(2):87–100. 73. Deval E, Gasull X, Noel J, Salinas M, Baron A, Diochot S, et al. Acid-sensing ion channels (ASICs): pharmacology and implication in pain. Pharmacol Ther. 2010;128(3):549–58. 74. Hadjikhani N, Sanchez Del Rio M, Wu O, Schwartz D, Bakker D, Fischl B, et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A. 2001;98(8):4687–92. 75. Holland PR, Akerman S, Andreou AP, Karsan N, Wemmie JA, Goadsby PJ. Acid-sensing ion channel 1: a novel therapeutic target for migraine with aura. Ann Neurol. 2012;72(4):559–63.
REVIEW ARTICLE
Emerging Targets in Migraine Jan Hoffmann • Peter J. Goadsby
Published online: 8 December 2013 Ó Springer International Publishing Switzerland 2013
Abstract Migraine is a common and highly disabling neurological disorder. Despite the complexity of its pathophysiology, substantial advances have been achieved over the past 20 years in its understanding, as well as the development of pharmacological treatment options. The development of serotonin 5-HT1B/1D receptor agonists (‘‘triptans’’) substantially improved the acute treatment of migraine attacks. However, many migraineurs do not respond satisfactorily to triptans and cardiovascular comorbidities limit their use in a significant number of patients. As migraine is increasingly considered to be a disorder of the brain, and preclinical and clinical data indicate that the observed vasodilation is merely an epiphenomenon, research has recently focused on the development of neurally acting compounds that lack vasoconstrictor properties. This review highlights the most important pharmacological targets for which compounds have been developed that are highly likely to enter or have already advanced into clinical trials for the acute and preventive treatment of migraine. In this context, preclinical and clinical data on compounds acting on calcitonin gene-related peptide or its receptor, the 5-HT1F receptor, nitric oxide synthase, and acid-sensing ion channel blockers are discussed.
1 Introduction Migraine is one of the most common and disabling neurological disorders and its economic impact ranges among the highest of all neurological diseases [1–5]. Still, public awareness of this socioeconomic burden is small and research funding is limited compared to other neurological research areas. However, significant advances in the acute and prophylactic treatment of migraine have been achieved over the past 20 years. The serotonin 5-HT1B/1D agonists (‘‘triptans’’) have revolutionized the acute treatment of migraine attacks and changed the lives of millions of migraineurs worldwide [6]. Preventive treatment options for episodic and chronic migraine have also been substantially expanded with new drugs such as topiramate [7–9] and onabotulinum toxin A [10–12]. Nevertheless, none of the preventive drugs available are migraine specific and all available pharmacological approaches, acute or preventive, are only effective in a limited number of migraineurs. In addition, the lack of individual predictability for the efficacy of a specific compound complicates treatment and patient compliance. Therefore, despite multiple available pharmacological treatment options, there is a significant need for novel therapeutic drugs for the acute and preventive treatment of migraine [13]. This review focuses on the most relevant new pharmacological targets.
2 Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonists (‘‘Gepants’’) J. Hoffmann P. J. Goadsby (&) Headache Group, Department of Neurology, University of California, San Francisco, 1701 Divisadero St, San Francisco, CA 94115, USA e-mail: [email protected]
Calcitonin gene-related peptide (CGRP) is a vasoactive neuropeptide located on unmyelinated C-fibers and thinly myelinated Ad-fibers of the trigeminal nerve system. It can be found in peripheral parts of the trigeminal system, such
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as the trigeminal ganglion [14, 15] or the perivascular nerve fibers surrounding meningeal blood vessels [16], as well as on its central parts such as the trigeminovascular complex (TCC), thalamus, and hypothalamus [17, 18]. Interestingly, it is also located on inhibitory structures such as the periaqueductal gray (PAG) [17]. Due to its potent vasodilator properties [19], it was initially postulated that this effect was relevant for its role in migraine pathophysiology [20]. However, it became clear that migraine is mainly a disorder of the brain rather than of peripheral structures, such as the meninges or its blood vessels [21– 23], and preclinical studies have been conducted that demonstrated the ability of CGRP to modulate neuronal activity in the TCC [24]. Further experimental data indicate its involvement in the transmission of pain signals from the TCC to higher brain regions such as the thalamus and cortex [23]. From a clinical perspective, the causal relationship between migraine and CGRP became evident after a series of clinical studies demonstrated that CGRP concentrations are elevated during spontaneous migraine attacks and return to baseline levels after sumatriptan treatment [25– 27]. Further studies showed that CGRP infusion in migraineurs is able to trigger migraine without aura [28]. The relevance of CGRP was finally confirmed in a proof-ofconcept trial that demonstrated clinical efficacy of the CGRP receptor antagonist BIBN4096BS (olcegepant) in the acute treatment of migraine [29]. However, its exact site of action, peripheral or central, has not yet been elucidated. In this context, it also remains to be clarified to what extent CGRP receptor antagonists are able to cross the blood–brain barrier, and whether the blood–brain barrier remains intact during a migraine attack. Research efforts then focused on the development of compounds that allow oral administration. As a result several ‘‘gepants’’ were developed and multiple clinical trials tested their efficacy. The first orally available CGRP receptor antagonist, telcagepant (MK-0974), was proven to be effective in the acute treatment of migraine [30–32]. Clinical trials demonstrated efficacy for 2-h pain relief, 2-h pain freedom, as well as sustained pain freedom for 2–24 and 2–48 h [31, 32]. In addition to being effective in pain relief, it was effective in alleviating associated symptoms such as nausea, photophobia, and phonophobia. BI44370TA is another orally available CGRP receptor antagonist that was found to be effective when tested in a phase II trial [33]. Unfortunately, despite being generally well-tolerated, these promising results were hampered after some patients in a trial investigating the potential of telcagepant as a preventive showed significant increases in liver transaminases [34]. Although these patients had received telcagepant twice daily and the enzyme elevations were not observed in the trials for the acute treatment of
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migraine, further research on the compound was terminated [34]. Research efforts on a second CGRP receptor antagonist, MK-3207, that was characterized by a higher bioavailability and potency was also terminated [35, 36]. Although it is not clear if the observed liver toxicity is a class effect or specifically tied to both MK-compounds, Boehringer Ingelheim also stopped further development on BI44370TA. However, Bristol-Myers Squibb initially developed the CGRP receptor antagonist BMS846372, which was further modified to increase aqueous solubility leading to the development of BMS-927711, and has now been demonstrated to be effective in acute migraine [37].
3 Monoclonal Antibodies Against CGRP or its Receptor Targeting CGRP [38] or elements of its receptor [39] with monoclonal antibodies has drawn much attention as a potential new pharmacological approach for the acute and prophylactic treatment of migraine. In principle, disruption of CGRP function in this way may have a similar beneficial effect on migraine as that observed with CGRP receptor antagonists. Compared with CGRP receptor antagonists, preclinical studies revealed a slower onset of action and a far longer half-life, which in theory suggest utility in prevention [38]. Initial preclinical studies addressing safety concerns for the use of monoclonal CGRP antibodies indicate that these molecules do not seem to affect heart rate and arterial blood pressure [38]. However, based on these data, a clear statement on its safety in patients with significant vascular pathology is currently not possible. Therefore, despite these promising results, further studies are needed to clarify the safety of these compounds. Preclinical studies using a monoclonal antibody against a C-terminal epitope of human a-CGRP (muMab7E9) were conducted on two established in vivo rat blood flow models known to be predictive of clinical efficacy to elucidate a potential effect in the treatment of migraine [40]. Intravenous administration of the anti-CGRP antibody inhibited electrically induced vasodilation of the skin or the middle meningeal artery (MMA), a mechanism that is mainly based on the neurogenic release of CGRP from sensory afferents [38]. The extent of the observed inhibition was similar to that observed in preclinical studies using CGRP receptor antagonists. The antibody was characterized by a slow onset as treatment effect after a single dose of antiCGRP antibody was achieved 1–2 h after administration and lasted for at least 7 days. Another potent selective human monoclonal antibody against CGRP developed by Eli Lilly and Company, LY2951742, impedes CGRP from binding to its receptor. Preclinical studies with subcutaneously administered
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LY2951742 demonstrated its ability to prevent capsaicininduced increase of dermal blood flow in rats, non-human primates, and healthy human volunteers [41]. The results of a safety, tolerability, and pharmacokinetic study of single, escalating subcutaneous doses of LY2951742 have not yet become available (NCT01337596). Currently, a phase II randomized, double-blind, placebo-controlled trial in migraineurs with or without aura is in progress to assess the efficacy and safety of LY2951742 (150 mg) in the prevention of migraine during 3 months of treatment (NCT01625988). Amgen developed a selective human monoclonal antibody, AA95, against the human CGRP receptor which was tested in a preclinical study using an in vivo model of capsaicin-induced increase of dermal blood flow in cynomolgus monkey. Intravenous administration of AA95 induced a dose-dependent inhibition of capsaicin-induced increase of dermal blood flow that lasted up to 7 days [39]. Taken together, interfering in CGRP function with selective monoclonal antibodies appears to be a promising pharmacological approach for the treatment of migraine. However, further studies on efficacy and safety are needed to clarify its potential for clinical use.
4 Serotonin 5-HT1F Receptor Agonists (‘‘Ditans’’) The effect of triptans is based on agonism at the 5-HT1B/1D receptors, and certainly some triptans act at the 5-HT1F receptor. The 5-HT1B and 5-HT1D receptors are located on meningeal arteries and peripheral trigeminal neurons, respectively [42]. However, in a migraine context, 5-HT1F receptors are found in the trigeminocervical complex (TCC), as are the 5-HT1B and 5-HT1D receptors, and in the trigeminal ganglion [42]. In experimental in vivo models of migraine, activation of 5-HT1F receptors inhibits neuronal activity in the TCC of the rat [43]. Initially, the peripheral component of triptans’ action was believed to be the crucial element of their mechanism. However, as experimental and clinical evidence indicates more and more that migraine is mainly a disorder of the brain [21], research efforts have expanded to the central 5-HT effects. The vascular component is now considered to be more an accompanying epiphenomenon than a causal mechanism of migraine [21, 22], with therapeutic indications coming from non-steroidal anti-inflammatory drugs (NSAIDs) [44–46] and CGRP receptor antagonists [29, 30, 32, 33], which are effective in migraine treatment and do not significantly constrict meningeal blood vessels. This is further supported by the fact that sumatriptan-induced pain relief does not correlate with the induced vasoconstriction [47]. Moreover, sildenafil is able to induce migraine without any change in the diameter of the middle cerebral artery [48]. As a result,
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5-HT1F receptor antagonists (‘‘ditans’’) were developed as they have no vasoconstrictor actions. The first neurally active, indole-based, selective 5-HT1F receptor agonist that was investigated in a randomized, double-blind, placebo-controlled, parallel-design clinical trial, LY334370, proved to be effective for the acute treatment of migraine attacks [49]. The primary endpoint, sustained response rate at 2 h, which was defined as a reduction in migraine headache from moderate or severe to mild or none at 2 h after dosing, without worsening within 24 h or the use of rescue medication, was reached by the group taking 60 mg (n = 30) and 200 mg (n = 21) [49]. Unfortunately, adverse events were frequent, with asthenia, dizziness, and somnolence being the most common ones reported [49]. Due to compound-specific safety concerns in animals, clinical development was stopped [50]. However, based on these results the centrally acting 5-HT1F receptor agonist lasmiditan (COL-144, LY573144), with a novel pyridinoyl-piperidine structure that is characterized by a higher receptor selectivity, has been developed [51]. In a clinical trial using a prospective, randomized, double-blind, placebo-controlled design with group-sequential adaptivetreatment assignment, intravenously administered lasmiditan proved to be effective for the acute treatment of migraine attacks at doses above 20 mg [50]. Adverse events were reported by 65 % of the subjects treated with lasmiditan (n = 88) compared with 45 % in the placebo group (n = 42) [50]. Efficacy of an oral formulation of lasmiditan was demonstrated in a phase II randomized, double-blind, parallel-group, dose-ranging study involving 391 patients. The primary endpoint, dose response for headache relief at 2 h, was achieved for 50, 100, 200, and 400 mg [52]. The efficacy in comparison with triptans and its safety in patient groups that cannot use triptans due to their vasoconstrictive properties, such as patients with a history of stroke or myocardial infarction, will finally define the future of this pharmacological mechanism in the treatment of acute migraine attacks.
5 Nitric Oxide Synthase Inhibitors Nitric oxide (NO) is involved in many physiological processes. Its most important property is the ability to induce vasodilation including cerebral and extracerebral arteries. Beside its vascular properties, NO is able to modulate neuronal activity in several regions of the CNS, including the PAG [53] as well as neurons of the TCC that receive meningeal input [54]. Furthermore, experimental data indicate an involvement of NO in the establishment of central sensitization [55], which is believed to be the pathophysiological correlate of migraine-associated allodynia [56, 57]. Interestingly, in animal models the systemic
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[54, 58] as well as the microiontophoretic administration of NO synthase (NOS) inhibitors [59] into the TCC reduce neuronal activity in the TCC. From a clinical perspective, the relationship between NO and migraine has a long history. The observation that workers in explosives factories had a significantly higher incidence of migraine led to the suspicion that glyceryl trinitrate (GTN), an NO-donor, was the responsible molecule for the attack induction. This idea was confirmed by a clinical study demonstrating that intravenous administration of GTN in migraineurs reliably induces migraine attacks without aura [60, 61]. Years later, Afridi et al. [62] showed that GTN not only induces the migraine attack itself, but also the preceding premonitory symptoms, which were identical to those reported in spontaneous migraine attacks [63] thereby highlighting the neuronal effects of NO. Based on these observations, several NOS inhibitors were developed and investigated in clinical trials. In principle, all three NOS isoforms, the neuronal (nNOS), endothelial (eNOS), and inducible (iNOS) NOS isoforms, could represent a potential pharmacological target. However, since in the context of migraine pathophysiology the neuronal effects of NO appear to prevail, the search for therapeutic compounds quickly shifted from non-specific NOS inhibitors to those that target only specific isoforms that have more influence on NO production at the neuronal level, namely nNOS and iNOS. However, the first compound tested for the treatment of acute migraine attacks was the non-specific NOS inhibitor L-NG methylarginine hydrochloride (L-NMMA) [64]. Despite encouraging response rates of 67 % in the L-NMMA group compared with 14 % in the placebo group, the results have to be interpreted with caution as the study suffered from some methodological shortcomings [65]. Poor oral absorption and an associated increase in systemic blood pressure as a result of eNOS inhibition made this compound unsuitable for clinical use [66]. More recently, the iNOS inhibitor GW274150 was tested for the acute [67] and preventive [68, 69] treatment of migraine. Despite the high efficacy of GW274150 in iNOS inhibition [70, 71], both well-designed trials were negative. Initial results with a novel nNOStriptan combination drug NXN-188 suggest that more needs to be understood to exploit this direction. However, preclinical results are encouraging as in experimental migraine models NXN-188 inhibits CGRP release [72].
6 Acid-Sensing Ion Channel Blockers Acid-Sensing Ion Channels (ASICs) are a family of cation channels gated by extracellular protons [73]. They are located in the peripheral and central nervous system and are expressed on sensory neurons of the cranial meninges
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as well as the trigeminal, vagal, and dorsal root ganglion [73]. The ASIC1a subunit is mainly found in the CNS and the ASIC3 subunit is largely located in the peripheral nervous system [73]. ASICs act as a sensor to decreased extracellular pH, which occurs during inflammatory pain in the periphery or central electrical events, such as cortical spreading depression (CSD), which is believed to be the pathophysiological correlate of migraine aura [74]. Therefore, they act as chemo-electric transducers. Due to their function and anatomical location, ASICs are of increasing interest as a potential therapeutic target for the treatment of migraine. In a series of preclinical in vivo studies and a small sample of patients with refractory migraine with prolonged aura, Holland et al. [75] investigated the effect of the potassium-sparing diuretic amiloride, the first blocker of ASICs to be described. In the experimental in vivo models of migraine, the authors demonstrated that intravenous amiloride 10 mg/kg significantly inhibited needle prickinduced CSDs. In transgenic mice with a deletion of the ASIC1-producing ACCN2 gene, the effect of amiloride was not observed. Taken together, the data suggest a potential therapeutic effect on migraine aura. Furthermore, amiloride inhibited neurogenic vasodilation of the MMA and stimulus-induced neuronal activity in the TCC, indicating an inhibitory effect on nociceptive processing within the trigeminal system and suggesting a pain-relieving effect in migraine. In the small open-label pilot study on seven migraineurs suffering from refractory migraine with persistent aura, the intravenous administration of amiloride 10–20 mg/kg/day significantly reduced headache severity and the frequency of aura in four patients during the observation period of 6–24 months [75]. In conclusion, preclinical and clinical data strongly suggest a possible therapeutic effect on migraine and migraine aura, highlighting the need for randomized placebo-controlled clinical trials.
7 Conclusions Despite the evident relief and increase in quality of life that triptans have brought to many migraineurs, there is still a substantial need for novel pharmacological strategies for the treatment of migraine. Among the broad range of pharmacological targets currently under investigation, CGRP and its receptor, the 5-HT1F receptor, NOS, and ASICs are among the targets that have the potential for clinical efficacy and are likely to enter or have already entered clinical trials. While clinical trials on CGRP receptor antagonists demonstrated their clinical efficacy, two advanced compounds have been hampered by liver toxicity issues. In contrast, antibodies against CGRP or its
Emerging Targets in Migraine
receptor may offer similar beneficial effects combined with a long-lasting effect that may reduce the risk of recurrence headache. Trials on 5-HT1F receptor agonists have shown clinical efficacy and their development is awaited with interest. Clinical efficacy could not be demonstrated for the acute and prophylactic treatment of migraine by iNOS inhibitors, and nNOS is now likely to be explored. In contrast, ASIC blockers may offer a completely novel pharmacological approach and initial positive results from preclinical studies have been complemented by the promising results of a small open-label study that suggests clinical efficacy for migraine and migraine aura. However, placebo-controlled randomized trials are needed to confirm these preliminary results. Acknowledgments JH has received honoraria for editorial work from Journal Watch Neurology and travel support from Allergan. PJG is on Advisory Boards for Allergan, Colucid, MAP pharmaceuticals, Merck, Sharpe and Dohme, eNeura, Neuraxon, Autonomic Technologies Inc., Boston Scientific, Electrocore, Eli-Lilly, Medtronic, Linde Industrial Gases, Arteaus, AlderBio, and Bristol-Myers Squibb. He has consulted for Pfizer, Nevrocorp, Lundbeck, Zogenix, Impax, and Dr.Reddy’s, and has been compensated for expert legal testimony. He has grant support from Allergan, Amgen, MAP pharmaceuticals, and Merck, Sharpe and Dohme. He has received honoraria for editorial work from Journal Watch Neurology and for developing educational materials and teaching for the American Headache Society. JH and PJG have received no funding for writing this review.
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