Supplementary Table 1 | Migraine therapeutics that have been tested in clinical trials
Mechanism/indication
Treatment
Calcitonin gene-related peptide (CGRP) mechanism antagonist
CGRP receptor antagonist (gepant)
Olcegepant1
Telcagepant, acute2
Telcagepant, preventative3
Rimagepant4
BI44370TA5
MK-32076
MK-1602 (NCT01613248)
CGRP antibody
ALD-4037
LY-29517428
LDR-101/TEV-481259,10
Current stage
Phase II
Phase II
Phase II*
Phase II
Phase II
Phase II*
Phase II
Phase III
Phase III
Phase III
CGRP receptor antibody
Serotonin-related
5-HT1F receptor agonist (ditan)
Nitric oxide synthase (NOS) inhibition
Pan NOS
AMG-33411
Phase III
Lasmiditan12
Phase III
546C8813
Phase II
Inducible NOS
GW274150 acute14
GW274150 preventive15
Phase II (F)
Phase II (F)
Neuronal NOS plus triptan
Glutamatergic targets
NMDA receptor migraine with prolonged aura
NXN-18816,17
Phase II (F)
Ketamine18
Phase II
Prevention of aura, not headache
Tonabersat19,20
Phase II
AMPA/kainate
Tezampanel/LY29355821
Phase II
iGluR5 (kainate) receptor
LY46619522
Phase II
mGluR5 (glurants)
ADX1005923
Phase II
AMPA receptor antagonist
Neuroinflammatory targets
TRPV1
BGG49224
Phase II (F)
SB-70549825
Phase II (F)
Phase II (F)
Substance P/neurokinin-1
Dapitant26
Lanepitant27
GR20517128
L-758,29829
Lanepitant,30 prevention
Phase II (F)
Phase II (F)
Phase II (F)
Phase II (F)
Phase II (F)
Neurogenic plasma protein extravasation (PPE)
CP-122,28831
4991W9332
Phase II (F)
Phase II (F)
Filorexant33
Phase II (F)
Candesartan33,35
Telmisartan36
Off-license
(F)
Other targets
Orexin 1 and 2 receptors (rexants)
Angiotensin receptor
Emerging targets
Acid-sensing ion channel (ASICs)
Amiloride37
Pituitary adenylate cyclase activating peptide (PACAP)
PACAP receptor antagonists38–40
Neuronal NOS
Neuronal NOS inhibition41
Phosphodiesterase inhibition
Neuromodulation strategies
Transcranial magnetic stimulation (TMS)
Ibudilast42
Single pulse TMS43,44
Marketed
Occipital nerve stimulation (ONS)
Chronic migraine45–47
Phase II (F)
Transcutaneous vagal nerve stimulation
Gammacore
Supraorbital nerve stimulation
Cefaly50
device48,49
Sphenopalatine ganglion stimulation
ATI device (NCT01540799)
(F): Study failed; * Liver toxicity led to termination of development
Phase II (F)
Marketed
Phase II
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
Olesen, J. et al. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of
migraine. New England Journal of Medicine 350, 1104–1110 (2004).
Ho, T.W. et al. Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related
peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, paralleltreatment trial. Lancet 372, 2115–2123 (2008).
Ho, T.W. et al. Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention.
Neurology (Minneap.) 83, 958–966 (2014).
Marcus, R. et al. BMS-927711 for the Acute Treatment of Migraine: A Double-Blind, Randomized, PlaceboControlled, Dose-Ranging Trial. Cephalalgia 33, 94 (2013).
Diener, H.-C. et al. BI 44370 TA, an oral CGRP antagonist for the acute treatment of migraine attacks: results from
a phase II study. Cephalalgia 31, 573–584 (2011).
Hewitt, D.J. et al. Randomized controlled trial of the CGRP receptor antagonist, MK-3207, in the acute treatment
of migraine. Cephalalgia 31, 712–722 (2011).
Dodick, D.W. et al. Randomized, Double-blind, Placebo-controlled, Phase II Trial of ALD403, an anti-CGRP peptide
antibody in the prevention of frequent episodic migraine. Lancet Neurology 13, 1100–1107 (2014).
Dodick, D.W. et al. CGRP Monoclonal Antibody LY2951742 for the Prevention of Migraine: A Phase 2,
Randomized, Double-Blind, Placebo-Controlled Study. Lancet Neurology 13, 885–892 (2014).
Bigal, M.E. et al. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency
episodic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet
Neurology, in press (2015).
Bigal, M.E. et al. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a
multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurology, in press (2015).
Lenz, R. et al. Results of a randomized, double-blind, placebo controlled, phase 2 study to evaluate the efficacy
and safety of AMG 334 for the prevention of episodic migraine. Cephalalgia 35, 5 (2015).
Farkkila, M. 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 11, 405–413 (2012).
Lassen, L.H., Ashina, M., Christiansen, I., Ulrich, V. & Olesen, J. Nitric oxide synthesis inhibition in migraine. The
Lancet 349, 401–402 (1997).
Palmer, J.E. et al. A randomised, single-blind, placebo-controlled, adaptive clinical trial of GW274150, a selective
iNOS inhibitor, in the treatment of acute migraine. Cephalalgia 29, 124 (2009).
Hoye, K. et 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 29, 132 (2009).
Medve, R.A. & Andrews, J.S. Effects of fixed dose combination of nNOS inhibition and 5HT agonism on
progression of migraine with and without aura. Cephalalgia 29, 126 (2009).
Hougaard, A., Hauge, A.W., Guo, S. & Tfelft-Hansen, P. The nitric oxide synthase inhibitor and serotonin-receptor
agonist NXN-188 during the aura phase of migraine with aura: a randomized, double-blind, placebo-controlled
cross-over study. Scandinavian Journal of Pain 4, 48–52 (2013).
Afridi, S., Giffin, N.J., Kaube, H. & Goadsby, P.J. A randomized controlled trial of intranasal ketamine in migraine
with prolonged aura. Neurology 80, 642–647 (2013).
Hauge, A.W., Asghar, M.S., Schytz, H.W., Christensen, K. & Olesen, J. Effects of tonabersat on migraine with aura:
a randomised, double-blind, placebo-controlled crossover study. Lancet Neurology 8, 718–723 (2009).
Goadsby, P.J., Ferrari, M.D., Csanyi, A., Olesen, J. & Mills, J.G. Randomized double blind, placebo-controlled
proof-of-concept study of the cortical spreading depression inhibiting agent tonabersat in migraine prophylaxis.
Cephalalgia 29, 742–750 (2009).
Sang, C.N. et al. LY293558, a novel AMPA/GluR5 antagonist, is efficacious and well-tolerated in acute migraine.
Cephalalgia 24, 596–602 (2004).
Johnson, K.W. et al. in Innovative Drug Development for Headache Disorders (eds. Olesen, J. & Ramadan, N.)
185–194 (Oxford University Press, Oxford, 2008).
Varon, S. F. et al. Healthcare resource utilization patterns among individuals with chronic migraine (CM) and
episodic migraine (EM). Cephalalgia 29, 60–61 (2009).
Gomez-Mancilla, B. et al. Randomized, multicenter trial to assess the efficacy, safety and tolerability of a single
dose of a novel AMPA receptor antagonist BGG492 for the treatment of acute migraine attacks. Cephalalgia 34,
103–113 (2014).
Chizh, B. et al. A randomised, two-period cross-over study to investigate the efficacy of the Trpv1 antagonist SB705498 in acute migraine. Eur J Pain 13, S202a–S202 (2009).
Diener, H.-C. & The RPR100893 Study Group. RPR100893, a substance-P antagonist, is not effective in the
treatment of migraine attacks. Cephalalgia 23, 183–185 (2003).
Goldstein, D.J. et al. Ineffectiveness of neurokinin-1 antagonist in acute migraine: a crossover study. Cephalalgia
17, 785–790 (1997).
Connor, H.E. et al. Clinical evaluation of a novel, potent, CNS penetrating NK1 receptor antagonist in the acute
treatment of migraine. Cephalalgia 18, 392 (1998).
Norman, B., Panebianco, D. & Block, G.A. A placebo-controlled, in-clinic study to explore the preliminary safety
and efficacy of intravenous L-758,298 ( a prodrug of the NK1 receptor antagonist L-754,030) in the acute
treatment of migraine. Cephalalgia 18, 407 (1998).
Goldstein, D.J. et al. Lanepitant, an NK-1 antagonist, in migraine prevention. Cephalalgia 21, 102–106 (2001).
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
Roon, K.I. et al. No acute antimigraine efficacy of CP-122,288, a highly potent inhibitor of neurogenic
inflammation: results of two randomized double-blind placebo-controlled clinical trials. Annals of Neurology 47,
238–241 (2000).
Earl, N.L., McDonald, S.A., Lowy, M.T. & 4991W93 Investigator Group. Efficacy and tolerability of the neurogenic
inflammation inhibitor, 4991W93, in the acute treatment of migraine. Cephalalgia 19, 357 (1999).
Chabi, A. et al. Randomized controlled trial of the orexin receptor antagonist filorexant for migraine prophylaxis.
Cephalalgia 35, 379–388 (2015).
Stovner, L.J. et al. A comparative study of candesartan versus propranolol for migraine prophylaxis: A
randomised, triple-blind, placebo-controlled, double cross-over study. Cephalalgia 34, 523–532 (2014).
Tronvik, E., Stovner, L.J., Helde, G., Sand, T. & Bovim, G. Prophylactic treatment of migraine with an angiotensin II
receptor blocker: a randomized controlled trial. Journal of the American Medical Association 289, 65–69 (2003).
Diener, H.C. et al. Telmisartan in migraine prophylaxis: a randomized, placebo-controlled trial. Cephalalgia 29,
921–927 (2009).
Holland, P.R. et al. Acid-sensing ion channel-1: a novel therapeutic target for migraine with aura. Annals of
Neurology 72, 559–563 (2012).
Amin, F.M. et al. Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary
adenylate cyclase-activating polypeptide-38. Brain 137, 779–794 (2014).
Zagami, A.S., Edvinsson, L. & Goadsby, P.J. Pituitary adenylate cyclase activating polypeptide and Migraine.
Annals of Clinical and Translational Neurology 1, 1036–1040 (2014).
Akerman, S. & Goadsby, P.J. Neuronal PAC1 receptors mediate delayed activation and sensitization of
trigeminocervical neurons: relevance to migraine. Science Translational Medicine 7, 308ra157 (2015).
Akerman, S., Williamson, D.J., Kaube, H. & Goadsby, P.J. Nitric oxide synthase inhibitors can antagonise
neurogenic and calcitonin gene-related peptide induced dilation of dural meningeal vessels. British Journal of
Pharmacology 137, 62–68 (2002).
Laursen, J.C. et al. Nitric oxide release from trigeminal satellite glial cells is attenuated by glial modulators and
glutamate. Int J Physiol Pathophysiol Pharmacol 5, 228–238 (2013).
Lipton, R.B. et al. Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: a
randomised, double-blind, parallel-group, sham-controlled trial. Lancet Neurol 9, 373–380 (2010).
Bhola, R. et al. Single-pulse transcranial magnetic stimulation (sTMS) for the acute treatment of migraine:
Evaluation of outcome data for the UK post market pilot program. Journal of Headache and Pain 16, 51 (2015).
Saper, J. et al. Occipital nerve stimulation for the treatment of intractable chronic migraine headache: ONSTIM
feasibility study. Cephalalgia 41, 271–285 (2011).
Silberstein, S. et al. The safety and efficacy of occipital nerve stimulation for the management of chronic
migraine. Cephalalgia 32, 1165–1179 (2012).
Lipton, R.B. et al. PRISM study: occipital nerve stimulation for treatment-refractory migraine. Cephalalgia 29, 30
(2009).
Goadsby, P.J., Grosberg, B.M., Mauskop, A. & Cady, R. Effect of non-invasive vagus nerve stimulation on acute
migraine: an open label pilot study. Cephalalgia 34, 986–993 (2014).
Silberstein, S.D. et al. Non-invasive Vagus Nerve Stimulation for Chronic Migraine Prevention in a Prospective,
Randomized, Sham-Controlled Pilot Study (the EVENT Study): Report from the Double-blind Phase. Headache 54,
1426 (2014).
Schoenen, J. et al. Migraine prevention with a supraorbital transcutaneous stimulator: a randomized controlled
trial. Neurology 80, 697–704 (2013).