1. TREATMENTS FOR ACUTE MIGRAINE : WHAT ’ S ON THE HORIZON ? Mark Weatherall BASH Hull 2011

2. A LITTLE HISTORY... ergot of rye 1868 salicylic acid 1870s ergotamine 1920s-30s dihydroergotamine (DHE) 1943 triptans 1990s sumatriptan then riza-, then ele-, then almo-, then zolmi-, then nara-, and finally frovatriptan

3. WHY DO WE NEED NEW OPTIONS ? poor response to current treatments tolerability issues contraindications stroke MI/IHD hypertension

4. WHAT APPROACHES ARE BEING TAKEN ? identify novel neurochemical targets (based on better understanding of migraine pathophysiology) develop new drugs for known targets develop new modes of delivering existing drugs develop non-pharmacological treatments

5. NEW ( ISH ) NEUROCHEMICAL TARGETS serotonin subtype receptors calcitonin gene-related peptide (CGRP) receptors glutamate receptors transient receptor potential vanilloid (TRPV1) receptors nitric oxide synthesis prostanoid receptors (cortical spreading depression)

7. THE SEROTONIN RECEPTOR FAMILIES seven families of serotonin receptors triptans are agonists at 5-HT 1B/1D receptors 5-HT 1B predominate in meningeal vessel walls 5-HT 1D predominate in trigeminal nerve fibres a specific 5-HT 1D agonist (PNU-142633) inhibits PPE potently, but was ineffective in clinical studies ? weak agonist ?? PPE not relevant in migraine pathogenesis

8. 5- HT 1F – A POSSIBLE TARGET ? 5-HT 1F receptors are found in trigeminal ganglion & TNC; no vasocontrictor activity LY-334370, a potent 5-HT 1F agonist, was effective against migraine, but caused unacceptable SE Proof-of-concept study of COL-144 (lasmitidan), an oral 5-HT 1F agonist, was published in Cephalalgia 2010

10. CGRP : IS THE FUTURE ‘ PANTS ’ OR ‘ GEPANTS ’? calcitonin gene-related peptide (CRGP), a potent vasodilator, is the most frequently expressed neuropeptide in trigeminal fibres and cell bodies in primary headaches, there is a clear association between the headache & CRGP release CRGP levels in the jugular vein are increased in migraine, CH & CPH CRGP levels in the antecubital vein increase in nitroglycerin-induced migraine; levels correlate with headache intensity sumatriptan normalises elevated CGRP levels as it terminates a migraine attack

11. CGRP ANTAGONISTS FOR MIGRAINE ? BIBN4096BS (olcegepant), an IV specific & potent CRGP receptor antagonist, shown in proof-of-concept trial published in 2004 to be effective and well-tolerated

12. TELCEGEPANT multicentre phase III R-PT-PC-DB-T of MK-0794 (telcagepant) oral 150/300 mg vs zolmitriptan 5 mg & placebo, published in The Lancet in December 2008

14. GLUTAMATE RECEPTOR ANTAGONISTS glutamate central in sensory & nociceptive systems throughout the CNS glutamate neurons in trigeminal ganglia express predominately 5-HT 1B/1D/1F receptors 3 subtypes of ionotropic glutamate receptors (iGluR): NDMA, AMPA, kainate LY-293558 (tezampanel), an AMPA/kainate antagonist, as effective as sumatriptan vs placebo other iGluR antagonists in Phase II trials metabotropic GluR antagonists may also be effective recent successful proof-of-concept trial of ADX10059, a mGluR5 antagonist

15. TRPV1 ANTAGONISTS TRPV1 receptors (activated by capsaicin) are found peripherally and centrally some trigeminal TRPV1 receptors may co-locate with CGRP receptors: ?involved in trigeminally-mediated sensitization SB-705498, a TRPV1 antagonist, in phase II studies

16. NITRIC OXIDE SYNTHESIS Nitric oxide (NO) is produced from nitric oxide synthetase (NOS): endothelial, neuronal & inducible NO may activate trigeminovascular fibres & release CGRP prolonged administration of triptans increases nNOS, CGRP & cutaneous allodynia GW274150, a selective iNOS inhibitor, was not effective against migraine NXN-188, a nNOS inhibitor & 5HT 1B/1D agonist has shown more positive results in Phase II

17. PROSTANOID RECEPTOR ANTAGONISTS prostaglandin E2 mediates pain and inflammation prostanoids induce CGRP release in animal models PGE2 levels are elevated in jugular venous blood in acute migraine attacks PGE2 acts through prostanoid receptors: EP4 is involved in cerebral vasular dilatation BGC20-1531, an EP4 receptor antagonist, is in phase II studies will such compounds be more effective than aspirin or the NSAIDs, which inhibit cyclo-oxygenase and thereby the production of prostaglandins?

19. THE MIGRAINE PHOENIX : DHE an old Rx: mode of action unclear DHE currently available only by IV infusion Migranal (DHE/caffeine combination) was available in the UK in the early 1990s but failed vs triptans because of inconsistent results & poor tolerability novel delivery methods are now being trialled: inhaled (MAP-004 - LEVADEX © ) now shown to be effective in phase III trials, with a trend towards better sustained pain freedom than triptans intranasal

20. YET MORE TRIPTAN CHOICES sumatriptan was originally available as s/c injection oral formulations followed rapidly, and more recently ‘melts’ and nasal sprays Sumatriptan is now out of patent needle-free injection (Intraject) transdermal patches (Zelrix) new delivery options (Optinose) combination with naproxen (SUM 85 mg NAP 500 mg)

22. TRANSCRANIAL MAGNETIC STIMULATION TMS devices deliver a brief magnetic pulse to the scalp and underlying cortex, altering firing patterns targets cortical spreading depression (CSD) CSD is a wave of excitation followed by a wave of inhibition

23. TMS FOR MIGRAINE R, DB, parallel-group, sham-controlled trial of single-pulse TMS for MA published in Lancet Neurology in 2010 significantly higher pain freedom seen with sTMS at 2, 24 and 48 hours than with sham treatment

24. IN SUMMARY, THEREFORE... the future’s bright (though not too bright, please)

25. THANK YOU