TREATMENTS FOR ACUTE MIGRAINE: WHAT’S ON THE HORIZON?Mark Weatherall

BASH Hull 2011

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 finallyfrovatriptan

WHY DO WE NEED NEW OPTIONS?

poor response to current treatments tolerability issues contraindications

stroke MI/IHD hypertension

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

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)

THE SEROTONIN RECEPTOR FAMILIES

seven families of serotonin receptors triptans are agonists at 5-HT1B/1D receptors

5-HT1B predominate in meningeal vessel walls

5-HT1D predominate in trigeminal nerve fibres

a specific 5-HT1D agonist (PNU-142633) inhibits PPE potently, but was ineffective in clinical studies ? weak agonist ?? PPE not relevant in migraine

pathogenesis

5-HT1F – A POSSIBLE TARGET?

5-HT1F receptors are found in trigeminal ganglion & TNC; no vasocontrictor activity

LY-334370, a potent 5-HT1F agonist, was effective against migraine, but caused unacceptable SE

Proof-of-concept study of COL-144 (lasmitidan), an oral 5-HT1F agonist, was published in Cephalalgia 2010

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

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

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

GLUTAMATE RECEPTOR ANTAGONISTS

glutamate central in sensory & nociceptive systems throughout the CNS glutamate neurons in trigeminal ganglia express

predominately 5-HT1B/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

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 TRPV1antagonist, in phase II studies

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 & 5HT1B/1D agonist has

shown more positive results in Phase II

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?

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

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)

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 followedby a wave ofinhibition

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

IN SUMMARY, THEREFORE...the future’s bright

(though not too bright, please)

THANK YOU