Telcagepant for acute

December 2008

This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes.

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December 2008 National Horizon Scanning Centre News on emerging technologies in healthcare

Telcagepant for acute migraine

Target group • Acute migraine: with or without aura - including multiple attacks and patients with stable vascular disease.

Background Migraine is a primary headache disorder manifesting as recurring attacks usually lasting for 4-72 hours and involving pain of moderate to severe intensity, often with nausea, sometimes vomiting, and/or sensitivity to light, sound, and other sensory stimuli. About 15% of people who have migraine experience visual or other neurological disturbance (aura)1.

Technology description Telcagepant (MK-0974) is an orally administered antagonist of the gene related (CGRP) receptor. CGRP is a that is believed to play a key role in the pathophysiology of migraine. Telcagepant blocks CGRP from binding to its receptors and is thereby thought to inhibit the transmission of pain signals that lead to migraine headaches. Telcagepant is intended for the acute treatment of migraine. The dosage is still to be determined.

Innovation and/or advantages Telcagepant is the first in a new drug class (CGRP receptor antagonists) and may have tolerability advantages when compared with .

Developer Merck & Co. Inc.

Availability, launch or marketing dates, and licensing plans: In phase III clinical trials.

NHS or Government priority area: This topic is relevant to the National Service Framework for Long-term (Neurological) Conditions (2005).

Relevant guidance • Clinical Knowledge Summaries. Migraine. 20082. • SIGN. Diagnosis and management of headache in adults. 20083. • British Association for the Study of Headache. Guidelines for all healthcare professionals in the diagnosis and management of migraine, tension-type, cluster and medication-overuse headache. 20074. • European Federation of Neurological Societies. Guideline on the drug treatment of migraine - report of an EFNS task force. 20065. • Migraine in Primary Care Advisers. Guidelines for the management of migraine in primary care: second edition. 20046.

Clinical need and burden of disease The prevalence of migraine is estimated to be between 5-25% in women and 2-10% in men. Acute migraine is self-limiting and only rarely results in permanent neurological complications. Recurrent migraine may cause disability through pain, and may affect daily functioning and quality of life1. The average duration of an untreated migraine 2 December 2008 National Horizon Scanning Centre News on emerging technologies in healthcare

attack is 18 hours and the average attack frequency is one per month5. In England, in 2007, there were 2,039,000 prescription items dispensed for acute migraine (a net ingredient cost of £62,116,000)7.

Existing comparators and treatments The current pharmaceutical options for acute migraine are: • Simple analgesics e.g. aspirin and (acetaminophen). • Non-steroidal anti inflammatory drugs (NSAIDS) e.g. ibuprofen, flurbiprofen, tolfenamic acid, naproxen sodium and diclofenac potassium. • 5HT1 agonists (triptans) e.g. , , , , , and . • Combinations of the above.

Efficacy and safety

Trial NCT002463378: NCT004429369: NCT0043223710: telcagepant vs rizatriptan or telcagepant vs zolmitriptan telcagepant vs placebo; placebo; phase II. or placebo; phase III. phase III. Sponsor Merck & Co. Inc. Merck & Co. Inc. Merck & Co. Inc. Status Published11. Published12. Complete, abstract13. Location USA. EU (incl. UK), USA. EU, Israel, Mexico, Columbia, USA. Design Randomised, double-blind, Randomised, double-blind, Randomised, double blind, placebo controlled. placebo controlled. placebo controlled. Participants n=330; 20-65 years; 1-6 n=1,380; adults; 1 year n=1,294; adults; 1 year and moderate or severe history of migraine. history of migraine. schedule migraine attacks per Randomised to telcagepant Randomised to month; no change in 150mg, 300mg, telcagepant 50mg, 150mg, migraine prophylaxis dose zolmitriptan 5mg or 300mg or placebo. within 3 months. placebo. A blinded optional A blinded optional second Stage 1 second dose of study dose of study treatment or Randomised to telcagepant treatment or own rescue own rescue medication 25, 50, 100, 200, 300, 400 medication could be taken could be taken 2 hrs or if or 600mg or rizatriptan at 2 hrs or if headache headache recurred 2-48hrs 10mg or placebo. recurred 2-48 hrs post post initial dose. A blinded optional second initial dose. dose (drug pre-specified at randomisation) 2 hrs. An interim efficacy analysis selected groups to continue into stage 2. Stage 2 Telcagepant 300, 400 or 600mg or rizatriptan 10mg or placebo groups continued. Follow-up 14 days. 14 days. 14 days. Primary Pain relief at 2hrs. Pain freedom, pain relief, Pain freedom, pain relief, outcome/s photophobia, phonophobia, photophobia, phonophobia, and nausea at 2hrs. and nausea at 2hrs. Secondary Pain freedom at 2hrs and Sustained pain freedom Sustained pain freedom outcomes sustained pain relief at from 2 to 24hrs; total from 2 to 24 hrs; total 24hrs. migraine freedom at 2hrs migraine freedom at 2hrs and 2-24 hrs. and 2 to 24hrs.

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Key results Telcagepant groups (25, Telcagepant 300mg more Telcagepant 150mg and 50, 100 and 200mg) effective than placebo for 300mg were significantly discontinued due to pain freedom (27% vs more effective than placebo insufficient efficacy. 10%; p<0·0001), pain relief on all primary and Average pain relief (55% vs 28% p<0·0001), secondary outcomes. response at 2hrs for the absences of phonophobia combined 300, 400 and (58% vs 37% p<0.0001), 600mg telcagepant groups photophobia (51% vs 29% (61.3%) compared to p<0.0001), and nausea placebo (46.3%) was (65% vs 55% p=0·0061). significant (p=0.015). The Efficacy of telcagepant overall treatment effect was 300mg and zolmitriptan also significant for pain 5mg were similar, and both freedom at 2hrs (p<0.001) were more effective than and 24hr sustained pain telcagepant 150mg. relief (p<0.001). Adverse AEs were similar among 31% of telcagepant 150mg, AEs were comparable effects active drug groups and 37% of telcagepant 300mg, between telcagepant and (AEs) higher than with placebo. 51% of zolmitriptan 5mg, placebo. 32.2% of The most common AEs and 32% of placebo groups telcagepant 50mg, 32.0% with telcagepant were reported AEs. of telcagepant 150mg, nausea, dizziness and 36.2% of telcagepant somnolence. 300mg and 32.2% of placebo groups reported AEs.

Trial NCT0066281814: telcagepant vs NCT0048370415: NCT0044320916: acetaminophen and placebo; telcagepant vs placebo; telcagepant vs stable vascular disease; phase III. phase III. rizatriptan benzoate; phase III. Sponsor Merck & Co. Inc. Merck & Co. Inc. Merck & Co. Inc. Status Ongoing. Ongoing. Ongoing. Location EU, USA and other countries. Europe (incl. UK), USA, Europe (incl. UK), Canada and other USA, Columbia and countries. Mexico. Design Randomised, double-blind, Randomised, double-blind, Randomised, double- placebo controlled, cross-over. placebo controlled. blind, active control. Participants n=400 (estimated); adults; stable n=1,800 (estimated); n=900 (estimated); and schedule vascular disease for 3 months or adults; 1 year history of adults; 1 year history more; history of migraine for migraine; 1 to 8 moderate of migraine. more than 1 year; 1-8 moderate or or severe migraine attacks Randomised to severe migraine attacks per month in the previous 2 months telcagepant or that last longer than 2hrs. lasting between 4-72hrs rizatriptan benzoate. Randomised to up to 12 doses of untreated. Duration of treatment telcagepant 300mg or 1 dose of Randomised to telcagepant 1 year. placebo and up to 11 doses of 140mg or 280mg for 4 acetaminophen (paracetamol) migraine attacks over 6 1000mg in 6 weeks, followed up months; or telcagepant to 12 doses of the other drug in 6 140mg for 1 attack and weeks. placebo for up to 3 other attacks over 6 months. Primary Pain freedom at 2hrs. Pain freedom; pain Adverse experiences, outcome/s relief; pain freedom laboratory values, consistency; pain relief ECGs, and vital consistency; absence of signs.

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photophobia; phonophobia and nausea at 2hrs post-dose. Secondary Pain relief; absence of Sustained pain freedom Pain freedom 2hrs outcomes photophobia; phonophobia and and total migraine post-dose. nausea at 2hrs; sustained pain freedom (both 2-24hrs freedom. and 2-48hrs). Expected Late 2009. Mid 2009. Mid 2009. reporting date

Estimated cost and cost impact The cost of telcagepant is yet to be determined. The cost of currently licensed oral migraine therapies isa,17:

Drug Dose Cost Tolfenamic acid 200mg repeated after 1–2hrs if necessary. £1.50 per 200mg. Diclofenac 50mg repeated after 2hrs if necessary; max. 200mg in £0.28 per 50mg. potassium 24hrs. Rizatriptan 10mg repeated after 2hrs if necessary; max. 20mg in £4.46 per 10mg. 24hrs. Zolmitriptan 2.5mg repeated after 2hrs if necessary; max. 10mg in £4.00 per 2.5mg. 24hrs.

Potential or intended impact – speculative

Patients ; Reduced morbidity: for people Reduced mortality or increased ; Improved quality of life for who do not get relief using current length of survival patients and/or carers: for people products who do not get relief using current products Quicker, earlier or more accurate Other: None identified diagnosis or identification of disease

Services Increased use Service reorganisation required Staff or training required

Decreased use Other: ; None identified

Costs Increased unit cost compared to Increased costs: more patients Increased costs: capital investment alternative coming for treatment needed New costs: Savings: ; Other: yet to be determined.

References

1 Morillo, L.E. Migraine headache. BMJ Clinical Evidence. 2003. http://clinicalevidence.bmj.com/ceweb/conditions/nud/1208/1208.jsp Accessed 07/10/08. 2 Clinical Knowledge Summaries. Migraine. http://www.cks.library.nhs.uk/migraine Accessed 20/10/08. 3 Scottish Intercollegiate Guidelines Network (SIGN). Diagnosis and management of headache in adults. 107. November 2008.

a 2 Costings based on average weight 67.5kg (men and women) and average surface area 1.7m . 5 December 2008 National Horizon Scanning Centre News on emerging technologies in healthcare

4 British Association for the Study of Headache. Guidelines for All Healthcare Professionals in the Diagnosis and Management of Migraine, Tension-Type, Cluster and Medication-Overuse Headache. 2007. http://216.25.88.43/upload/NS_BASH/BASH_guidelines_2007.pdf Accessed 14/10/08. 5 European Federation of Neurological Societies. Guideline on the drug treatment of migraine - report of an EFNS task force. 2006. http://www3.interscience.wiley.com/cgi- bin/fulltext/118554617/PDFSTART?CRETRY=1&SRETRY=0 Accessed 20/10/08. 6 Migraine in Primary Care Advisers. Guidelines for the management of migraine in primary care: second edition. 2004. http://www.mipca.org.uk/pdf/newsletters/NL8_Guidelines_2ndEd.pdf Accessed 20/10/08. 7 The Information Centre, Prescribing Support Unit. Prescription cost analysis data. 135-136. 2008. 8 ClinicalTrials.gov. A dose-finding study of MK0974 in acute migraine. http://clinicaltrials.gov/ct2/show/NCT00246337?term=NCT00246337&rank=1 Accessed 23/10/08. 9 ClinicalTrials.gov. MK0974 pivotal study 1 - ww (with active comparator). http://clinicaltrials.gov/ct2/show/NCT00442936?term=MK-0974&rank=8 Accessed 23/10/08. 10 ClinicalTrials.gov. Safety and efficacy study of MK0974 in the acute migraine. http://clinicaltrials.gov/ct2/show/NCT00432237?term=MK-0974&rank=6 Accessed 23/10/08. 11 Ho TW, Mannix LK, Fan X, et al. Randomized controlled trial of an oral CGRP , MK- 0974, in acute treatment of migraine. Neurology. 2008 Apr 15; 70(16): 1304-12. 12 Ho TW, Ferrari MD, Dodick DW 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, parallel-treatment trial. The Lancet. 2008 Dec 20; 372 (9656): 2115-23. 13Connor, et al. Efficacy and Safety of telcagepant (MK-0974), a Novel Oral CGRP Receptor Antagonist, for Acute Migraine Attacks. Poster, European Headache and Migraine Trust International Congress, London, England, September 2008. 14ClinicalTrials.gov. Treatment of migraine in patients with stable vascular disease. http://clinicaltrials.gov/ct2/show/NCT00662818?term=MK-0974&rank=2#locn Accessed 23/10/08. 15ClinicalTrials.gov. Acute treatment of multiple with or without aura in adults. http://clinicaltrials.gov/ct2/show/NCT00483704?term=NCT00483704&rank=1 Accessed 11/12/08. 16ClinicalTrials.gov. MK0974 Long Term Safety Study. http://clinicaltrials.gov/ct2/show/NCT00443209?term=NCT00443209&rank=1 Accessed 11/12/08 17British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BMJ Group and RPS Publishing. London; September 2008.

The National Institute for Health Research National Horizon Scanning Centre Research Programme is funded by the Department of Health. The views expressed in this publication are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health

The National Horizon Scanning Centre, Department of Public Health and Epidemiology University of Birmingham, Edgbaston, Birmingham, B15 2TT, England Tel: +44 (0)121 414 7831 Fax +44 (0)121 414 2269 www.pcpoh.bham.ac.uk/publichealth/horizon

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