Eplivanserin for chronic characterised by difficulties with sleep maintenance

April 2009

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.

The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research

April 2009 National Horizon Scanning Centre News on emerging technologies in healthcare

Eplivanserin for chronic insomnia characterised by difficulties with sleep maintenance

Target group • Chronic insomnia: characterised by difficulties with sleep maintenance e.g. duration and number of nocturnal awakenings.

Technology description Eplivanserin (SR46349, Ciltyri) is an antagonist of the 5-HT2A receptor and is first in a new non-sedating drug class known as ASTARs (Antagonists of Two A Receptors). Eplivanserin is administered orally at 5mg once daily in the evening.

Innovation and/or advantages Eplivanserin is a new drug class for this indication and may deliver safety advantages compared to current drugs in terms of residual effects, dependence potential and rebound.

Developer -aventis.

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

NHS or Government priority area This topic is not related to current NHS or government priorities.

Relevant guidance • NICE technology appraisal. , and for the short-term management of insomnia. 2004 (review date: April 2010)1. • Clinical Knowledge Summaries (CKS). Insomnia. Latest revision July 2006 (revision planned in 2009)2.

Clinical need and burden of disease Chronic insomnia may lead to psychiatric problems, e.g. depression, panic disorder, abuse of or other drugs, reduced health-related quality of life and cognitive impairment in the elderly.

The prevalence of insomnia symptoms that occur at least three nights per week or often or always is estimated as 16-21%3, which would equate to between 8.7-11.4 million people in England and Wales. The prevalence of insomnia symptoms with daytime consequences ranged from 9-15%, while 8-18% had dissatisfaction with sleep quality and quantity. The prevalence of insomnia diagnoses according to the DSM-IVa classification was 6%, which equates to 3.2 million people in England and Wales.

In England in 2007 approximately 10 million prescription items for the BNF class 4.1.1 () were dispensed in the community at a cost of £31.8 million (Prescription Cost Analysis).

a 4th Edition of the Diagnostic and Statistical Manual of Mental Disorders 2 April 2009 National Horizon Scanning Centre News on emerging technologies in healthcare

Existing comparators and treatments Non-drug therapies are the main strategy for managing chronic insomnia2. Hypnotic drug therapy is considered appropriate for the management of severe insomnia interfering with normal daily life1. It is recommended that hypnotics should be prescribed for short periods of time only, in strict accordance with their licensed indications. NICE recommend that because of the lack of compelling evidence to distinguish between zaleplon, zolpidem, zopiclone (Z drugs) or the shorter-acting hypnotics, that the drug with the lowest purchase cost should be prescribed.

Efficacy and safety

Trial EPLILONG; NCT00253903; GEMS; NCT00253968; eplivanserin eplivanserin vs. placebo; phase III vs. placebo; phase III Sponsor Sanofi-aventis Sanofi-aventis Status Unpublished Unpublished Location EU (inc UK), USA, Canada and other EU (inc UK), USA, Canada and other countries countries Design Randomised, double blind, placebo Randomised, double blind, placebo controlled controlled Participants and n=1,145; adults; primary insomnia n=962; adults; primary insomnia schedule according to DSM-IV-Text Revision according to DSM-IV-TR criteria. (TR) criteria. Randomised to eplivanserin 5mg or Randomised to eplivanserin 5mg or placebo (2:1) for 12 weeks. placebo (3:1) for 12 weeks. Follow-up Open treatment phase extension with Single blind placebo run-out for 2 eplivanserin for 40 weeks weeks Single blind placebo run-out for 2 weeks at the end of treatment period Primary Mean patient-reported wake time after Mean pr-WASO outcome sleep onset (pr-WASO) Secondary Mean of Functional Outcome of Sleep Mean of FOSQ items 1 & 2 outcomes Questionnaire (FOSQ) items 1 & 2 (concentration/memory) and 4 & 10 (concentration/memory) and 4 & 10 (hobby/work); number of awakenings; (hobby/work); number of awakenings; pr-TST; QoS; refreshing QoS total sleep time (pr-TST); quality of sleep (QoS); refreshing QoS Expected Poster to be presented at Sleep Poster to be presented at Sleep reporting date Congresses in 2010 Congresses in 2010

Trial EPOCH; NCT00308503; eplivanserin vs. placebo; phase III Sponsor Sanofi-aventis Status Unpublished Location USA, Canada and Australia Design Randomised, double blind, placebo controlled Participants and n=608; adults; primary insomnia according to DSM-IV-TR criteria. schedule Randomised to eplivanserin 5mg per day or placebo (1:1) for 6 weeks. Primary Night polysomnography wake time after sleep onset (PSG-WASO) outcome Secondary General productivity domain of FOSQ; pr-WASO; PSG-Number of Awakenings outcomes (PSG-NAW); QoS Expected Poster to be presented at APSS June 2009 (spectral analysis) reporting date

Trial DREAMS; NCT00679900; eplivanserin ECLIPSE; NCT00805350; 3 April 2009 National Horizon Scanning Centre News on emerging technologies in healthcare

vs. ; phase III eplivanserin vs. placebo; phase III Sponsor Sanofi-aventis Sanofi-aventis Status Ongoing Ongoing Location EU, Turkey, Chile EU, USA and Canada Design Randomised, double blind, active Randomised, double blind, placebo control controlled Participants and n=266; adults; primary insomnia n=600; adults; primary insomnia schedule according to DSM-IV-TR criteria. according to DSM-IV-TR criteria. Randomised to eplivanserin 5mg or Randomised to eplivanserin 5mg or lormetazepam for 4 weeks placebo for 6 weeks Primary Sleepiness in morning measured on Mean night polysomnography wake outcome visual analog scale of the sleep time after sleep onset (PSG-WASO) questionnaire and PSG-Number of Awakenings (PSG-NAW) at 6 weeks Secondary Next-day residual effects (ability to Other PSG sleep parameters; sleep outcomes concentrate - sleep questionnaire); architecture; patient-reported sleep rebound effect measured by patient- parameters measured on sleep reported wake time after sleep onset (pr- questionnaire WASO) and pr-Sleep Onset Latency (SOL) on sleep questionnaire during run-out; subjective sleep parameters Expected Completion date: March 2009 Completion date: June 2009 reporting date Publication: 2010 Publication: 2010

Estimated cost and cost impact The cost of eplivanserin is not yet known. No additional costs are expected. The cost of other licensed treatments are4:

Drug Dose at bedtime 28 day cost Zoplicone 7.5mg £1.71 Zaleplon 10mg £7.52 Zolpidem 10mg £2.44 5-10mg 72p-£1.44 10-20mg £1.41-£2.97 2mg £14.36

Potential or intended impact – speculative

Patients Reduced morbidity Reduced mortality or increased ; Improved quality of life for length of survival patients and/or carers 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 alternative coming for treatment investment needed New costs: Savings: ; Other: depends on comparative cost 4 April 2009 National Horizon Scanning Centre News on emerging technologies in healthcare

References

1 National Institute for Health and Clinical Excellence. Zaleplon, zolpidem and zopiclone for the management of insomnia. Technology appraisal TA77. London: NICE. April 2004. 2 Clinical Knowledge Summaries (CKS). Insomnia. Latest revision 2006. www.cks.library.nhs.uk 3 Ohayon MM. Epidemiology of insomnia: what we know and what we still need to learn. Sleep Medicine Reviews 2002;6:97-111. 4 British 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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