2. What is insomnia? Insomnia is defined as a complaint of one or more of the following: Difficulty falling asleep Difficulty maintaining sleep Poor quality of sleep or non-refreshing sleep The term “sleep quality” cannot be measured objectively as it contains purely subjective aspects such as “depth” or “restful” sleep These symptoms are associated with significant daytime distress Diagnostic and Statistical Manual of Mental Disorders: Diagnostic Criteria for Primary Insomnia, Fourth Edition, American Psychiatric Association; 2000:597-661 Organisation WH. Tenth revision of the International Classification of Diseases, Chapter V (F): Mental and Behavioural Disorders. Clinical descriptions and diagnostic guidelines. WHO 1992; Geneva:182/184

3. Insomnia prevalence increases with age Insomnia severity and age 1 1. Weyerer and Dilling, Sleep.1991 Oct;14(5):392-8 2. Lemoine et al, Journal of Sleep Research, Vol 16 issue 4, in press Approximately 50% of the elderly population report on insomnia and overall dissatisfaction with quality of sleep 2

4. Clinical Perspective Insomnia, particularly poor sleep quality is associated with:  Significant daytime distress and functioning  Adverse effects on psychosocial, physical and occupational functioning characterized by Fatigue or lethargy, Mood disturbances, Cognitive impairments, Motor impairments, increased risk of falls and accidents Social discomfort, absenteesm Non-specific physical ailments  Poor Quality of life Subjective sleep quality and daytime dysfunction are the best predictors of impaired quality of life Increased health care costs Lemoine et al, Journal of Sleep Research, Vol 16 issue 4, in press Brassington GS et al. J Am Geriatr Soc. 2000;48:1234-1240 Leger D, et al. Sleep. 1999 May 1;22 Suppl 2:S394-401.

6. Why is good quality sleep necessary?  Restorative function for the brain and the body  Important role in learning and memory  Better daytime functioning  Better quality of life  Better mood  Less fatigue  Less accidents Maquet P., 2001, Ohayon et al., 2001, Sateia et al., 2000, Zammit et al., 1999 American Psychiatric Association. Task Force on DSM-IV. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Washington, DC: American Psychiatric Association;, 2000.

7. Twice as many road accidents in insomniacs with global sleep dissatisfaction Insomnia car drivers with Global Sleep Dissatisfaction (GSD) had almost two times more road accidents compared to insomnia drivers without GSD p<0.01 Ohayon et al, Sleep,2001: 24: 780-7.

8. Poor sleep quality has serious medical implications Poor Sleep Quality, more than Sleep Quantity correlates to fatigue, depression, anxiety and physical morbidity * p<0.01 * * ** Physical HealthAnxietyDepressionFatigue After Pilcher et al,, J Psychosom Res. 1997

9. Good Quality/Restorative Sleep  Clinically oriented sleep medicine has shifted from sleep quantity to sleep quality  Sleep quality is better related to health and affects balance and satisfaction with life that sleep quantity  Poor sleep quality and daytime dysfunction increase with age  The German Society of Sleep Medicine has published a formal consensus that defined non-restorative sleep to be the key syndrome in the clinical algorithm to diagnose and treat sleep disorders Hajak G. Eur Arch Psychiatry Clin Neurosci 2001;251(2):49-56. Riemann D FJ, Mayer G, Peter JH. The Guidelines for "Non-Restorative Sleep": Relevance for the Diagnosis and Therapy of Insomnia. Somnologie 2003;7(2):66-76.

10. Characteristics of an ideal hypnotic

11. Sedative Hypnotics:side effects  In meta-analyses, sedative hypnotics has been shown to be associated with frequent and serious adverse events (Number needed to harm= 6) Type of adverse events versus placbo Cognitive adverse events (hangover) (p<0.01) Psychomotor adverse events (p=0.07) Residual Morning or daytime fatigue (p<0.001) Performance tasks the morning after significantly impaired Amnesia  It has been shown that use of benzodiazepines is associated with increased risk of falls and road accidents  It is widely recognised that benzodiazepines has potential to produce physical and/or psychological dependence Glass J, Lanctot KL, et al, BMJ. 2005 Nov 19;331(7526):1169. Hallfors D and Saxe L. American Journal of public health. Sept. 1993, Vol.83, N9 Leipzig RM et al, J.Am Geriatri Soc, 1999 Jan; 47 (1):30-9 Barbone F et al, Lancet 1998 Oct 24;352(9137):1331-6

12. Issues in using hypnotics in elderly  Benzodiazepines may contribute to psychomotor impairment and increase the risk of falls and car accidents  The use of benzodiazepines among elderly patients has been associated with intellectual and cognitive impairment  Older people are more susceptible to the side effects of benzodiazepines (especially if they have additional risk factors for cognitive or psychomotor AEs), so for these patients the risk-benefit analysis might not be favourable  There is a need for a drug with a safe profile in the context of potentially long-term use and low levels of drug-drug interactions Cumming RG, et al. CNS Drugs 825–837, 2003 Gray S, et al. Drug Safety 21:101–122, 1999 Glass J, et al. BMJ. 2005 Nov 19;331(7526):1169. Epub 2005 Nov 11. Review. Barbone F, et al. Lancet. 1998 Oct 24;352(9137):1331-6

13. Key unmet needs in treatment of insomnia  Treatments improving the next day alertness  More effective in the elderly population  Improvement in sleep maintenance  Lack of potential for tolerance and addiction  No effects on memory  No rebound insomnia  No psychomotor impairments (no risk of falls)  Increased quality of life Datamonitor, published 04/2007

14. Melatonin  An endogenous physiological sleep regulator  Secreted during night time by the pineal grand  Synchronizes the biological clock  Involved in sleep control Zisapel. Sleep and sleep disturvances: biological basis and clinical implications. Cell. Mol.Life Sci.

15. Melatonin’s Natural Secretion Profile 6-SMT (ug/h) Saliva Plasma urine Arendt Bojkowski et al. J Clin Endocrinol Metab 60:1166-73.

16. Melatonin – one of the key components for quality sleep  An important physiological sleep regulator  An important cue of the internal biological clock  Sharp increase in sleep propensity at night occurs 2 hours after the onset of endogenous melatonin Zisapel Cell Mol Life Sci. 2007 May;64(10):1174-86.

17. Melatonin production decreases with age

18. Circadin ® - a prolonged release melatonin (2 mg) formulation Circadin is a prolonged- release matrix tablet formulation of melatonin, which circumvents the fast clearance of the hormone by releasing the hormone in the gastro-intestinal tract over an extended period of time and thereby mimics physiological pattern of melatonin secretion EPAR, Assessment report for Circadin. Procedure No.EMEA/H/C/695

19. Circadin ® mimics the physiological profile of melatonin at night Circadin® - a prolonged release melatonin formulation Data on file (Neurim)

20. Circadin ® Pharmacokinetics Cmax (pg/ml) Tmax (hours) Plateau time (h) Basal state Median Range 51 30-126 18 16-22 6.6 4.7-9.6 Drug fasting Median Range 393 180-855 1.5 0.5-3 4.4 3.1-9.9 Drug with meal Median Range 390 205-1020 2.5 1-4 3.1 1.7-5-5 EPAR, Assessment report for Circadin. Procedure No.EMEA/H/C/695

21. The Circadin ® equation Poor sleep quality in 55+ years is associated with reduced melatonin production Circadin ® is formulated to mimic physiological pattern of melatonin secretion Treatment with Circadin ® restores sleep quality and consequently daytime functioning + =