Table of Contents

ABOUT DATAMONITOR HEALTHCARE 2
About the Central Nervous System pharmaceutical analysis team 2
CHAPTER 1 EXECUTIVE SUMMARY 3
Scope of analysis 3
Datamonitor insight into the narcolepsy market 4
Contributing experts 5
Related reports 5
CHAPTER 2 MARKET DEFINITION AND OVERVIEW 7
Definitions 8
Narcolepsy - a chronic sleep disorder 8
Market definition 8
Market overview 8
Narcolepsy market has recorded substantial growth since 2004 8
Significant value growth of the narcolepsy market driven by Provigil and Xyrem 8
Market volume growth is attributed to an improved recognition of the disorder 9
Sales value in the US dominates the narcolepsy market 10
Disparity between sales and narcolepsy population distributions across the seven major markets 11
Sales in Japan are affected by the lack of recognition of the disorder and the low price of drugs 12
The low market value in the 5EU is linked to lower drug prices and the absence of direct-to-consumer advertising 13
CHAPTER 3 DISEASE OVERVIEW 15
Characteristics of narcolepsy 16
Features and symptoms of narcolepsy 16
Symptoms of narcolepsy 16
Associated features of narcolepsy 16
Severity of narcolepsy 17
Mild narcolepsy - mild sleepiness or rare cataplexy 18
Moderate narcolepsy - moderate sleepiness and infrequent cataplexy 18
Severe narcolepsy - severe sleepiness and daily cataplexy 18
Duration criteria also used to define narcolepsy severity 18
Prevalence of narcolepsy 19
Narcolepsy affects fewer than 500,000 sufferers across the seven major markets 19
Disparity among prevalence rates could result from genetic or methodological variations 19
Cataplexy and narcolepsy 22
Cataplexy occurs in the majority of patients with narcolepsy 22
Course of narcolepsy 24
Narcolepsy is a non-progressive disorder that begins mostly during adolescence 24
Etiology of narcolepsy 25
Causes of narcolepsy 25
Similarity between rapid eye movement sleep atonia and cataplexy in narcolepsy 25
Strong association between the HLA complex and narcolepsy 26
Hypocretin deficiency identified in more than 85% of patients with narcolepsy 26
Environmental factors may also play a significant role in the development of narcolepsy 28
Diagnosis of narcolepsy 28
Diagnosis criteria and tools 28
Diagnostic criteria of narcolepsy 28
Polysomnography and Multiple Sleep Latency Test 29
Excessive daytime sleepiness diagnosed using specific tools 30
Blood and cerebrospinal fluid testing assessing hypocretin levels 30
Differential diagnosis required to avoid misdiagnosis of narcolepsy 30
Diagnosis rate of narcolepsy 31
Less than 50% of patients with narcolepsy are correctly diagnosed 31
Population unfamiliarity with the disorder induces late presentation to a physician 32
A significant proportion of patients appear to be misdiagnosed 32
Management of narcolepsy and guidelines 33
Behavioral approaches 33
Pharmacological management of narcolepsy and guidelines 34
Provigil and Xyrem are first-line treatment options for narcolepsy 34
Treatment for excessive daytime sleepiness 35
Treatments for cataplexy 38
CHAPTER 4 UNMET NEEDS 40
Overview of the key unmet needs 41
Description of key unmet needs 41
Greater efficacy 41
Full restoration of alertness in patients with narcolepsy still remains a challenge 41
More widely available cataplexy treatments 42
Restrictions on the distribution of Xyrem provide an opportunity for alternative treatments 42
Improved side-effect profile 43
Products with a well-tolerated side-effect profile would provide a greater range of accepted treatment options 43
Longer duration of action 44
First-line treatments with a longer duration of action will improve patients' quality of life 44
Broader clinical trials 45
Clinical evidence will help to position alternative drugs in the treatment pathway 45
CHAPTER 5 BRAND DYNAMICS 47
Current therapies 49
Provigil is the clear sales value leader in the narcolepsy market 49
Provigil (modafinil, Cephalon) 51
Drug overview 51
Narcolepsy-specific sales analysis 54
Summary of Provigil's clinical trial data in narcolepsy 56
Future outlook 58
Xyrem (sodium oxybate, Jazz Pharmaceuticals) 59
Drug overview 59
Narcolepsy-specific sales analysis 64
Summary of Xyrem's clinical trial data in narcolepsy 66
Future outlook 68
Label expansion as a lifecycle management strategy for narcolepsy drugs 69
Narcolepsy as a strategic point of entry into the sleepiness- and fatigue-associated market 70
Expanding drug label to other intrinsic sleep disorders 70
Hypersomnia 70
Obstructive sleep apnea/hypopnea syndrome 71
Targeting circadian rhythm sleep disorders 71
Jet lag - a significant patient population 71
Shift work sleep disorder 72
Treatments for circadian rhythm sleep disorders 72
Datamonitor insight 74
CHAPTER 6 PIPELINE ANALYSIS 75
Narcolepsy pipeline overview in 2008 76
Current narcolepsy pipeline shows a distinct lack of investment 76
Registered pipeline drugs 77
Nuvigil (armodafinil, Cephalon) 77
Nuvigil - longer acting single isomer formulation of modafinil (Provigil) 77
Phase III clinical trial lacks active comparator to demonstrate the efficacy and safety of Nuvigil in narcolepsy patients over Provigil 78
Development of Nuvigil as a lifecycle management strategy to offset generic modafinil competition 79
Phase II histamine H3 antagonists 84
GSK-189254 (GlaxoSmithKline) 84
Recent Phase II trial termination casts doubt over the drug's development status 84
Phase II clinical trial was initiated in November 2006 84
JNJ-17216498 (Johnson & Johnson) 85
Product's development status uncertain after completing Phase II study in December 2007 85
Bold Phase II clinical trial employed Provigil as a comparator 86
Potential of histamine H3 antagonists in narcolepsy and sleep disorders 86
Hypocretin deficiency in narcolepsy potentially linked to histaminergic system 87
Centrally acting H3 histamine antagonists do not induce peripheral effects such as allergic reactions 87
Potential activity on excessive daytime sleepiness and cataplexy in narcolepsy 88
Side effects of Histamine H3 antagonists limited in animal studies 89
Potential to also work in other sleep disorders 89
BIBLIOGRAPHY 91
Journals 91
Websites 96
Annual reports 101
Datamonitor reports 101
APPENDIX 102
Data definitions, limitations and assumptions 102
Standard units 102
Japanese market data 102
About Datamonitor 102
About Datamonitor Healthcare 103
About the Central Nervous System analysis team 104
Disclaimer 105
List of Tables
Table 1: Prevalence of narcolepsy in the US, Japan and 5EU, 2008 19
Table 2: Studies estimating the prevalence of narcolepsy 22
Table 3: Narcolepsy-specific sales ($000s) of the current prescribed therapies across the seven major markets, 2004-07 49
Table 4: Provigil (modafinil, Cephalon) - key facts, 2008 51
Table 5: Clinical trial results for Provigil in narcolepsy patients 57
Table 6: Xyrem (sodium oxybate, Jazz Pharmaceuticals) - key facts, 2008 60
Table 7: Summary of outcomes in clinical trials supporting the efficacy of Xyrem in the treatment of cataplexy attacks 66
Table 8: Clinical trials results for the assessment of the Xyrem efficacy in excessive daytime sleepiness in narcolepsy patients 67
Table 9: Clinical Global Impression of Change in day and nighttime symptoms for Xyrem 67
Table 10: Pipeline drugs for narcolepsy, 2008 76
Table 11: Clinical trial results for Nuvigil in narcolepsy patients 79
Table 12: Ongoing clinical trials for Nuvigil (armodafinil), sponsored by Cephalon, 2008 83
Table 13: Clinical trial summary for GlaxoSmithKline's GSK-189254 in narcolepsy, 2008 85
Table 14: Clinical trial summary for Johnson & Johnson's JNJ-17216498 in narcolepsy, 2008 86
List of Figures
Figure 1: Narcolepsy-specific sales value ($m) across the seven major markets, 2004-07 9
Figure 2: Narcolepsy-specific sales volume (standard units) across the seven major markets, 2004-07 10
Figure 3: Narcolepsy-specific sales revenue ($m) in the US, Japan and 5EU, 2007 11
Figure 4: Narcolepsy population and distribution of value ($) and volume (standard unit) sales across the seven major markets, 2007 12
Figure 5: Age at onset of narcolepsy in 50 patients as reported by Guilleminault et al., 1976 24
Figure 6: Treatment guidelines for narcolepsy developed by the American Academy of Sleep Medicine, 2007 34
Figure 7: Treatment guidelines for narcolepsy as recommended by the European Federation of Neurological Societies, 2006 35
Figure 8: Key unmet needs in narcolepsy treatment, 2008 41
Figure 9: Narcolepsy-specific sales revenue ($m) by brands and classes across the seven major markets, 2007 50
Figure 10: Provigil (modafinil, Cephalon) sales ($m) distribution by diagnostic value in the US, 2007 54
Figure 11: Provigil (modafinil, Cephalon) narcolepsy-specific sales ($000s) across the seven major markets, 2004-07 55
Figure 12: Provigil's (modafinil, Cephalon) narcolepsy-specific sales and non-DTC promotional spend in the US and 5EU, 2007 56
Figure 13: Xyrem (sodium oxybate, Jazz Pharmaceuticals and UCB) narcolepsy-specific sales ($000s) across the seven major markets, 2005-07 64
Figure 14: Xyrem's (sodium oxybate, Jazz Pharmaceuticals and UCB) narcolepsy-specific sales and non-DTC promotional spend in the US and 5EU, 2007 65
Figure 15: Market potential of treatment for excessive sleepiness beyond narcolepsy 69
Figure 16: Cephalon's pricing strategy with Actiq and its follow-on product, Fentora, Q3 2003-Q2 2008. 82