Table of Contents

Stakeholder Opinions: Narcolepsy - Entry-point to a lucrative fatigue-associated market - Full analysis of the current narcolepsy market, with indication-specific value and volume product sales between 2004-07 in the seven major markets, as well as an assessment of off-label prescribing, indication expansions and key pipeline drugs.

Product Code: dmhc2475

Publication Date: 18-Dec-2008

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Overview

Introduction

Narcolepsy is a chronic sleep disorder, which affects fewer than 500,000 sufferers across the seven major markets (7MM). The narcolepsy market value has grown considerably since 2004 to reach $230m in 2007 driven largely by the significant penetration of Provigil (modafinil; Cephalon) and Xyrem (sodium oxybate; Jazz Pharma) and the associated increase in the awareness of the disorder.

Scope

· Patient Patient potential including disease definition, etiology, prevalence, diagnosis, and treatment guideline review.

· Review of the key unmet needs in the treatment of narcolepsy as identified by key opinion leaders interviewed for the report.

· Analysis of narcolepsy market IMS sales data from 2004 to 2007 for major marketed narcolepsy drugs: Provigil and Xyrem.

· Pipeline analysis with detailed profile for Nuvigil (armodafinil, Cephalon) and the theory behind potential label expansions beyond narcolepsy.

Highlights

Although generic versions of Cephalon's market leading treatment, Provigil (modafinil), are expected to launch in 2012, Datamonitor expects Cephalon to retain a significant position in the narcolepsy market by switching patients over from Provigil to its follow-up product, Nuvigil (armodafinil).

Despite Xyrem's (sodium oxybate) proven efficacy and its broader narcolepsy coverage than Provigil, Xyrem's sales continue to be limited because of its black box warning, restricted distribution and comparatively high price.

Targeting narcolepsy as a primary indication and then expanding Provigil's label coverage to other sleep disorders has proven commercially successful for Cephalon. Datamonitor believes companies could take this strategy a step further by using narcolepsy as an entry point to access the broader fatigue- or sleepiness-associated market.

Reasons to Purchase

· Quantify the narcolepsy market value in the US, 5EU and Japan and identify the drivers and resistors in this market.

· Understand key opinion leader (KOL) views on topical issues in the current and future treatment of narcolepsy and associated disorders.

· Appreciate the potential of off-label prescribing and indication expansions for treatments possessing narcolepsy as the primary indication.

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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	106
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

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