Commercial and Pipeline Insight: Fibromyalgia - Approvals legitimize condition and expose underserved patient population

CHAPTER 1 EXECUTIVE SUMMARY 3
Scope of the analysis 3
Contributing experts 4
Datamonitor insight into the fibromyalgia market 5
Relevant reports 8

CHAPTER 2 MARKET OVERVIEW AND POTENTIAL 10
Definition and etiology 11
The cause and underlying mechanisms of fibromyalgia remain unknown 11
Research finds various chemical imbalances in patients 13
Proof of a genetic basis is hampered by patient heterogeneity 14
Diagnosis 14
American College of Rheumatology (1990) research criteria for fibromyalgia 15
1. History of widespread pain has been present for at least 3 months 15
2. Pain in 11 of 18 tender point sites on digital palpation 15
Co-morbidities 17
There are significant overlaps with other conditions 17
Epidemiology of fibromyalgia 18
Prevalence and incidence 19
Fibromyalgia is around seven times more common in women than men and increases with age 20
Experts and patient groups believe fibromyalgia is more common 21
Referral patterns, diagnosis and treatment rates 23
Patients are generally referred by primary care physicians to rheumatologists 23
Over half of the prevalent fibromyalgia population remain undiagnosed 24
Nearly all diagnosed patients receive drug therapy of some sort 25
Market sizing 25
Cheap generic drugs have historically made up the vast majority of fibromyalgia prescriptions 25
Clinical unmet needs 26
Need for a better understanding of disease etiology and pathophysiology 27
Need to improve pain reduction and control 28
Need to reduce sleep disturbances 29

CHAPTER 3 MARKETED BRAND DYNAMICS AND TREATMENT GUIDELINES 31
Marketed brands overview 32
Lyrica (pregabalin) 32
Drug overview 32
Forecast to 2017 38
Drug assessment 39
SWOT analysis 41
Pivotal clinical trial data 41
Other controlled clinical trials of Lyrica in fibromyalgia 45
Safety and tolerability 47
Treatment guidelines 49
European guidelines - EULAR evidence-based guidelines 49
Objectives - to provide evidence-based recommendations for the treatment of fibromyalgia 49
Methodology - developed by a multidisciplinary fibromyalgia task force representing 11 European countries 49
Results - 146 pharmacological and non-pharmacological studies were evaluated 51
EULAR recommendations 51
Meta-analysis was hampered by high variability in outcome measures used 53
US guidelines - the 2004 American Pain Society Guidelines 53
APS guidelines developed by an interdisciplinary panel of 13 pain management experts 53
APS guidelines recommend physicians start patients with a tricyclic antidepressant or cyclobenzaprine 54
New guidelines need to include new possible first-line options 54

CHAPTER 4 FORECAST ANALYSIS 56
Key events 57
Product launches in the US and 5EU 58
Product launches in Japan 58
Patent expiries 59
Data definitions, limitations and assumptions 61
Standard units 61
Derivation of sales forecasts and pricing trends 61
Forecast methodology 61

CHAPTER 5 PIPELINE OVERVIEW - R&D DYNAMICS AND APPROACH 62
Pipeline overview 63
Pipeline mainly consists of drugs indicated for other CNS indications 63
Classification of pipeline products 65
SNRI/NSRI antidepressants 65
GABA receptor modulators 66
Dopamine receptor agonists 67
Alpha adrenoceptor modulators 67
Others 68
Clinical trial design 68
Trials need to show improvements in both pain outcomes and function measures 68
Visual Analog Scale 69
Patient Experience Diary (PED) 69
Brief Pain Inventory 70
Patient Global Impression of Change (PGIC) scale 70
SF-36 physical component summary (PCS) score 70
Fibromyalgia Impact Questionnaire (FIQ) 71
OMERACT aims to standardize fibromyalgia endpoint requirements and measures 71
Agencies will review their clinical trial requirements based on OMERACT findings 71
OMERACT 8 continued work initiated at the first fibromyalgia workshop 2 years earlier 72

CHAPTER 6 LATE-STAGE DRUG ANALYSIS & FORECASTS 73
Late-stage pipeline comparative forecasts 74
Late-stage pipeline drug assessment summary 74
SNRI/NSRI antidepressant pipeline drugs 75
Cymbalta (duloxetine) 76
Drug overview 76
Forecasts to 2017 79
Drug assessment 80
Marketing factors 81
Patient potential 86
Clinical trial data 88
Milnacipran 97
Drug overview 97
Forecasts to 2017 99
Drug assessment 101
Marketing factors 101
Patient potential 104
Clinical trial data 105
Pristiq (desvenlafaxine) 114
Drug overview 114
Clinical trial data 115
AD-337 115
Drug overview 115
Clinical trial data 116
GABA receptor modulator pipeline drugs 117
Xyrem (sodium oxybate) 117
Drug overview 117
Forecasts to 2017 119
Drug assessment 120
Marketing factors 121
Patient potential 124
Clinical trial data 127
Lunesta (eszopiclone) 130
Drug overview 130
Clinical trial data 130
Dopamine receptor agonist pipeline drugs 131
Neupro (rotigotine) 133
Drug overview 133
Clinical trial data 134
Terguride 135
Drug overview 135
Clinical trial data 135
Alpha adrenoceptor modulator pipeline drugs 136
Esreboxetine 137
Drug overview 137
Clinical trial data 137
AGN 203818 139
Drug overview 139
Other pipeline drugs 139
Vimpat (lacosamide) 140
Drug overview 140
Clinical trial data 141
Neurotropin 142
Drug overview 142
Clinical trial data 142
NRC-027F 143
Drug overview 143
Flupirtine 143
Drug overview 143
Clinical trial data 144
PF-738502 145
Drug overview 145

CHAPTER 7 COMMERCIAL IMPACT AND CASE STUDY ANALYSIS 146
Introduction 147
Evaluation of Pfizer's successful Lyrica launch strategy 147
Pfizer sponsored unbranded fibromyalgia advertising campaign 148
Pfizer launches branded DTC campaign 150

BIBLIOGRAPHY 155
Journal papers, books, and conference abstracts 155
Websites 164
Datamonitor reports 171

APPENDIX 173
Market sizing calculations 173
Methodology, assumptions and caveats 176
Top 10 prescribed products for fibromyalgia (minus Lyrica and Cymbalta) in the 5EU and Japan in 2007 178
Clinical guidelines - classification schemes 179
Recently discontinued fibromyalgia projects or those assumed on-hold 180
5EU IMS standard unit dose-dependent Lyrica prices 181
Report methodology 181
Contributing experts 183
About Datamonitor 183
About Datamonitor Healthcare 184
About the Disease analysis team 184
Disclaimer 186

List of Tables
Table 1: Prevalence of symptoms in fibromyalgia patients 11
Table 2: Key fibromyalgia epidemiology study results, 1995-2006 19
Table 3: Prevalence of fibromyalgia across the seven major markets, 2008 20
Table 4: Fibromyalgia prevalence as quoted by various fibromyalgia organizations/associations, 2008 22
Table 5: Lyrica: key facts, 2008 32
Table 6: Key events impacting Lyrica, 2008-2017 39
Table 7: Summary of the 14-week Lyrica Phase III fibromyalgia trial 42
Table 8: Baseline characteristic of patients* enrolled in the Crofford et al. (2005) pregabalin trial 45
Table 9: Adverse reaction* incidence of Lyrica in controlled trials for fibromyalgia 47
Table 10: EULAR recommendations for the management of fibromyalgia, 2007 52
Table 11: Stepwise fibromyalgia management as recommended by the 2004 American Pain Society treatment guidelines 54
Table 12: Summary of findings from pharmacological studies in fibromyalgia according to Arnold (2006) 55
Table 13: Forecast launch dates of fibromyalgia drugs in the US and 5EU, 2008-2017 58
Table 14: Forecast launch dates of fibromyalgia drugs in Japan, 2008-2017 58
Table 15: Key patent expiries for key marketed and late-stage pipeline fibromyalgia drugs in the US and 5EU 59
Table 16: Pipeline drugs in clinical development for fibromyalgia, 2008 63
Table 17: Key SNRI/NSRI antidepressants in late-stage development for fibromyalgia, 2008 76
Table 18: Cymbalta: key facts, 2008 77
Table 19: Key events impacting Cymbalta, 2008-2017 80
Table 20: Duloxetine in fibromyalgia treatment-emergent adverse events: 6-month treatment phase1 93
Table 21: Results of the Arnold et al. (2005) duloxetine trial 96
Table 22: Milnacipran: key facts, 2008 98
Table 23: Key events impacting milnacipran, 2008-2017 100
Table 24: The most common treatment emergent adverse events of milnacipran in placebo-controlled trial fibromyalgia 111
Table 25: Key GABA receptor modulators in late-stage development for fibromyalgia, 2008 117
Table 26: Xyrem: key facts, 2008 118
Table 27: Key events impacting Xyrem, 2008-2017 120
Table 28: Key dopamine receptor agonists in late-stage development for fibromyalgia, 2008 132
Table 29: Key alpha adrenoceptor modulators in late-stage development for fibromyalgia, 2008 136
Table 30: Key 'other' products in late-stage development for fibromyalgia, 2008 140
Table 31: Total US fibromyalgia market value estimation, 2004-07 173
Table 32: Total 5EU fibromyalgia market value estimation, 2004-07 174
Table 33: Total Japan fibromyalgia market value estimation, 2004-07 175
Table 34: Top 10 prescribed products for fibromyalgia (minus Lyrica and Cymbalta) in the 5EU and Japan, 2007 178
Table 35: Breakdown of the evidence and strength criteria used in the EULAR fibromyalgia management recommendations, 2007 179
Table 36: Recently discontinued or fibromyalgia projects or those assumed on-hold, 2008 180
Table 37: IMS standard unit price of Lyrica at three different doses across the 5EU, 2007 181
Table 38: Datamonitor drug assessment parameters 182

List of Figures
Figure 1: Drug assessment summary overview of key marketed and key pipeline fibromyalgia drugs, 2008 7
Figure 2: Historical (2004-07) and forecast (2008-2017) fibromyalgia sales revenue for key marketed and pipeline drugs across the seven major markets 8
Figure 3: The fibromyalgia 'tender points' 16
Figure 4: Estimated value of fibromyalgia sales in seven major markets, 2004-07 26
Figure 5: Timeline of Lyrica's fibromyalgia clinical and regulatory development, 2004-08 33
Figure 6: Lyrica dosing for fibromyalgia 35
Figure 7: Fibromyalgia-specific sales ($m) forecast for Lyrica in the seven major markets, 2008-2017 38
Figure 8: Datamonitor's competitive positioning analysis for Lyrica in fibromyalgia across the seven major markets, 2008-2017 40
Figure 9: Lyrica SWOT analysis in the fibromyalgia market, 2008 41
Figure 10: Lyrica Patient Global Impression of Change results 43
Figure 11: Diagram of patient flow in the Crofford et al. (2005) pregabalin trial 46
Figure 12: Incidence of selected adverse reactions and discontinuation rates in controlled fibromyalgia trials of Lyrica 48
Figure 13: Impact of key events on the fibromyalgia market, 2008-2017 57
Figure 14: Comparative fibromyalgia-specific sales ($m) forecast for key late-stage pipeline drugs (and Cymbalta) in the seven major markets, 2008-2017 74
Figure 15: Drug assessment summary overview of key late-stage pipeline fibromyalgia drugs, 2008 75
Figure 16: Fibromyalgia-specific sales ($m) forecast for Cymbalta in the seven major markets, 2008-2017 79
Figure 17: Datamonitor's competitive positioning analysis for Cymbalta in fibromyalgia across the seven major markets,, 2008-2017 81
Figure 18: Cymbalta home page, 2008 (up to June 13, 2008) 84
Figure 19: Cymbalta home page, 2008 (June 16, 2008) 86
Figure 20: Phase III duloxetine fibromyalgia study design 90
Figure 21: Brief Pain Inventory (BPI) average pain scores of duloxetine in fibromyalgia patients: ≥30% improvement from baseline to endpoint at 3 and 6 month acute treatment phases 91
Figure 22: Brief Pain Inventory (BPI) average pain scores of duloxetine in fibromyalgia patients: ≥50% improvement from baseline to endpoint at 3 and 6 month acute treatment phases 92
Figure 23: Diagram of patient flow in the Arnold et al. (2005) duloxetine trial 94
Figure 24: Fibromyalgia-specific sales ($m) forecast for milnacipran in the seven major markets, 2008-2017 99
Figure 25: Datamonitor's competitive positioning analysis for milnacipran in fibromyalgia across the seven major markets,, 2008-2017 101
Figure 26: Composite responder rates-for fibromyalgia syndrome (Pain + PGIC + SF-36 PCS); completer analysis at 3 and 6 months from milnacipran Study FMS-031 109
Figure 27: Composite responder rates-for fibromyalgia Pain (Pain + PGIC); completer analysis at 3 and 6 months from milnacipran Study FMS-031 110
Figure 28: Diagram of patient flow in the Vitton et al. (2004) milnacipran trial 113
Figure 29: Fibromyalgia-specific sales ($m) forecast for Xyrem in the seven major markets, 2008-2017 119
Figure 30: Datamonitor's competitive positioning analysis for Xyrem in fibromyalgia across the seven major markets,, 2008-2017 121
Figure 31: Sodium oxybate fibromyalgia clinical program overview 127
Figure 32: Pfizer sponsored My Fibro Relief website 149
Figure 33: Lyrica website homepage 152
Figure 34: US Lyrica promotional spend versus standard unit prescriptions, 2007 153