Contents:

CHAPTER 1 EXECUTIVE SUMMARY 3 Scope of the analysis 3 Our insight into the Parkinsons disease market 3 Contributing experts 6 Related reports 6 CHAPTER 2 INTRODUCTION AND SCOPE 8 Coverage of the Stakeholder Insight Survey 8 Disease definition and epidemiology 9 Presentation, diagnosis and comorbidities 9 Pharmacological treatment trends 9 Key prescribing influences 9 Treatment outcomes and surgery 9 Future trends 10 CHAPTER 3 COUNTRY TREATMENT TREES 11 Introduction to treatment trees 11 First-line treatment trees 12 US 12 Japan 13 France 14 Germany 15 Italy 16 Spain 17 UK 18 Second-line treatment trees 19 US 19 Japan 20 France 22 Germany 23 Italy 25 Spain 26 UK 28 CHAPTER 4 EPIDEMIOLOGY AND PATIENT SEGMENTATION 30 Disease definition 31 The etiology of PD is not yet clear 31 Parkinsons disease is typically classified by the Hoehn and Yahr scale 32 Patient population is generally well spread across the three disease severities 33 Epidemiology of Parkinsons disease 36 Parkinsons disease rarely affects adults younger than 50 years of age 37 Prevalence of Parkinsons disease 38 Over 1.4 million individuals across the US, Japan and 5EU are estimated to suffer from PD 39 European and Japanese epidemiology studies 40 Italy 40 UK 41 Japan 42 CHAPTER 5 PRESENTATION, DIAGNOSIS AND COMORBIDITIES 43 Presentation 44 Time to presentation 44 Early symptoms are generally very subtle and often go unnoticed 44 Improving presentation rates 46 Internet and patient advocacy groups are essential awareness drivers 46 Improved education of the public and primary care physicians is needed 47 The four common presentations of PD 48 Tremor 48 Rigidity 49 Akinesia and bradykinesia 49 Postural instability 50 Diagnosis 50 An accurate diagnosis of PD comes from combined neurological, laboratory and imaging evaluations 50 Neurological evaluation of PD 52 Laboratory evaluation of PD 55 Imaging studies for PD 56 Delays in the diagnosis of PD 59 Misdiagnosis is as high as 20-30% in the early stages 59 It takes on average 11 weeks from presentation to a physician to an accurate diagnosis of PD 59 Differential diagnosis to rule out other possible neurological conditions 61 More than half of prevalent early-stage PD patients remain undiagnosed 62 Over 80% of patients are characterized as having either early- or mid-stage PD at diagnosis 65 Comorbidities (non-motor symptoms) of PD 67 Depression is the most common comorbidity at each stage of the disease 68 Depression 69 Dementia 69 Psychosis 70 Sleep disturbances 70 CHAPTER 6 TREATMENT OPTIONS AND GUIDELINES 71 Treatment options 72 Non-pharmacological treatment 72 Non-pharmacological only approaches are largely shelved once mid-stage PD is reached 72 Pharmacological treatment 74 Dopaminergics 74 Dopamine agonists 76 Catechol-O-methyltransferase inhibitors 78 Monoamine oxidase inhibitors 80 Other treatments 81 Surgical treatment 83 Surgery becomes an option when PD symptoms cannot be adequately controlled with medication 83 Deep brain stimulation is now the current standard surgical practice for PD 84 Duodopa pump provides continuous dopaminergic stimulation 86 Treatment guidelines 86 The treatment of PD is a highly individualized process 86 US-guidelines based on AAN recommendations 87 New guidelines issued by the AAN in 2006 are more proscriptive than prescriptive 88 UK-National Institute for Health and Clinical Excellence guidelines 89 Recommended pharmacological therapy in early PD 90 Recommended pharmacotherapy in later PD 92 Guidance on surgery for PD 93 Other guidelines by region 94 CHAPTER 7 PRESCRIBING TRENDS IN PARKINSONS DISEASE 95 Pharmacological prescribing trends 96 Caveats-prescribing trends 96 Seven major market overview of prescribing trends 96 A greater proportion of patients progress to second-line therapy as the disease severity advances 96 Physician type responsible for initial prescription of PD therapy 97 Neurologists make the majority of initial treatment decisions for PD in the 7MMs 97 Role of pharmacological treatment in the management of PD 99 UK neurologists report waiting the longest period of time before initiating pharmacological therapy once early-stage PD has been diagnosed 99 Pharmacological therapy is not deemed essential in patients characterized as having early-stage PD 102 Pharmacological and non-pharmacological therapy is combined in more than half of all advanced-stage PD patients in Germany and the UK 103 Prescribing trends in early-stage PD 105 The proposed neuroprotective properties of the MAO-B inhibitors and dopamine agonists are still to be proven 105 Age and symptom severity dictates first-line therapy decisions 106 Boehringer Ingelheims pramipexole (Mirapex) leads the way in first-line early-stage PD management 108 Initiation of pharmacological therapy with levodopa remains high 110 First-line selegiline monotherapy is rarely seen 111 Monotherapy largely dominates early-stage PD management 111 Some 40% of early-stage patients progress to second-line therapy within 20 months 112 60% of early-stage PD patients who progress to second-line therapy have a drug added-on to their first-line regimen 113 Levodopa-carbidopa or levodopa monotherapy are the most commonly added-on products at second-line for early-stage PD 113 Pramipexole and ropinirole are the most common second-line regimens switched to at early-stage 116 Prescribing trends in mid-stage PD 118 Fixed-dose combinations containing levodopa and dopamine agonist therapy make up first-line therapy for mid-stage PD 119 Levodopa-carbidopa therapy is prescribed first-line to a fifth of all mid-stage PD patients in the US 119 Over half of all mid-stage PD patients receive combination therapy 121 50% of mid-stage patients progress to second-line therapy within 2 years 122 Adding-on accounts for the greater proportion of second-line dynamics for mid-stage PD 123 Entacapone is the most commonly added-on therapy at second-line in mid-stage PD 123 Second-line mid-stage PD sees like-for-like dopamine agonist switching and movement towards more complex fixed-dose combination products 125 Prescribing trends in advanced-stage PD 128 Levodopa-carbidopa fixed-dose combination products dominate first-line therapy for advanced PD 129 Monotherapy is rare in advanced-stage PD 130 Over 70% of UK patients progress to second-line therapy for advanced-stage PD 131 Neurologists continue to add-on therapy in the majority of advanced PD cases 132 Amantadine and rasagiline are highly popular add-ons in second-line for advanced PD 133 Apomorphine adding-on is highest in France and Spain 135 Levodopa-benserazide viewed as a second-line alternative to levodopa-carbidopa 138 CHAPTER 8 PRESCRIBING INFLUENCES AND BRAND ASSESSMENT 140 Factors influencing physician decision making 141 Side-effect profile is the number one influential factor 143 Mid- and advanced-stage pharmacotherapy is governed by managing the side effects of levodopa 144 Dopamine agonist side effects are mostly cognitive in nature 145 A drugs ability to reduce OFF periods has a high influence on prescribing decisions 145 The goals of therapy are to reduce OFF periods as much as possible 146 Ability to minimize dyskinesias was rated the most influential attribute in Japan 147 Ability to use as either monotherapy or adjunctive therapy becomes more influential as the disease progresses 148 Ability to delay the use of levodopa therapy influences only initial treatment decisions 149 Ability to enhance the benefit of levodopa therapy has led to the development of a number of products 149 Physician perception of key brands 150 Neurologists in Japan are most satisfied with current therapies 151 Interpreting a brand map 152 Brand comparison shows levodopa remains the "gold standard" symptomatic PD treatment 154 Sinemet (carbidopa-levodopa) 156 Parcopa (carbidopa-levodopa) 159 Madopar (levodopa-benserazide) 160 Stalevo (carbidopa-levodopa-entacapone) 162 The dopamine agonists and now Azilect continue to battle it out for market position 169 Requip (ropinirole) 171 Mirapex (pramipexole) 174 Neupro (rotigotine) 177 Apokyn (apomorphine) 184 Azilect (rasagiline) 188 Comtan (entacapone) 191 CHAPTER 9 TREATMENTS OUTCOMES AND SURGERY 194 Treatment outcomes 195 Only 36% of advanced-stage patients are adequately controlled by pharmacological therapy 195 Intolerable side effects are the key reason for discontinuing or switching treatment 197 Although pill burden affects patient quality of life, it has a low influence on discontinuing or switching therapies 197 Surgical treatment of Parkinsons disease 198 Progression to surgery 198 More than half of the 9% of PD patients who require surgery go on to receive it 198 The invasive nature of surgical techniques limits their use 200 Surgical techniques used 202 Deep Brain Stimulation is by far the most common surgical technique used across the seven major markets 202 Outcome of surgery 204 Over 50% of patients will experience both a reduction in PD symptoms and a reduction in the dose of pharmacological medication with each surgical technique 204 BIBLIOGRAPHY 207 Journal papers 207 Websites 213 APPENDIX A 217 Physician research methodology 217 Physician sample breakdown 217 US 217 Japan 218 France 218 Germany 219 Italy 219 Spain 220 UK 220 Contributing experts 221 APPENDIX B 222 The survey questionnaire 222 Physicians details 222 Screening questions 223 INTRODUCTION 224 Section 1-Patient segmentation and diagnosis of Parkinsons disease 224 Section 2-Treatment of Parkinsons disease 230 Early-stage pharmacological treatment 232 Mid-stage pharmacological treatment 235 Advanced-stage pharmacological treatment 239 Section 3-Key prescribing factors 243 Section 4-Treatment outcomes and Surgery 246 Demographics 249 Disclaimer 251 List of Tables Table 1: The five stages of PD according to the Hoehn and Yahr scale 33 Table 2: Prevalence of PD across the seven major markets, 2007 39 Table 3: Unified Parkinsons Disease Rating Scale-cognition, behavior and mood 54 Table 4: Proportion of prevalent PD population diagnosed at each disease stage across the seven major markets, 2007 64 Table 5: Options for initial pharmacotherapy in early PD as proposed in NICE guidelines, 2006 91 Table 6: Options for adjuvant pharmacotherapy in later PD as proposed in NICE guidelines, 2006 92 Table 7: Percentage of interviewed neurologists selecting each regimen as a first-line therapy for early-stage PD, 2007 108 Table 8: Early-stage PD second-line therapy patient progression details, 2007 112 Table 9: Percentage of drugs added-on at second-line to the dopamine agonists selected for first-line early-stage PD therapy across the seven major markets, 2007 115 Table 10: Most common selected second-line regimens after switching from first-line dopamine agonist monotherapy for early-stage PD across the seven major markets, 2007 117 Table 11: Percentage of interviewed neurologists selecting each regimen as a first-line therapy for mid-stage PD, 2007 119 Table 12: Percentage of patients receiving each drug regimen as first-line for mid-stage PD, 2007 121 Table 13: Mid-stage PD second-line therapy patient progression details, 2007 122 Table 14: Advanced-stage PD second-line therapy patient progression details, 2007 132 Table 15: Factors that influence drug choice for the management of PD, 2007 142 Table 16: Number and percentage of neurologists able to rate each brand 150 Table 17: Overall performance of each Parkinsons disease drug against six attributes according to interviewed neurologists in the seven major markets, 2007 151 Table 18: The overall performance of each drug against all attributes, and with attribute weightings applied 154 Table 19: Sinemets attribute scores, by country 158 Table 20: Comparison of Parcopas and Sinemets US attribute scores 160 Table 21: Madopars attribute scores, by country 161 Table 22: Stalevos attribute scores, by country 164 Table 23: Requips attribute scores, by country 172 Table 24: Mirapexs attribute scores, by country 176 Table 25: Neupros attribute scores, by country 179 Table 26: Apokyns attribute scores, by country 185 Table 27: Treatment-emergent adverse events (incidence =10%) and associated rate of discontinuation during open-label long-term use of Apokyn (n=550) 187 Table 28: Azilects attribute scores, by country 190 Table 29: Comtans attribute scores, by country 192 Table 30: Reasons for patients discontinuing a therapy/switching to an alternative drug therapy on a scale of 1 to 10, where 1=factor of low influence and 10=factor of high influence, 2006 197 Table 31: US-physician sample breakdown, 2007 217 Table 32: Japan-physician sample breakdown, 2007 218 Table 33: France-physician sample breakdown, 2007 218 Table 34: Germany-physician sample breakdown, 2007 219 Table 35: Italy-physician sample breakdown, 2007 219 Table 36: Spain-physician sample breakdown, 2007 220 Table 37: UK-physician sample breakdown, 2007 220 List of Figures Figure 1: Diagrammatic overview of the coverage of the Stakeholder Insight: Parkinsons Disease survey, 2007 8 Figure 2: Parkinsons disease treatment tree split by disease severity in the US, 2007 12 Figure 3: Parkinsons disease treatment tree split by disease severity in Japan, 2007 13 Figure 4: Parkinsons disease treatment tree split by disease severity in France, 2007 14 Figure 5: Parkinsons disease treatment tree split by disease severity in Germany, 2007 15 Figure 6: Parkinsons disease treatment tree split by disease severity in Italy, 2007 16 Figure 7: Parkinsons disease treatment tree split by disease severity in Spain, 2007 17 Figure 8: Parkinsons disease treatment tree split by disease severity in the UK, 2007 18 Figure 9: Second-line early-stage Parkinsons disease treatment dynamics in the US, 2007 19 Figure 10: Second-line mid-stage Parkinsons disease treatment dynamics in the US, 2007 19 Figure 11: Second-line advanced-stage Parkinsons disease treatment dynamics in the US, 2007 20 Figure 12: Second-line early-stage Parkinsons disease treatment dynamics in Japan, 2007 20 Figure 13: Second-line mid-stage Parkinsons disease treatment dynamics in Japan, 2007 21 Figure 14: Second-line advanced-stage Parkinsons disease treatment dynamics in Japan, 2007 21 Figure 15: Second-line early-stage Parkinsons disease treatment dynamics in France, 2007 22 Figure 16: Second-line mid-stage Parkinsons disease treatment dynamics in France, 2007 22 Figure 17: Second-line advanced-stage Parkinsons disease treatment dynamics in France, 2007 23 Figure 18: Second-line early-stage Parkinsons disease treatment dynamics in Germany, 2007 23 Figure 19: Second-line mid-stage Parkinsons disease treatment dynamics in Germany, 2007 24 Figure 20: Second-line advanced-stage Parkinsons disease treatment dynamics in Germany, 2007 24 Figure 21: Second-line early-stage Parkinsons disease treatment dynamics in Italy, 2007 25 Figure 22: Second-line mid-stage Parkinsons disease treatment dynamics in Italy, 2007 25 Figure 23: Second-line advanced-stage Parkinsons disease treatment dynamics in Italy, 2007 26 Figure 24: Second-line early-stage Parkinsons disease treatment dynamics in Spain, 2007 26 Figure 25: Second-line mid-stage Parkinsons disease treatment dynamics in Spain, 2007 27 Figure 26: Second-line advanced-stage Parkinsons disease treatment dynamics in Spain, 2007 27 Figure 27: Second-line early-stage Parkinsons disease treatment dynamics in the UK, 2007 28 Figure 28: Second-line mid-stage Parkinsons disease treatment dynamics in the UK, 2007 28 Figure 29: Second-line advanced-stage Parkinsons disease treatment dynamics in the UK, 2007 29 Figure 30: Proportion of diagnosed PD patients suffering from each disease severity, 2007 34 Figure 31: PD progression timeline from onset of early-stage disease to death as indicated by interviewed neurologists, 2007 36 Figure 32: Age at diagnosis for each stage of PD, 2007 37 Figure 33: Average time in months from the onset of symptoms of PD to initial presentation to a physician, 2007 45 Figure 34: Percentage of neurologists using each diagnostic imaging technique to make a diagnosis of PD, 2007 57 Figure 35: The number of weeks between presentation to a physician and an accurate diagnosis of PD, 2007 60 Figure 36: Percentage of prevalent PD population diagnosed vs undiagnosed for each disease stage, 2007 63 Figure 37: Proportion of interviewed neurologists PD patients characterized as having each stage of the disease, 2007 66 Figure 38: Proportion of interviewed neurologists PD patients with each severity of the disease at initial diagnosis, 2007 67 Figure 39: Proportion of PD patients suffering with each comorbidity at the three stages of the disease, 2007 68 Figure 40: Mean percentage of pharmacological and non-pharmacological PD therapy across the seven major markets, 2007 73 Figure 41: Mechanism of action of levodopa therapy 74 Figure 42: Mechanism of action of AADC inhibitors (DDIs) 75 Figure 43: Mechanism of action of COMT inhibitor (entacapone) 79 Figure 44: Mechanism of action of MAO-B inhibitors 81 Figure 45: Pharmacological treatment algorithm for PD 87 Figure 46: The dynamics of pharmacological treatment in PD management, 2007 97 Figure 47: Physician type breakdown of the initial treatment decision of PD in the seven major markets, 2007 98 Figure 48: Weeks between diagnosis of PD and the initiation of pharmacological therapy by disease stage, 2007 100 Figure 49: Percentage of patients receiving pharmacological therapy for PD across the seven major markets by stage, 2007 102 Figure 50: Percentage of patients receiving pharmacological and non-pharmacological therapy for PD across the seven major markets by stage, 2007 103 Figure 51: Early-stage second-line management strategies for pramipexole across the seven major markets, 2007 105 Figure 52: First-line treatment regimens for early-stage PD in the seven major markets, 2007 109 Figure 53: Monotherapy vs combination therapy split for early-stage PD management, 2007 111 Figure 54: Patients who progress to second-line early-stage PD therapy and receive add-on or are switched, 2007 113 Figure 55: Second-line drug add-ons for early-stage PD in the seven major markets, 2007 114 Figure 56: Most common drug regimens switched to at second-line for early-stage PD across the seven major markets, 2007 116 Figure 57: Mid-stage second-line management strategies for levodopa-carbidopa (Sinemet, Parcopa) across the seven major markets, 2007 118 Figure 58: First-line treatment regimens for mid-stage PD in the seven major markets, 2007 120 Figure 59: Monotherapy and combination therapy split for mid-stage PD management, 2007 122 Figure 60: Patients who progress to second-line mid-stage PD therapy and receive add-on or switch, 2007 123 Figure 61: Second-line drug add-ons for mid-stage PD in the seven major markets, 2007 124 Figure 62: Most common drug regimens switched to at second-line for mid-stage PD across the seven major markets, 2007 126 Figure 63: Advanced-stage second-line management strategies for levodopa-carbidopa (Sinemet, Parcopa) across the seven major markets, 2007 128 Figure 64: First-line treatment regimens for advanced-stage PD in the seven major markets, 2007 129 Figure 65: Monotherapy and combination therapy split for advanced-stage PD management, 2007 131 Figure 66: Patients who progress to second-line advanced-stage PD therapy and receive add-on or switch, 2007 132 Figure 67: Second-line drug add-ons for advanced-stage PD in the seven major markets, 2007 133 Figure 68: Number of times neurologists added on Apokyn in second-line for advanced-stage PD across the seven major markets, 2007 136 Figure 69: Most common drug regimens switched to at second-line for advanced-stage PD across the seven major markets, 2007 139 Figure 70: Average rating of factors which influence drug choice for the management of PD, 2007 141 Figure 71: Neurologists scores of side-effect profile, by brand 143 Figure 72: Importance of a drugs ability to minimize dyskinesias on prescribing decisions by country, 2007 147 Figure 73: Overview brand map of attributes versus brand perception 153 Figure 74: Physician perception of levodopa-based combination products 155 Figure 75: Levodopa-based combination brand map of attributes versus brand perception 156 Figure 76: PD-specific Sinemet sales, 2003-06 157 Figure 77: Sinemet map, country preference to prescribing attributes 159 Figure 78: PD-specific Madopar sales, 2003-06 161 Figure 79: Madopars attribute scores, by country 162 Figure 80: PD-specific Stalevo sales, 2003-06 163 Figure 81: Stalevos attribute scores, by country 164 Figure 82: Proportion of patients receiving Stalevo at first-line for each stage of PD, 2007 166 Figure 83: Physician perception of the dopamine agonists, Azilect and Comtan 169 Figure 84: Non-levodopa containing product brand map of attributes versus brand perception 170 Figure 85: PD-specific Requip sales, 2003-06 171 Figure 86: Requips overall attribute scores 173 Figure 87: PD-specific Mirapex sales, 2003-06 175 Figure 88: Mirapex and Requip overall attribute scores 177 Figure 89: Diagrammatic representation of Neupros mode of action 178 Figure 90: PD-specific quarterly Neupro sales in Germany, Spain and the UK, Q3-2006-Q2-2007 181 Figure 91: Country rating of Neupro, Requip and Mirapex on the ability to use as either monotherapy or adjunctive therapy 182 Figure 92: Proportion of patients receiving Neupro at first-line for each stage of PD, 2007 183 Figure 93: Apokyns overall attribute scores 186 Figure 94: PD- specific quarterly US Apokyn sales, Q1 2006-Q2 2007 188 Figure 95: PD- specific Azilect sales, H2 2005-H1 2007 189 Figure 96: Percentage of patients adequately controlled by pharmacological therapy at each stage of the disease as indicated by interviewed neurologists across the seven major markets, 2007 195 Figure 97: Percentage of PD patients requiring and receiving surgery across the seven major markets, 2007 199 Figure 98: Ratings of the reasons why patients do not receive surgery in the seven major markets, 2007 200 Figure 99: Percentage of neurologists with patients who receive surgery utilizing each PD surgical technique, 2007 203 Figure 100: Percentage of patients who undergo surgery and receive each surgical technique, 2007 204 Figure 101: Mean percentage of patients for whom each surgical technique results in a reduction in Parkinsons disease symptoms and a reduction in the dose of pharmacological medication across the seven major markets, 2007 205

Companies Mentioned

AM nv Boehringer Ingelheim GmbH Bristol-Myers Squibb Company Britannia Building Society Cytokine PharmaSciences, Inc Danka Business Systems PLC Electronic Data Systems Corporation Eli Lilly and Company GlaxoSmithKline Plc Gottschalks Inc H.J. Heinz Company Hughes Communications Inc IMS Health Insight Communications Company, Inc. Medtronic, Inc. Merck & Co., Inc. NICE Systems Ltd Novartis AG Pepper Construction Group, LLC Pfizer Inc Safety Insurance Group, Inc. Schwarz Pharma AG Solvay Group Taylor Corporation Vernalis Group PLC