1 Table of Contents 1 Table of Contents 2 1.1 List of Tables 3 1.2 List of Figures 3 2 Executive Summary 4 2.1 High Unmet Needs Remain in Parkinson’s Disease Market 4 2.2 Diverse and Innovative Pipeline to Shift Focus to Disease Modification 4 2.3 Deals Landscape Presents Substantial Investment Opportunities 4 3 The Case for Innovation 5 3.1 Growing Opportunities for Biologic Products 6 3.2 Diversification of Molecular Targets 6 3.3 Innovative First-in-Class Product Developments Remain Attractive 6 3.4 Regulatory and Reimbursement Policy Shifts Favor First-in-Class Product Innovation 7 3.5 Sustained Innovation 7 3.6 GBI Research Report Guidance 8 4 Clinical and Commercial Landscape 9 4.1 Disease Overview 9 4.2 Epidemiology 9 4.3 Disease Etiology 10 4.3.1 Exposure to Environmental Toxins 10 4.3.2 Genetic Causes of Familial Parkinson’s Disease 10 4.3.3 Susceptibility Genes for Parkinson’s Disease 12 4.4 Disease Pathophysiology 12 4.4.1 Basal Ganglia Anatomy and Physiology 12 4.4.2 Process Underlying Neurodegeneration 15 4.5 Disease Symptoms 19 4.6 Co-morbidities and Complications 19 4.7 Diagnosis 19 4.8 Classification of Disease Stages 20 4.8.1 Hoehn and Yahr Scale 20 4.8.2 Unified Parkinson’s Disease Rating Scale 20 4.8.3 Scale for the Assessment of Positive Symptoms 22 4.8.4 Mini Mental State Examination 22 4.9 Prognosis and Disease Staging 22 4.10 Treatment Options 23 4.10.1 Pharmacotherapy 23 4.10.2 Non-pharmacological Treatment 25 4.11 Overview of Marketed Products 25 4.11.1 Molecule Type and Target Analysis 26 4.11.2 Treatment Algorithm 27 4.12 Current Unmet Needs 33 5 Assessment of Pipeline Product Innovation 35 5.1 Parkinson’s Disease Pipeline by Molecule Type, Phase and Therapeutic Target 35 5.2 Comparative Distribution of Programs between Parkinson’s Disease Market and Pipeline by Therapeutic Target Family 40 5.3 First-in-Class Pipeline Programs Targeting Novel Molecular Targets 40 6 Signaling Pathways, Genetics and Innovation Alignment 45 6.1 The Complexity of Signaling Networks in the Central Nervous System 45 6.2 Signaling Pathways and First-in-Class Molecular Target Integration 46 6.3 First-in-Class Target Matrix Assessment 46 7 First-in-Class Target Evaluation 49 7.1 Pipeline Programs Targeting α-synuclein 49 7.2 Pipeline Programs Targeting DJ-1 52 7.3 Pipeline Programs Targeting Parkin 54 7.4 Pipeline Programs Targeting High Affinity Nerve Growth Factor Receptor 56 7.5 Pipeline Programs Targeting C-jun N-Terminal Kinase 58 7.6 Pipeline Programs Targeting Leucine-Rich Repeat Kinase 2 60 7.7 Pipeline Programs Targeting Growth Hormone Secretagogue Receptor Type 1 62 7.8 Pipeline Programs Targeting Metabotropic Glutamate Receptor 4 64 7.9 Pipeline Programs Targeting NAD-dependent Protein Deacetylase Sirtuin-2 67 7.10 Overview of Pipeline Programs Targeting Progranulin 68 7.11 Conclusion 71 8 Deals and Strategic Consolidations 72 8.1 Industry-Wide First-in-Class Deals 72 8.2 Licensing Deals 73 8.3 Co-development Deals 77 8.4 First-in-Class Programs not Involved in Licensing or Co-development Deals 80 9 Appendix 82 9.1 Abbreviations 82 9.2 Bibliography 84 9.3 Research Methodology 93 9.4 Secondary Research 94 9.4.1 Marketed Product Heatmaps and Treatment Algorithm 94 9.4.2 Pipeline Analysis 94 9.4.3 First-in-Class Matrix Assessment 94 9.4.4 First-in-Class Target Profiles 95 9.4.5 Licensing and Co-development Deals 95 9.5 Contact Us 95 9.6 Disclaimer 95

1.1 List of Tables Table 1: Definition of the Stages of Disability in Hoehn and Yahr Scale, 1967 20 Table 2: Evaluation of Disability by Unified Parkinson Disease Rating Scale, 2013 21
1.2 List of Figures Figure 1: Innovation Trends in Product Approvals, 1987-2013 5 Figure 2: Sales Performance of First-in-Class and Non-First-in-Class Products Post Marketing Approval, 2006-2013 7 Figure 3: Indirect and Direct Pathways in Basal Ganglia 14 Figure 4: Molecular Targets of Marketed Products 27 Figure 5: Treatment Algorithm of Parkinson’s Disease 28 Figure 6: Efficacy and Safety of Treatments for Early Parkinson’s Disease 30 Figure 7: Efficacy and Safety of Treatments for Advanced Parkinson’s Disease 32 Figure 8: Efficacy and Safety of Treatment for Non-Motor Symptoms in Parkinson’s Disease 33 Figure 9: Developmental Pipeline Overview 36 Figure 10: Parkinson’s Disease Pipeline by Molecular Target 37 Figure 11: Parkinson’s Disease Pipeline by Molecular Target 39 Figure 12: Molecular Target Category Comparison, Pipeline and Marketed Products 40 Figure 13: Molecular Target Category Comparison, Pipeline First-in-Class and Established Molecular Targets 42 Figure 14: Parkinson’s Disease, Global, First-in-Class Pipeline Products 43 Figure 15: First-in-Class Molecular Target Analysis Matrix 48 Figure 16: Data and Evidence for α-synuclein as a Therapeutic Target 51 Figure 17: Pipeline Programs Targeting α-synuclein 52 Figure 18: Data and Evidence for DJ-1 as a Therapeutic Target 54 Figure 19: Pipeline Programs Targeting DJ-1 54 Figure 20: Data and Evidence for Parkin as a Therapeutic Target 55 Figure 21: Pipeline Programs Targeting Parkin 55 Figure 22: Data and Evidence for High Affinity Nerve Growth Factor Receptor as a Therapeutic Target 57 Figure 23: Pipeline Programs Targeting High Affinity Nerve Growth Factor Receptor 57 Figure 24: Data and Evidence for C-Jun N-Terminal Kinases as a Therapeutic Target 59 Figure 25: Pipeline Programs Targeting C-Jun N-Terminal Kinase 60 Figure 26: Data and Evidence for Leucine-Rich Repeat Kinase 2 as a Therapeutic Target 61 Figure 27: Pipeline Programs Targeting Leucine-Rich Repeat Kinase 2 62 Figure 28: Data and Evidence for Growth Hormone Secretagogue Receptor as a Therapeutic Target 64 Figure 29: Pipeline Programs Targeting Growth Hormone Secretagogue Receptor Type 1 64 Figure 30: Data and Evidence for Metabotropic Glutamate Receptor 4 as a Therapeutic Target 66 Figure 31: Pipeline Programs Targeting Metabotropic Glutamate Receptor 4 67 Figure 32: Data and Evidence for NAD-dependent Protein Deacetylase Sirtuin-2 as a Therapeutic Target 68 Figure 33: Pipeline Programs Targeting NAD-Dependent Protein Deacetylase Sirtuin-2 68 Figure 34: Data and Evidence for Progranulin as a Therapeutic Target 70 Figure 35: Pipeline Programs Targeting Progranulin 70 Figure 36: Industry-Wide Deals by Stage of Development, 2006-2014 72 Figure 37: Industry-Wide Deals by Stage of Development, 2006-2014 73 Figure 38: Licensing Deals, 2006-2015 74 Figure 39: Licensing Deals by Molecule Type, 2006-2015 75 Figure 40: Licensing Deals by Molecular Target, 2006-2015 75 Figure 41: Summary of Licensing Deals, 2006-2015 76 Figure 42: Co-development Deals, 2006-2015 77 Figure 43: Co-development Deals by Phase and Molecule Type, 2006-2015 78 Figure 44: Co-development Deals by Molecular Target, 2006-2015 78 Figure 45: Summary of Co-development Deals, 2006-2015 79 Figure 46: First-in-Class Programs with no Recorded Prior Deal Involvement, 2006-2015 81