Frontier Pharma: Neurodegenerative Diseases – Protein Misfolding Targets and Neuromodulators Dominate the First-in-Class Pipeline and Lead the Way as Potential Disease-Modifying Therapies in AD and PD

Neurodegenerative diseases are becoming increasingly prevalent due to an aging population, but this diverse therapy area remains largely untreatable with current therapies. Neurodegenerative diseases are characterized by neuronal death within the brain and/or central nervous system (CNS), leading to progressive decline in functional neurological capacities. It has a devastating effect on quality of life and independence, often requiring full-time care during the later disease stages. Conditions within the therapy area are diverse, and exhibit specific pathophysiologies and etiologies, while affecting people of all ages. This report examines the entire neurodegenerative disease therapy area, with a particular focus on the three most prevalent neurodegenerative disorders: Alzheimer’s disease (AD), Parkinson’s disease (PD) and multiple sclerosis (MS). AD and PD represent the most pressing challenges within the disease cluster, due to rapidly increasing prevalence driven by aging populations. Both AD and PD remain ineffectively treated despite substantial investment into R&D by pharmaceutical companies, due to high clinical trial failure rates. As a result there are no disease-modifying therapies for these two indications, with available treatments able to provide only marginal symptomatic relief. MS, the autoimmune disease of the CNS, contrasts with the rest of this cluster, as it affects a different population demographic, and has a lucrative pharmacological market following breakthrough success in the past decade.

Scope

Unmet need is extremely high in AD and PD, with MS showing continued promise in the development of effective therapies

– What are the most important etiological risk factors and pathophysiological processes implicated in AD, PD and MS?

– What is the current treatment algorithm?

– How effective are current therapies for these indications, and how does this impact prognosis?

The AD pipeline is large and contains a very high proportion of first-in-class product innovation.

– Which molecule types and molecular targets are most prominent across AD, PD and MS?

– What are the connections, in terms of first-in-class innovation, between AD, PD and MS?

– Which first-in-class targets are most promising?

– How does the level of first-in-class innovation change within different target classes?

– How do identified first-in-class molecular targets apply to AD, PD, MS and the wider therapeutic area?

– How does first-in-class target diversity differ by stage of development and molecular target class?

The deals landscape is active and dominated by immunomodulator products

– Which indications attract the highest deal values?

– How has deal activity fluctuated over the past decade?

– Which first-in-class pipeline products have no prior involvement in licensing or co-development deals?

Reasons to buy

- Appreciate the current clinical and commercial landscapes by considering disease symptoms, pathogenesis, etiology, co-morbidities and complications, epidemiology, diagnosis, prognosis and treatment options.

- Identify leading products and key unmet needs within the market.

- Recognize innovative pipeline trends by analyzing therapies by stage of development, molecule type and molecular target.

- Assess the therapeutic potential of first-in-class targets. Using proprietary matrix assessments, first-in-class targets in the pipeline have been assessed and ranked according to clinical potential. Individual matrix assessments are provided for targets categorized into four major classes: protein misfolding, neuromodulators, immunomodulators and neuroprotectants. The most promising first-in-class targets are reviewed in greater detail.

- Consider first-in-class pipeline products with no prior involvement in licensing and co-development deals, which may represent potential investment opportunities.

Table of Contents

1 Table of Contents

1 Table of Contents 2

1.1 List of Tables 4

1.2 List of Figures 4

2 Executive Summary 7

2.1 Robust Pipeline with Attempts to Meet Unmet Needs 7

2.2 Drugs Targeting Aβ and Elements of Protein Misfolding Pathways Offer Potential New Therapies for the Treatment of AD and PD 7

2.3 Neurodegenerative Disease Pipeline Emphasizes Move Away from Conventional Areas towards Targets Related to Protein Misfolding and Neuroprotection 7

3 The Case for Innovation 9

3.1 Growing Opportunities for Biologic Products 10

3.2 Diversification of Molecular Targets 10

3.3 Innovative First-in-Class Product Development Remains Attractive 10

3.4 Regulatory and Reimbursement Policy Shifts Favor First-in-Class Product Innovation 11

3.5 Sustained Innovation in Neurodegenerative Diseases 11

3.6 GBI Research Report Guidance 12

4 Clinical and Commercial Landscape 13

4.1 Therapy Area Overview 13

4.1.1 Alzheimer’s Disease 13

4.1.2 Parkinson’s Disease 14

4.1.3 Multiple Sclerosis 14

4.2 Disease Symptoms 14

4.3 Epidemiology 15

4.3.1 Alzheimer’s Disease 16

4.3.2 Parkinson’s Disease 16

4.3.3 Multiple Sclerosis 16

4.4 Etiology 17

4.4.1 Alzheimer’s Disease 17

4.4.2 Parkinson’s Disease 18

4.4.3 Multiple Sclerosis 18

4.5 Pathophysiology 19

4.5.1 Alzheimer’s Disease 19

4.5.2 Parkinson’s Disease 21

4.5.3 Multiple Sclerosis 23

4.5.4 Neurodegenerative Disease Area 24

4.6 Diagnosis 25

4.6.1 Alzheimer’s Disease 25

4.6.2 Parkinson’s Disease 25

4.6.3 Multiple Sclerosis 26

4.7 Comorbidities and Complications 26

4.8 Prognosis 27

4.8.1 Alzheimer’s Disease 27

4.8.2 Parkinson’s Disease 27

4.8.3 Multiple Sclerosis 28

4.9 Treatment Options 28

4.9.1 Alzheimer’s Disease 28

4.9.2 Parkinson’s Disease 29

4.9.3 Multiple Sclerosis 30

4.10 Overview of Marketed Products in Neurodegeneration 31

5 Assessment of Pipeline Product Innovation 33

5.1 Overview 33

5.2 Pipeline by Stage of Development and Molecule Type 33

5.2.1 Neurodegenerative Disease Overall 33

5.2.2 Key Neurodegenerative Disease Indications 34

5.3 Pipeline by Molecular Target 36

5.3.1 Neurodegenerative Disease Overall 36

5.3.2 Key Neurodegenerative Disease Indications 39

5.4 Comparative Distribution of Programs between the Market and Pipeline by Molecular Target Class 40

5.5 First-in-Class Programs Targeting Novel Molecular Targets 41

6 Signaling Network and Innovation Alignment within Neurodegenerative Disease 80

6.1 Complexity of Signaling Networks in Neurodegenerative Disease 80

6.2 Signaling Pathways and First-in-Class Molecular Target Integration 80

6.3 First-in-Class Matrix Assessment 81

7 First-in-Class Target and Pipeline Program Evaluation 86

7.1 Pipeline Programs Targeting Protein Misfolding and Aggregation 86

7.1.1 Pipeline Programs Targeting α-synuclein 86

7.1.2 Pipeline Programs Targeting Glucosylceramidase 89

7.1.3 Pipeline Programs Targeting Amyloid Precursor Protein, Amyloid Protein and Peptide, Amyloid Beta Peptide, Amyloid Beta Protein, Beta-amyloid Protein 40 and Beta-amyloid Protein

42. 91

7.2 Pipeline Programs Targeting Neuromodulators 99

7.2.1 Pipeline Programs Targeting GTP cyclohydrolase I 99

7.2.2 Pipeline Programs Targeting Acetylcholine Receptor Subunit Nicotinic Alpha-6 101

7.2.3 Pipeline Programs Targeting Metabotropic glutamate receptor 4 103

7.3 Pipeline Programs Targeting Immunomodulators 105

7.3.1 Pipeline Programs Targeting Integrin alpha m 105

7.3.2 Pipeline Programs Targeting Leukocyte immunoglobulin like receptors B1 and B2 106

7.3.3 Pipeline Program Targeting Tumor Necrosis Factor Superfamily Member 10 108

7.4 Pipeline Programs Targeting Neuroprotectants 109

7.4.1 Pipeline Programs Targeting Rho-Associated Protein Kinase 2 109

7.4.2 Pipeline Programs Targeting Angiotensin receptor type 2 111

7.5 Conclusion 112

8 Strategic Consolidations 113

8.1 Industry-Wide First-in-Class Deals 113

8.2 Licensing Deals 114

8.2.1 Deals by Region, Value and Year 114

8.2.2 Deals by Stage of Development and Value 115

8.2.3 Deals by Molecule Type, Molecular Target and Value 116

8.2.4 List of Deals with Disclosed Deal Values 117

8.3 Co-development Deals 120

8.3.1 Deals by Region, Value and Year 120

8.3.2 Deals by Stage of Development and Value 121

8.3.3 Deals by Molecule Type, Molecular Target and Value 121

8.3.4 List of Deals with Disclosed Deal Values 122

8.4 First-in-Class Programs with and without Prior Involvement in Licensing and Co-development Deals 125

9 Appendix 132

9.1 References 132

9.2 Abbreviations 144

9.3 Disease List 145

9.3.1 Alzheimer’s Disease 145

9.3.2 Parkinson’s Disease 145

9.3.3 Multiple Sclerosis 145

9.3.4 Other 145

9.4 Top 10 First-in-Class Targets for Alzheimer’s Disease, Parkinson’s Disease and Multiple Sclerosis 146

9.5 Research Methodology 148

9.5.1 Data integrity 148

9.5.2 Innovative and meaningful analytical techniques and frameworks: 148

9.5.3 Evidence based analysis and insight: 148

9.6 Secondary Research 148

9.6.1 Market Analysis 148

9.6.2 Pipeline Analysis 148

9.6.3 First-in-Class Matrix Assessment 149

9.6.4 First-in-Class Target Profiles 149

9.6.5 Licensing and Co-Development Deals 149

9.7 Contact Us 149

9.8 Disclaimer 149

List of Tables

1.1 List of Tables

Table 1: Neurodegenerative Disease, Global, Symptoms of AD, PD and MS, 2017 15

Table 2: Neurodegenerative Disease, Global, Epidemiology of Common Neurodegenerative Diseases, 2017 16

Table 3: Neurodegenerative Disease, Global, Common Comorbidities Associated with AD, PD and MS, 2017 27

Table 4: Neurodegenerative Disease, Global, Key Features and Pipeline Activity of Synuclein and α-synuclein, 2017 87

Table 5: Neurodegenerative Disease, Global, Pipeline Programs Targeting Synuclein and α-synuclein, 2017 88

Table 6: Neurodegenerative Disease, Global, Key Features and Pipeline Activity of Glucosylceramidase, 2017 90

Table 7: Neurodegenerative Disease, Global, Pipeline Programs Targeting Glucosylceramidase, 2017 90

Table 8: Neurodegenerative Disease, Global, Key Features and Pipeline Activity of Amyloid Precursor Protein and Amyloid Protein and Peptide, 2017 92

Table 9: Neurodegenerative Disease, Global, Key Features and Pipeline Activity of Amyloid Precursor Protein and Amyloid Protein and Peptide, 2017 93

Table 10: Neurodegenerative Disease, Global, Key Features and Pipeline Activity of GTP Cyclohydrolase I, 2017 101

Table 11: Neurodegenerative Disease, Global, Pipeline Programs Targeting GTP Cyclohydrolase I, 2017 101

Table 12: Neurodegenerative Disease, Global, Key Features and Pipeline Activity of Acetylcholine receptor subunit nicotinic alpha-6, 2017 102

Table 13: Neurodegenerative Disease, Global, Pipeline Programs Targeting Acetylcholine receptor subunit nicotinic alpha-6, 2017 103

Table 14: Neurodegenerative Disease, Global, Key Features and Pipeline Activity of Metabotropic glutamate receptor 4, 2017 104

Table 15: Neurodegenerative Disease, Global, Pipeline Programs Targeting Metabotropic glutamate receptor 4, 2017 105

Table 16: Neurodegenerative Disease, Global, Key Features and Pipeline Activity of Integrin alpha m, 2017 106

Table 17: Neurodegenerative Disease, Global, Pipeline Programs Targeting Integrin alpha m, 2017 106

Table 18: Neurodegenerative Disease, Global, Key Features and Pipeline Activity of Leukocyte immunoglobulin receptor B1/2, 2017 107

Table 19: Neurodegenerative Disease, Global, Pipeline Programs Targeting Leukocyte immunoglobulin receptor B1/2, 2017 108

Table 20: Neurodegenerative Disease, Global, Key Features and Pipeline Activity of Tumor necrosis superfamily member 10, 2017 109

Table 21: Neurodegenerative Disease, Global, Pipeline Programs Targeting Tumor necrosis superfamily member 10, 2017 109

Table 22: Neurodegenerative Disease, Global, Key Features and Pipeline Activity of Rho-associated protein kinase 2, 2017 110

Table 23: Neurodegenerative Disease, Global, Pipeline Programs Targeting Rho-associated protein kinase 2, 2017 111

Table 24: Neurodegenerative Disease, Global, Key Features and Pipeline Activity of Angiotensin receptor type 2, 2017 112

Table 25: Neurodegenerative Disease, Global, Pipeline Programs Targeting Angiotensin receptor type 2, 2017 112

List of Figures

1.2 List of Figures

Figure 1: Neurodegenerative Disease, US, Innovation Trends in Product Approvals, 1987-2015 9

Figure 2: Neurodegenerative Disease, US, Sales Performance of First-in-Class and Non-First-in-Class Products Post Marketing Approval, 2006-2013 11

Figure 3: Neurodegenerative Disease, Global, Overview of Marketed Products, 2017 32

Figure 4: Neurodegenerative Disease, Global, Pipeline by Therapy Area, 2017 33

Figure 5: Neurodegenerative Disease, Global, Pipeline by Stage of Development and Molecule Type, 2017 34

Figure 6: Neurodegenerative Disease, Global, Pipeline by Key Indications and Stage of Development, 2017 35

Figure 7: Neurodegenerative Disease, Global, Pipeline by Key Indications and Molecule Type, 2017 36

Figure 8: Neurodegenerative Disease, Global, Pipeline by Molecular Target and Stage of Development, 2017 38

Figure 9: Neurodegenerative Disease, Global, Pipeline Breakdown of Key Molecular Target Classes, 2017 39

Figure 10: Neurodegenerative Disease, Global, Pipeline Breakdown of Key Indications by Molecular Target Class, 2017 40

Figure 11: Neurodegenerative Disease, Global, Pipeline and Marketed Products by Molecular Target Class, 2017 41

Figure 12: Neurodegenerative Disease, Global, Pipeline by Molecular Target Class, First-in-Class Status and Stage of Development, 2017 42

Figure 13: Neurodegenerative Disease, Global, Pipeline by Molecular Target Class, First-in-Class Status and Key Indication, 2017 43

Figure 14: Neurodegenerative Disease, Global, Percentage Distribution of First-in-Class and Non-First-in-Class Pipeline Products by Stage of Development and Molecular Target Class (%), 2017 43

Figure 15: Neurodegenerative Disease, Global, Ratio of First-in-Class Products to First-in-Class Targets by Stage of Development and Molecular Target Class, 2017 44

Figure 16: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 1 45

Figure 17: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 2 46

Figure 18: Neurodegenerative Disease , Global, List of All Pipeline Programs, 2017 Part 3 47

Figure 19: Neurodegenerative Disease , Global, List of All Pipeline Programs, 2017 Part 4 48

Figure 20: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 5 49

Figure 21: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 6 50

Figure 22: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 7 51

Figure 23: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 8 52

Figure 24: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 9 53

Figure 25: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 10 54

Figure 26: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 11 55

Figure 27: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 12 56

Figure 28: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 13 57

Figure 29: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 14 58

Figure 30: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 15 59

Figure 31: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 16 60

Figure 32: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 17 61

Figure 33: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 18 62

Figure 34: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 19 63

Figure 35: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 20 64

Figure 36: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 21 65

Figure 37: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 22 66

Figure 38: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 23 67

Figure 39: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 24 68

Figure 40: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 25 69

Figure 41: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 26 70

Figure 42: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 27 71

Figure 43: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 28 72

Figure 44: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 29 73

Figure 45: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 30 74

Figure 46: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 31 75

Figure 47: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 32 76

Figure 48: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 33 77

Figure 49: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 34 78

Figure 50: Neurodegenerative Disease, Global, List of All Pipeline Programs, 2017 Part 35 79

Figure 51: Neurodegenerative Disease, Global, First-in-Class Molecular Target Matrix Assessment for Protein Misfolding, 2017 83

Figure 52: Neurodegenerative Disease Therapeutics Market, Global, First-in-Class Molecular Target Matrix Assessment for Neuromodulators, 2017 83

Figure 53: Neurodegenerative Disease Therapeutics Market, Global, First-in-Class Molecular Target Matrix Assessment for Immunomodulators, 2017 84

Figure 54: Neurodegenerative Disease Therapeutics Market, Global, First-in-Class Molecular Target Matrix Assessment for Neuroprotectants, 2017 85

Figure 55: Neurodegenerative Disease, Global, Industry-Wide Licensing Deals by Stage of Development and First-in-Class Status, 2006-2014 113

Figure 56: Neurodegenerative Disease, Global, Industry-Wide Licensing Deals by Deal Value, Upfront Payment Value, Stage of Development and First-in-Class Status, 2006-2014 114

Figure 57: Neurodegenerative Disease, Global, Licensing Deals by Region, Value and Year, 2006-2017 115

Figure 58: Neurodegenerative Disease, Global, Licensing Deals by Deal Value, Upfront Payment Value and Stage of Development, 2006-2017 116

Figure 59: Neurodegenerative Disease, Global, Number and Aggregate Deal Value of Licensing Deals by Molecule Type and Molecular Target, 2006-2017 117

Figure 60: Neurodegenerative Disease, Global, Licensing Deals with Disclosed Deal Values, 2006-2017 118

Figure 61: Neurodegenerative Disease, Global, Licensing Deals with Disclosed Deal Values, 2006-2017 119

Figure 62: Neurodegenerative Disease, Global, Co-development Deals by Region, Value and Year, 2006-2017 120

Figure 63: Neurodegenerative Disease, Global, Co-development Deals by Deal Value, Upfront Payment Value and Stage of Development, 2006-2017 121

Figure 64: Neurodegenerative Disease, Global, Number and Aggregate Deal Value of Co-development Deals by Molecule Type and Molecular Target, 2006-2017 122

Figure 65: Neurodegenerative Disease, Global, Co-development Deals with Disclosed Deal Values, 2006-2017 123

Figure 66: Neurodegenerative Disease, Global, Co-development Deals with Disclosed Deal Values, 2006-2017 124

Figure 67: Neurodegenerative Disease, Global, First-in-Class Pipeline Products With and Without Prior Involvement in Licensing or Co-development Deals, 2017, Part 1 126

Figure 68: Neurodegenerative Disease, Global, First-in-Class Pipeline Products With and Without Prior Involvement in Licensing or Co-development Deals, 2017, Part 2 127

Figure 69: Neurodegenerative Disease, Global, First-in-Class Pipeline Products With and Without Prior Involvement in Licensing or Co-development Deals, 2017, Part 3 128

Figure 70: Neurodegenerative Disease, Global, First-in-Class Pipeline Products With and Without Prior Involvement in Licensing or Co-development Deals, 2017, Part 4 129

Figure 71: Neurodegenerative Disease, Global, First-in-Class Pipeline Products With and Without Prior Involvement in Licensing or Co-development Deals, 2017, Part 5 130

Figure 72: Neurodegenerative Disease, Global, First-in-Class Pipeline Products with and without Prior Involvement in Licensing or Co-development Deals, 2017, Part 6 131

Figure 73: Neurodegenerative Disease, Global, Top 10 Ranked Matrix Targets in Alzheimer’s Disease, 2017 146

Figure 74: Neurodegenerative Disease, Global, Top 10 Ranked Matrix Targets in Parkinson’s Disease, 2017 147

Figure 75: Neurodegenerative Disease, Global, Top 10 Ranked Matrix Targets in Multiple Sclerosis, 2017 147

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