Global Neurodegenerative Diseases Drugs Market to 2023 – MS Set to Dominate with Tecfidera and Ocrevus, as Disease-Modifying Pipeline Therapies for Alzheimer’s Disease and SMA Show Clinical and Commercial Potential

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 five most prevalent neurodegenerative disorders: Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD).

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.

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. Recent approvals for Ocrevus and Tecfidera are expected to sustain the market in the near future.

Scope

– Unmet need is extremely high in AD, PD, ALS and HD, but MS and spinal muscular atrophy (SMA) show continued promise in the development of effective therapies

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

– What is the current treatment algorithm?

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

– The neurodegenerative disease pipeline is large. Does the current pipeline innovation hold the potential to change the market over the forecast period?

– Which molecule types and molecular targets are most prominent across the five key indications?

– What is the risk of a neurodegenerative drug failing to make the market?

– What is the risk of a drug failing at a specific phase, molecular target class and indication?

– The neurodegenerative disease market landscape is forecast to undergo a period of substantial change following key approvals, patent expiries and acquisitions.

– What strategies have these companies adopted to achieve market growth?

– Which of the leading companies will have the highest market share by 2023?

– Which pipeline products are forecast to achieve the highest revenues on the market by 2023?

– 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?

– How do deal frequency and value compare between target families and molecule types?

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. This review also provides a detailed look at clinical trials, providing an insight into the risk associated with bringing neurodegenerative disease drugs to market.

- Predict growth in market size, with in-depth market forecasting from 2016 to 2023. The forecast will provide an understanding of how epidemiology trends, new drug entries and new drug patent expirations will influence market value.

- Identify the key pipeline products, with a particular focus on those due to be brought to the market in the near future, including sales forecasts for these products.

- Identify the leading companies in the market, in terms of market share and growth. Company analysis determines how dependent the key companies are on revenues derived from the neurodegenerative market. In addition, analysis determines the primary factors that will drive market growth for the key companies in the market.

- Consider the licensing and co-development deal landscape for neurodegenerative disease drugs.

Table of Contents

1 Table of Contents

1 Table of Contents 5

1.1 List of Tables 7

1.2 List of Figures 8

2 Introduction 13

2.1 Therapy Area Introduction 13

2.1.1 Alzheimer’s Disease 13

2.1.2 Parkinson’s Disease 14

2.1.3 Multiple Sclerosis 15

2.1.4 Huntington’s Disease 15

2.1.5 Amyotrophic Lateral Sclerosis 16

2.2 Symptoms 17

2.3 Diagnosis 18

2.3.1 Alzheimer’s Disease 18

2.3.2 Parkinson’s Disease 19

2.3.3 Multiple Sclerosis 20

2.3.4 Huntington’s Disease 21

2.3.5 Amyotrophic Lateral Sclerosis 21

2.4 Etiology and Pathophysiology 22

2.4.1 Alzheimer’s Disease 22

2.4.2 Parkinson’s Disease 24

2.4.3 Multiple Sclerosis 26

2.4.4 Huntington’s Disease 27

2.4.5 Amyotrophic Lateral Sclerosis 28

2.5 Epidemiology 29

2.5.1 Alzheimer’s Disease 29

2.5.2 Parkinson’s Disease 30

2.5.3 Multiple Sclerosis 32

2.5.4 Huntington’s Disease 33

2.5.5 Amyotrophic Lateral Sclerosis 34

2.6 Prognosis and Disease Staging 35

2.6.1 Alzheimer’s Disease 35

2.6.2 Parkinson’s Disease 36

2.6.3 Multiple Sclerosis 39

2.6.4 Huntington’s Disease 40

2.6.5 Amyotrophic Lateral Sclerosis 41

2.7 Treatment 42

2.7.1 Alzheimer’s Disease 43

2.7.2 Parkinson’s Disease 43

2.7.3 Multiple Sclerosis 46

2.7.4 Huntington’s Disease 47

2.7.5 Amyotrophic Lateral Sclerosis 47

3 Key Marketed Products 49

3.1 Overview 49

3.2 Current and Future Trends in the MS Market 50

3.3 Copaxone (glatiramer acetate) - Teva 51

3.4 Tecfidera (dimethyl fumarate) - Biogen 53

3.5 Gilenya (fingolimod) - Novartis 55

3.6 Avonex (Interferon beta-1a) - Biogen 57

3.7 Tysabri (natalizumab) - Biogen 58

3.8 Ocrevus (ocrelizumab) - F. Hoffmann-La Roche Ltd. 60

3.9 Namenda/Ebixa/Axura/Abixa Memary (memantine hydrochloride) - Merz/Lundbeck/Forest/Daiichi/ Sankyo 62

3.10 Aricept (donepezil) - Eisai/Pfizer 64

3.11 Azilect (rasagiline mesylate) -Teva 66

3.12 Neupro (rotigotine) - UCB 67

3.13 Radicut (edaravone) - Mitsubishi Tanabe Pharma Corp 69

3.14 Xenazine (tetrabenazine) - Valeant Pharmaceuticals International Inc. 70

3.15 Spinraza (nusinersen) - Biogen 72

4 Pipeline Landscape Assessment 75

4.1 Overview 75

4.2 Pipeline Development Landscape 76

4.2.1 Neurodegenerative Disease Overall 76

4.2.2 Key Neurodegenerative Disease Indications 77

4.3 Molecular Targets in the Pipeline 80

4.3.1 Neurodegenerative Disease Overall 80

4.3.2 Key Neurodegenerative Disease Indications 83

4.4 Clinical Trials 85

4.4.1 Failure Rate by Stage of Development, Indication, Molecule Type and Molecular Target 85

4.4.2 Clinical Trial Duration by Stage of Development, Indication, Molecular Type and Molecular Target 88

4.4.3 Clinical Trial Size by Stage of Development, Indication, Molecule Type and Molecular Target 92

4.4.4 Aggregate Clinical Program Size by Stage of Development, Indication, Molecular Type and Molecular Target 95

4.5 Assessment of Key Pipeline Products 98

4.5.1 Aducanumab - Biogen/Eisai 98

4.5.2 Azeliragon - vTv Therapeutics 100

4.5.3 ChariSMA - AveXis 101

4.5.4 Omaveloxolone - Reata Pharmaceuticals 102

4.5.5 Siponimod - Novartis 104

4.5.6 Ozanimod - Celgene 105

4.5.7 Elenbecestat - Eisai 106

4.5.8 BAN-2401 - Sage Therapeutics 107

4.5.9 IONIS-HTTRx 108

4.6 Conclusion 110

5 Multi-scenario Market Forecast to 2023 111

5.1 Overall Market Size 111

5.2 Generic Penetration 113

5.3 Revenue Forecast by Molecular Target 115

5.3.1 Neuromodulators 115

5.3.2 Immunomodulators 116

5.3.3 Stress-related Targets 116

5.3.4 Protein Misfolding Targets 117

5.3.5 Neuroprotectants 118

6 Company Analysis and Positioning 119

6.1 Revenue and Market Share Analysis by Company 122

6.1.1 Biogen - Aducanumab and Tecfidera Cement Biogen as the Market Leader 128

6.1.2 Roche - Increasing Sales of Ocrevus to Drive Market Size 130

6.1.3 Novartis - Gradual Decline in Revenue due to Gilenya Patent Expiration Offset by Large Pipeline 131

6.1.4 Teva - Gradual Decline in Revenue due to Patent Expiration of Premium Product Copaxone 133

6.1.5 Eisai - Elenbecestat and BAN-2401 Driving New Market Growth for Eisai 134

6.1.6 Sanofi - Aubagio and Lemtrada on Course for Blockbuster Status in 2023 135

6.2 Company Landscape 136

6.3 Marketed and Pipeline Portfolio Analysis 137

6.3.1 Conclusion 139

7 Strategic Consolidations 140

7.1 Licensing Deals 140

7.1.1 Deals by Region, Year and Value 140

7.1.2 Deals by Indication 142

7.1.3 Deals by Stage of Development and Value 143

7.1.4 Deals by Molecule Type and Molecular Target 144

7.1.5 Table for Licensing Deals Valued Above $100m 145

7.2 Co-development Deals 148

7.2.1 Deals by Region, Year and Value 148

7.2.2 Deals by Indication 149

7.2.3 Deals by Stage of Development and Value 150

7.2.4 Deals by Molecule Type, Mechanism of Action and Value 151

7.2.5 Table for Co-development Deals Valued Above $100m 152

8 Appendix 154

8.1 Bibliography 154

8.2 All Pipeline Drugs by Phase 170

8.2.1 Discovery 170

8.2.2 Preclinical 174

8.2.3 IND/CTA-Filed/Phase 0 188

8.2.4 Phase I 189

8.2.5 Phase II 191

8.2.6 Phase III 193

8.2.7 Pre-registration 193

8.3 Abbreviations 194

8.4 Disease List 196

8.4.1 Alzheimer’s disease 196

8.4.2 Parkinson’s disease 196

8.4.3 Multiple sclerosis 196

8.4.4 Amyotrophic lateral sclerosis 196

8.4.5 Huntington’s disease 196

8.4.6 Other 196

8.5 Methodology 197

8.5.1 Coverage 197

8.5.2 Secondary Research 197

8.5.3 Market Size and Revenue Forecasts 198

8.5.4 Pipeline Analysis 198

8.5.5 Competitive Landscape 198

8.6 Contact Us 199

8.7 Disclaimer 199

List of Tables

1.1 List of Tables

Table 1: Neurodegenerative Disease Drugs Market, Symptoms of AD, PD, MS, HD and ALS, 2017 17

Table 2: Neurodegenerative Disease Drugs Market, Global, Epidemiology, 2017 29

Table 3: Neurodegenerative Disease Drugs Market, Global, Alzheimer’s Disease Neurological Tests and Disease Staging, 2017 36

Table 4: Neurodegenerative Disease Drugs Market, Global, Parkinson’s Disease UPRDS Scale, 2017 37

Table 5: Neurodegenerative Disease Drugs Market, Global, Parkinson’s Disease Revised Hoehn and Yahr Scale, 2017 38

Table 6: Neurodegenerative Disease Drugs Market, Global, Huntington’s Disease Unified Huntington’s Disease Rating Scale, 2017 40

Table 7: Neurodegenerative Disease Drugs Market, Global, Huntington’s Disease Shoulson and Fahn Staging Scale, 2017 41

Table 8: Neurodegenerative Disease Drugs Market, Global, Amyotrophic Lateral Sclerosis King’s Method, 2017 42

Table 9: Neurodegenerative Disease Drugs Market, Global, Treatment Options Available for Parkinson’s Disease, 2017 44

Table 10: Neurodegenerative Disease Drugs Market, Global, Approved Indications for Copaxone, 2018 52

Table 11: Neurodegenerative Disease Drugs Market, Global, Approved Indications for Tecfidera, 2018 54

Table 12: Neurodegenerative Disease Drugs Market, Global, Approved Indications for Gilenya, 2018 55

Table 13: Neurodegenerative Disease Drugs Market, Global, Approved Indications for Avonex, 2018 57

Table 14: Neurodegenerative Disease Drugs Market, Global, Approved Indications for Tysabri, 2018 59

Table 15: Neurodegenerative Disease Drugs Market, Global, Approved Indications for Ocrevus, 2018 61

Table 16: Neurodegenerative Disease Drugs Market, Global, Approved Indications for Namenda/Ebixa/Axura/Abixa/Memary, 2018 63

Table 17: Neurodegenerative Disease Drugs Market, Global, Approved Indications for Aricept, 2018 65

Table 18: Neurodegenerative Disease Drugs Market, Global, Approved Indications for Azilect, 2018 66

Table 19: Neurodegenerative Disease Drugs Market, Global, Approved Indications for Neupro, 2018 67

Table 20: Neurodegenerative Disease Drugs Market, Global, Approved Indications for Radicut 2018 69

Table 21: Neurodegenerative Disease Drugs Market, Global, Approved Indications for Xenazine, 2018 71

Table 22: Neurodegenerative Disease Drugs Market, Global, Approved Indications for Spinraza, 2018 73

Table 23: Neurodegenerative Disease Drugs Market, Global, Usage of Generics Across Key Indications, 2018 114

List of Figures

1.2 List of Figures

Figure 1: Neurodegenerative Disease Drugs Market, Global, Epidemiology Patterns for Alzheimer’s Disease, 2016-2023 30

Figure 2: Neurodegenerative Disease Drugs Market, Global, Epidemiology Patterns for Parkinson’s Disease, 2016-2023 31

Figure 3: Neurodegenerative Disease Drugs Market, Global, Epidemiology Patterns for Multiple Sclerosis, 2016-2023 33

Figure 4: Neurodegenerative Disease Drugs Market, Global, Epidemiology Patterns for Huntington’s Disease, 2016-2023 34

Figure 5: Neurodegenerative Disease Drugs Market, Global, Epidemiology Patterns for Amyotrophic Lateral Sclerosis, 2016-2023 35

Figure 6: Neurodegenerative Disease Drugs Market, Global, Multiple Sclerosis Disease Profiling, 2017 39

Figure 7: Neurodegenerative Disease Drugs Market, Global, Annual Revenue for Key Players, 2006-2023 50

Figure 8: Neurodegenerative Disease Drugs Market, Global, Market Share of Copaxone, Tecfidera, Gilenya, Avonex, Tysabri and Ocrevus Within MS, 2006-2023 51

Figure 9: Neurodegenerative Disease Drugs Market, Global, Annual Revenue for Copaxone ($bn), 2006-2023 53

Figure 10: Neurodegenerative Disease Drugs Market, Global, Annual Revenue for Tecfidera, 2013-2023 55

Figure 11: Neurodegenerative Disease Drugs Market, Global, Annual Revenue for Gilenya, 2011-2023 57

Figure 12: Neurodegenerative Disease Drugs Market, Global, Annual Revenue for Avonex, 2006-2023 58

Figure 13: Neurodegenerative Disease Drugs Market, Global, Annual Revenue for Tysabri, 2006-2023 60

Figure 14: Neurodegenerative Disease Drugs Market, Global, Annual Revenue for Ocrevus, 2017-2023 62

Figure 15: Neurodegenerative Disease Drugs Market, Global, Annual Revenue for Namenda/ Ebixa/ Axura/ Abixa/ Memary, 2006-2023 64

Figure 16: Neurodegenerative Disease Drugs Market, Global, Annual Revenue for Aricept, 2006-2023 65

Figure 17: Neurodegenerative Disease Drugs Market, Global, Annual Revenue for Azilect, 2006-2023 67

Figure 18: Neurodegenerative Disease Drugs Market, Global, Annual Revenue for Neupro, 2006-2023 68

Figure 19: Neurodegenerative Disease Drugs Market, Global, Annual Revenue for Radicut, 2006-2023 70

Figure 20: Neurodegenerative Disease Drugs Market, Global, Annual Revenue for Xenazine, 2006-2023 72

Figure 21: Neurodegenerative Disease Drugs Market, Global, Annual Revenue for Spinraza ($bn), 2016-2023 74

Figure 22: Neurodegenerative Disease Drugs Market, Global, Overall Pharmaceutical Industry Pipeline by Therapy Area, 2018 75

Figure 23: Neurodegenerative Disease Drugs Market, Global, Pipeline by Stage of Development, Molecule Type and Program Type, 2018 77

Figure 24: Neurodegenerative Disease Drugs Market, Global, Pipeline by Key Indications and Stage of Development, 2018 78

Figure 25: Neurodegenerative Disease Drugs Market, Global, Pipeline by Key Indications and Molecule Type, 2018 79

Figure 26: Neurodegenerative Disease Drugs Market, Global, Pipeline by Stage of Development and Molecular Target, 2018 82

Figure 27: Neurodegenerative Disease Drugs Market, Global, Pipeline by Molecular Target, 2018 83

Figure 28: Neurodegenerative Disease Drugs Market, Global, Pipeline by Key Indications and Molecular Target, 2018 84

Figure 29: Neurodegenerative Disease Drugs Market, Global, Clinical Trial Attrition Rates by Stage of Development (%), 2006-2018 85

Figure 30: Neurodegenerative Disease Drugs Market, Global, Clinical Trial Attrition Rates by Stage of Development and Indication (%), 2006-2018 86

Figure 31: Neurodegenerative Disease Drugs Market, Global, Clinical Trial Attrition Rates by Stage of Development and Molecule Type (%), 2006-2018 87

Figure 32: Neurodegenerative Disease Drugs Market, Global, Clinical Trial Attrition Rates by Stage of Development and Molecular Target (%), 2006-2018 88

Figure 33: Neurodegenerative Disease Drugs Market, Global, Clinical Trial Duration by Stage of Development (months), 2006-2018 89

Figure 34: Neurodegenerative Disease Drugs Market, Global, Clinical Trial Duration by Stage of Development and Indication (months), 2006-2018 90

Figure 35: Neurodegenerative Disease Drugs Market, Global, Clinical Trial Duration by Stage of Development and Molecule Type (months), 2006-2018 91

Figure 36: Neurodegenerative Disease Drugs Market, Global, Clinical Trial Duration by Stage of Development and Molecular Target (months), 2006-2018 92

Figure 37: Neurodegenerative Disease Drugs Market, Global, Clinical Trial Size by Stage of Development, 2006-2018 92

Figure 38: Neurodegenerative Disease Drugs Market, Global, Clinical Trial Size by Stage of Development and Indication, 2006-2017 93

Figure 39: Neurodegenerative Disease Drugs Market, Global, Clinical Trial Size by Stage of Development and Molecule Type, 2006-2018 94

Figure 40: Neurodegenerative Disease Drugs Market, Global, Clinical Trial Size by Stage of Development and Molecular Target, 2006-2018 95

Figure 41: Neurodegenerative Disease Drugs Market, Global, Clinical Program Size by Stage of Development, 2006-2018 96

Figure 42: Neurodegenerative Disease Drugs Market, Global, Clinical Program Size by Stage of Development and Indication, 2006-2018 96

Figure 43: Neurodegenerative Disease Drugs Market, Global, Clinical Program Size by Stage of Development and Molecule Type, 2006-2018 97

Figure 44: Neurodegenerative Disease Drugs Market, Global, Clinical Program Size by Stage of Development and Molecular Target, 2006-2017 98

Figure 45: Neurodegenerative Disease Drugs Market, Global, Revenue for Aducanumab ($bn), 2020-2023 100

Figure 46: Neurodegenerative Disease Drugs Market, Global, Revenue for Azeliragon ($bn), 2019-2023 101

Figure 47: Neurodegenerative Disease Drugs Market, Global, Revenue for ChariSMA ($bn), 2019-2023 102

Figure 48: Neurodegenerative Disease Drugs Market, Global, Revenue for Omaveloxolone ($bn), 2019-2023 104

Figure 49: Neurodegenerative Disease Drugs Market, Global, Revenue for Siponimod ($bn), 2019-2023 105

Figure 50: Neurodegenerative Disease Drugs Market, Global, Revenue for Ozanimod ($bn), 2018-2023 106

Figure 51: Neurodegenerative Disease Drugs Market, Global, Revenue for Elenbecestat ($m), 2020-2023 107

Figure 52: Neurodegenerative Disease Drugs Market, Global, Revenue for BAN-2401 ($m), 2020-2023 108

Figure 53: Neurodegenerative Disease Drugs Market, Global, Revenue for IONIS-HTTRx ($m), 2020-2023 109

Figure 54: Neurodegenerative Disease Drugs Market, Global, Market Size ($bn), 2016-2023 111

Figure 55: Neurodegenerative Disease Therapeutics Market, Global, Annual Revenue Forecast for Key Products ($m), 2016-2023 112

Figure 56: Neurodegenerative Disease Drugs Market, Global, Key Products Market Share, 2016-2023 113

Figure 57: Neurodegenerative Disease Drugs Market, Global, Annual Revenue by Premium and Generic Products ($bn), 2016-2023 114

Figure 58: Neurodegenerative Disease Drugs Market, Global, Annual Revenue Forecast for Neuromodulators ($bn), 2016-2023 115

Figure 59: Neurodegenerative Disease Drugs Market, Global, Annual Revenue Forecast for Immunomodulators ($bn), 2016-2023 116

Figure 60: Neurodegenerative Disease Drugs Market, Global, Annual Revenue Forecast for Stress-related inhibitors ($bn), 2016-2023 117

Figure 61: Neurodegenerative Disease Drugs Market, Global, Annual Revenue Forecast for Protein Misfolding and Aggregation Inhibitors ($bn), 2016-2023 118

Figure 62: Neurodegenerative Disease Drugs Market, Global, Annual Revenue Forecast for Neuroprotectants ($bn), 2016-2023 118

Figure 63: Neurodegenerative Disease Drugs Market, Global, Company Analysis Matrix, 2016-2023 119

Figure 64: Neurodegenerative Disease Drugs Market, Global, Cluster Graph by Growth and Market Share, 2016-2023 120

Figure 65: Neurodegenerative Disease Drugs Market, Global, Forecast Revenue by Company, 2016-2023 122

Figure 66: Neurodegenerative Disease Drugs Market, Global, Forecast Market Share by Company (%), 2016-2023 126

Figure 67: Neurodegenerative Disease Drugs Market, Global, Companies by Compound Annual Growth Rate (%), 2016-2023 127

Figure 68: Neurodegenerative Disease Drugs Market, Global, Revenue by Product Type, 2016-2023 128

Figure 69: Neurodegenerative Disease Drugs Market, Global, Biogen Annual Revenue Forecast ($bn), 2016-2023 130

Figure 70: Neurodegenerative Disease Drugs Market, Global, Roche Annual Revenue Forecast ($bn), 2016-2023 131

Figure 71: Neurodegenerative Disease Drugs Market, Global, Novartis AG Annual Revenue Forecast ($bn), 2016-2023 133

Figure 72: Neurodegenerative Disease Drugs Market, Global, Teva Annual Revenue Forecast ($bn), 2016-2023 134

Figure 73: Neurodegenerative Disease Drugs Market, Global, Eisai Annual Revenue Forecast ($bn), 2016-2023 135

Figure 74: Neurodegenerative Disease Drugs Market, Global, Sanofi Annual Revenue Forecast ($bn), 2016-2023 136

Figure 75: Neurodegenerative Disease Drugs Market, Global, Companies by Type, 2018 137

Figure 76: Neurodegenerative Disease Drugs Market, Global, High-Activity and Late-Stage Developers by Level of Neurodegenerative Specialization, 2018 137

Figure 77: Neurodegenerative Disease Drugs Market, Global, Proportion of Total Company Revenue Attributed to Neurodegenerative Disorders, 2016-2023 139

Figure 78: Neurodegenerative Disease Drugs Market, Global, Licensing Deals by Region, Year and Value, 2006-2018 141

Figure 79: Neurodegenerative Disease Drugs Market, Global, Licensing Deal Volume and Value by Indication, 2006-2018 142

Figure 80: Neurodegenerative Disease Drugs Market, Global, Licensing Deals by Deal Value, Upfront Payment Value and Stage of Development, 2006-2018 143

Figure 81: Neurodegenerative Disease Drugs Market, Global, Number and Aggregate Deal Value of Licensing Deals by Molecule Type and Molecular Target, 2006-2018 144

Figure 82: Neurodegenerative Disease, Global, Licensing Deals with Disclosed Deal Values, 2006-2018 145

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