PharmaFocus: Biomarkers in Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is characterized by memory loss, cognitive impairment, and functional decline. The disease has emerged as a major global health priority especially because of its rapidly accelerating prevalence worldwide. In order to tackle the AD scourge , there is an urgent need for tools that will allow for the early and accurate diagnosis of AD, as well as the identification of populations at risk. A biomarker is an indicator of biological processes that can be objectively measured and evaluated, and well-validated biomarkers are required to satisfy these needs in AD. The search for biomarkers that are reflective of the disease process in AD has been and continues to be an active area of research, but has been hampered by a lack of clear understanding of the pathological mechanisms that underlie the disease. Nonetheless, several biomarkers have been developed to date that indicate the presence of AD pathology and AD-associated neuronal injury in vivo. Such biomarkers have the potential for clinical use in etiological determination, predictive prognosis, monitoring disease progression, and in clinical trials of potential disease-modifying therapies for AD .

Scope

Overview of Alzheimer's disease, including disease etiology and pathophysiology and how these inform biomarker targets.

Overview of AD biomarkers, the major classes of biomarkers an the different potential roles of biomarkers in clinical use and drug development.

Key topics covered include amyloid biomarkers, tau biomarkers, and other molecular biomarkers for AD in development with product profiles for marketed as well as promising pipeline assays. Also discussed are functional and structural imaging biomarkers for AD.

Analysis of the unmet needs, and opportunities within the AD biomarker arena, as well as drivers and barriers impacting the AD biomarker market . Insightful review of the regulatory considerations impacting biomarker development, market access and use in clinical drug development

Reasons to buy

Develop and design your in-licensing and out-licensing strategies through a review of pipeline products and technologies, and by identifying the companies with the most robust pipeline.

Develop business strategies by understanding the factors shaping and driving AD biomarker development and market adoption.

Drive revenues by understanding the key trends, innovative products and technologies, and companies likely to impact the AD biomarker market in future.

Organize your sales and marketing efforts by identifying the market categories and segments that present maximum opportunities for consolidations, investments and strategic partnerships.

Companies mentioned

Eli Lilly (Avid Radiopharmaceuticals)

GE Healthcare

Piramal Imaging

Innogenetics

Navidea

Amorfix Life Sciences

Araclon Biotech

Cognoptix

Proteome Sciences

Exonhit

Cytox

DiaGenic

Amarantus Biosciences

Sanofi

Eli Lilly (Avid Radiopharmaceuticals)

GE Healthcare

Piramal Imaging

Innogenetics

Navidea

Amorfix Life Sciences

Araclon Biotech

Cognoptix

Proteome Sciences

Exonhit

Cytox

DiaGenic

Amarantus Biosciences

Sanofi

Table of Contents

1 Table of Contents7

1.1 List of Tables12

1.2 List of Figures.15

2 Introduction .16

2.1 Catalyst 16

2.2 Related ...

1 Table of Contents7

1.1 List of Tables12

1.2 List of Figures.15

2 Introduction .16

2.1 Catalyst 16

2.2 Related Reports .16

2.3 Upcoming Related Reports.17

3 Alzheimer’s Disease Overview 18

3.1 Continuum of AD – Preclinical, MCI and AD Dementia.18

3.1.1 Preclinical AD.19

3.1.2 MCI.20

3.1.3 AD Dementia 21

3.2 Etiology and Pathophysiology.21

3.2.1 Etiology.21

3.2.2 Pathophysiology .25

4 AD Biomarkers – Overview36

4.1 What are Biomarkers?36

4.2 Criteria for Good Biomarkers 37

4.2.1 Sensitivity and Specificity of Biomarkers.38

4.3 Role of Biomarkers in AD Diagnosis.39

4.3.1 Challenges in Establishing AD Biomarkers as Diagnostic Tools .40

4.4 Role of Biomarkers in Drug Development.40

4.5 Biomarker Development and Validation43

4.6 Classes of AD Biomarkers by Pathophysiological Mechanism44

4.6.1 Temporal Evolution of Biomarkers 46

5 Unmet Needs Assessment 49

5.1 Overview49

5.2 Unmet Needs Analysis .50

5.2.1 Patient and Physician Knowledge/Awareness of AD Diagnosis 50

5.2.2 Generalized Biomarker Unmet Needs.53

5.2.3 Unmet Need for Diverse Types of Biomarkers 56

6 AD Biomarkers Market Drivers and Barriers 61

6.1 Driver: Increasing prevalence of AD corresponding to a growth in the aging population will rapidly expand the biomarker market size 61

6.2 Driver: Anticipated future cost of biologic AD treatments will drive the use of biomarker diagnostics .62

6.3 Driver: Favorable regulatory standards for the application of biomarkers in drug discovery63

6.4 Barrier: Present lack of disease-modifying treatments hinders the use of diagnostic tests63

6.5 Barrier: Rigorous, expensive, and time-consuming nature of biomarker development and validation64

6.6 Barrier: Reimbursement restrictions for diagnostic testing 65

6.7 Barrier: Healthcare system and physician practice barriers limit patient referral to specialists and the use of biomarker tests65

7 Amyloid Beta Biomarkers 68

7.1 Overview of Biomarker Class .68

7.2 Drug Therapies Targeting Amyloid Beta.69

7.2.1 Overview 69

7.2.2 Representative Pipeline Drugs69

7.3 Amyloid Biomarker Assays.70

7.3.1 Amyloid PET-Imaging.71

7.3.2 CSF-Based Amyloid Assays.82

7.3.3 Other Amyloid Assays in Development .89

8 Tau-Related Biomarkers92

8.1 Overview of Biomarker Class .92

8.2 Drug Therapies Targeting Tau92

8.2.1 Overview 92

8.2.2 Representative Products.92

8.3 Tau Biomarker Assays .94

8.3.1 CSF-Based Tau Assays95

8.3.2 Promising Pipeline Products - Tau PET Imaging Ligands .100

9 Beyond Amyloid and Tau: Other Molecular AD Biomarkers in Development .102

9.1 Overview102

9.1.1 Neuronal and Synaptic Degeneration .102

9.1.2 Inflammation and Oxidative Stress .103

9.2 Promising Pipeline Products.106

9.2.1 Alzheimer’s CSF 16-Plex Assay (Proteome Sciences) .106

9.3 Blood-Based Biomarkers107

9.3.1 Overview 107

9.3.2 Promising Pipeline Products .108

10 Functional Brain Imaging Biomarkers 116

10.1 Overview of Biomarker Class .116

10.2 Functional Brain Imaging Assays116

10.2.1 FDG-PET117

10.2.2 FMRI Biomarkers of AD120

11 Structural Brain Imaging Biomarkers .125

11.1 Overview of Biomarker Class .125

11.2 Structural Brain Imaging Assays.126

11.2.1 MRI Hippocampal Volumetry 127

11.2.2 Other Structural Imaging Biomarkers in Pipeline Development.130

12 Regulatory Considerations Impacting AD Biomarkers .132

12.1 Clinical Trial Design in AD Drug Development132

12.1.1 Regulatory Agency Recommendations.135

12.1.2 Key Opinion Leaders on the Use of Biomarkers in Drug Clinical Trials .136

12.1.3 Mapping the Use of Biomarkers in Key AD Drug Clinical Trials.140

12.1.4 AD Drug Approval, Population or Stage-Specific Indications, and Off-Label Use142

12.2 Reimbursement of Biomarker-Based Testing .143

12.2.1 Concerns Limiting Reimbursement of Biomarker Testing for AD.143

12.2.2 Region-Specific Differences in Biomarker Test Reimbursement Policies and Pathways in the US and EU147

13 Outlook and Opportunities for AD Biomarkers .150

13.1 Overview150

13.2 Key Players, Partnerships, and Associations152

13.2.1 National and International AD Biomarkers Consortia 152

13.2.2 Private Industry Biomarker Partnerships.154

13.3 Opportunity Analysis.155

13.3.1 Opportunity: Biomarkers to Determine Appropriate Use of Treatment.156

13.3.2 Opportunity: Biomarkers as Populations Screens for Alzheimer’s Disease .157

13.3.3 Opportunity: Continued Development of Varied Biomarkers of Pathophysiology 157

14 Appendix .158

14.1 Bibliography158

14.2 Abbreviations173

14.3 Research Methodology.177

14.4 Physicians and Specialists Included in this Study.178

14.5 About the Authors.180

14.5.1 Authors.180

14.5.2 Global Head of Healthcare181

14.6 About GlobalData .182

14.7 Disclaimer 182

List of Tables

Table 1: Biomarkers in the AD Market: Key Events and Pipeline Assessment6

Table 2: Biomarker Unmet Needs – Current Level of Attainment34

Table 3: AD Biomarkers ...

Table 1: Biomarkers in the AD Market: Key Events and Pipeline Assessment6

Table 2: Biomarker Unmet Needs – Current Level of Attainment34

Table 3: AD Biomarkers – Market Drivers and Barriers, 201347

Table 4: AD – Amyloid-Targeting Phase III Pipeline, 201356

Table 5: AD – Amyloid-Targeting Phase II Pipeline, 201356

Table 6: Aß Biomarkers by Stage of Development, 201357

Table 7: SWOT Analysis of Amyloid PET Imaging in AD, 201365

Table 8: Product Profile of Amyvid, 201366

Table 9: SWOT Analysis of Amyvid, 201367

Table 10: Product Profile of [18F] Flutemetamol, 201368

Table 11: SWOT Analysis of [18F] Flutemetamol, 201368

Table 12: Product Profile of [18F] Florbetaben, 201369

Table 13: SWOT Analysis of [18F] Florbetaben, 201369

Table 14: Product Profile of NAV4694, 201370

Table 15: SWOT Analysis of NAV4694, 201370

Table 16: Characteristics of ELISA and xMAP Immunoassay Platforms for the Measurement of CSF Biomarkers in AD72

Table 17: SWOT Analysis of CSF-Based Amyloid Tests, 201373

Table 18: Product Profile of INNOTEST ß-Amyloid1-42, 201374

Table 19: SWOT Analysis of INNOTEST ß-Amyloid1-42, 201375

Table 20: Product Profile of INNO-BIA AlzBio3, 201376

Table 21: SWOT Analysis of INNO-BIA AlzBio3, 201376

Table 22: Product Profile of EP-AD Diagnostic CSF Test, 201377

Table 23: SWOT Analysis of EP-AD Diagnostic CSF Test, 201377

Table 24: Product Profile of ABtest, 201378

Table 25: SWOT Analysis of ABtest, 201378

Table 26: Product Profile of SAPPHIRE II Eye Test, 201379

Table 27: SWOT Analysis of SAPPHIRE II Eye Test, 201379

Table 28: AD, Tau-Targeting Therapies, Phase III Pipeline, 201380

Table 29: AD, Tau-Targeting Therapies, Phase II Pipeline, 201380

Table 30: AD, Tau-Targeting Therapies, Phase I Pipeline, 201380

Table 31: Tau Biomarkers by Stage of Development, 201381

Table 32: SWOT Analysis of CSF-based Tau Assays, 201384

Table 33: Product Profile of INNOTEST hTau Ag, 201385

Table 34: SWOT Analysis of INNOTEST hTau Ag, 201385

Table 35: Product Profile of INNOTEST PHOSPHO-TAU(181P), 201386

Table 36: SWOT Analysis of INNOTEST PHOSPHO-TAU(181P), 201387

Table 37: SWOT Analysis of Tau PET Imaging in AD, 201389

Table 38: Potential Biomarkers of AD, 201393

Table 39: Product Profile of Alzheimer’s CSF 16-Plex Assay, 201394

Table 40: SWOT Analysis of Alzheimer’s CSF 16-Plex Assay, 201395

Table 41: Product Profile of AclarusDx, 201398

Table 42: SWOT Analysis of AclarusDx, 201398

Table 43: Product Profile of ADpredict Screening Test, 201399

Table 44: SWOT Analysis of ADpredict Screening Test, 201399

Table 45: Product Profile of Alzheimer’s Plasma 9-Plex Assay, 2013100

Table 46: SWOT Analysis of Alzheimer’s Plasma 9-Plex Assay, 2013101

Table 47: Product Profile of ADtect, 2013102

Table 48: SWOT Analysis of ADtect, 2013102

Table 49: Product Profile of MCItect, 2013103

Table 50: SWOT Analysis of MCItect, 2013103

Table 51: Product Profile of LymPro Test, 2013104

Table 52: SWOT Analysis of LymPro Test, 2013104

Table 53: Functional Brain Imaging Biomarkers by Stage of Development, 2013105

Table 54: SWOT Analysis of FDG- PET Imaging in AD, 2013109

Table 55: SWOT Analysis of FMRI Biomarkers in AD, 2013112

Table 56: Structural Brain Imaging Biomarkers by Stage of Development, 2013114

Table 57: SWOT Analysis of MRI Hippocampal Volumetry, 2013118

Table 58: Features of an Early-AD Therapy Clinical Trial, 2013121

Table 59: Summary of the FDA Guidance for Drug Development in Early AD, 2013122

Table 60: Biomarker Use in Ongoing AD Drug Clinical Trials, 2013128

List of Figures

Figure 1: The Continuum of Alzheimer’s Disease10

Figure 2: Atrophy of the Brain in Alzheimer’s Disease15

Figure 3: Key Pathological Features in Alzheimer ...

Figure 1: The Continuum of Alzheimer’s Disease10

Figure 2: Atrophy of the Brain in Alzheimer’s Disease15

Figure 3: Key Pathological Features in Alzheimer’s Disease16

Figure 4: Non-Amyloidogenic Metabolism of APP17

Figure 5: Amyloidogenic Metabolism of APP18

Figure 6: Neurofibrillary Tangles20

Figure 7: Oxidative Damage due to Free Radicals23

Figure 8: Biomarkers in Drug Discovery28

Figure 9: AD Biomarker Tests by Pathophysiology31

Figure 10: Dynamic Changes in Alzheimer’s Disease Biomarkers32

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