Large and Innovative Pipeline

The active Alzheimer’s Disease (AD) pipeline is populated with 583 products, with a highly diverse range of molecular targets. GBI Research analysis revealed a high degree of innovation in this indication, with 46% of the pipeline being first-in-class products, acting on over 40 first-in-class molecular targets. In addition, the pipeline is characterized by the strong presence of therapies that target multiple components implicated in the amyloid cascade, several molecular targets of which are known to trigger familial AD. Given that the currently approved therapies for AD are limited to acetylcholinesterase inhibitors and glutamate receptor antagonists, the pipeline offers a broad range of treatment options that may possess disease-modifying properties. However, evaluation of the Preclinical and clinical evidence for their therapeutic potential reveals that the novelty of the molecular target is not sufficient to effectively reduce the rate of AD progression in human patients.

Disease-Modifying Therapies Show Promise in Early-Stage Development

Programs undergoing Preclinical development exhibit diverse disease-modifying mechanisms of action, and many represent strong alternatives to targets with a direct role in the amyloid and tau processes due to their roles in promoting neuronal survival and plasticity, a process critical to memory and cognition. Brain-Derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF) are considered promising targets in AD, primarily due to their potency in exhibiting significant neuroprotective effects in Preclinical studies. Members of the caspase-mediated apoptotic cascade also show therapeutic potential, as early investigations have revealed an ability to modulate molecular mechanisms underlying synaptic plasticity in animal models, which translates into amelioration of behavioral deficits. Thus, growing insights into disease-causing processes in AD are being translated into a growing population of innovative therapeutic targets, as reflected in the highly innovative pipeline.

The merits of novel molecular targets depend largely on the body of Preclinical evidence underpinning their relevance to AD pathology. Many endpoints in Preclinical investigations focus on amelioration of amyloid burden and tau pathology, as well as cognitive performance in animal model systems. Based on these assessment criteria, it appears that programs targeting the amyloid cascade, tau pathology, and the promotion of neuronal survival and plasticity all demonstrate promising efficacy profiles. Other first-in-class targets that are less directly aligned to these three processes may not be able to confer disease-modifying properties and therefore lack clinical and commercial potential.

Active Deals Landscape with Numerous Investment Opportunities

The AD deals landscape has been highly active over the past eight years, with 83 licensing agreements and 103 co-development deals. Overall, non-first-in-class programs tend to have lower valuations than first-in-class programs across all stages of drug development, which highlights their commercial attractiveness, even in early-stage development. Although first-in-class programs are associated with greater risk, they have more potential to revolutionize or improve therapeutic options, meaning that identifying promising first-in-class compounds early in development offers the greatest potential commercial benefit to pharmaceutical companies.

With 153 first-in-class products that are currently in development having not yet been involved in a licensing or co-development deal, there are numerous opportunities for in-licensing or co-development in this indication.

Scope

The report covers and includes –

• A brief introduction to AD, including symptoms, pathophysiology, and overview of pharmacotherapy and treatment algorithms
• The changing molecular target landscape between market and pipeline and particular focal points of innovation in the pipeline
• A comprehensive review of the pipeline for first-in-class therapies, analyzed on the basis of stage of development, molecule type and molecular target
• Identification and assessment of first-in-class molecular targets with a particular focus on early-stage programs for which clinical utility has yet to be evaluated, as well as literature reviews of novel molecular targets
• Assessment of the licensing and co-development deal landscape for AD therapies and benchmarking of deals involving first-in-class versus non-first-in-class-products

Reasons to buy

The report will assist business development and enable marketing executives to strategize their product launches, by allowing them to –

• Understand the focal shifts in molecular targets in the AD pipeline
• Understand the distribution of pipeline programs by phase of development, molecule type and molecular target
• Access a scientific and clinical analysis of first-in-class developmental programs for AD, benchmarked against non-first-in-class targets
• Access a list of the first-in-class therapies potentially open to deal-making opportunities

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 Large and Innovative Pipeline 4
2.2 Therapies Promoting Neuronal Survival and Plasticity Show Promise in Early-Stage Development 4
2.3 Extensive Investment in Amyloid-Beta-Targeting Programs despite Historically High Attrition Rates in Clinical Evaluation 4
2.4 Active Deals Landscape with Numerous Investment Opportunities 5

3 The Case for Innovation 6
3.1 Growing Opportunities for Biologic Products 7
3.2 Diversification of Molecular Targets 7
3.3 Innovative First-in-Class Product Developments Remain Attractive 7
3.4 Regulatory and Reimbursement Policy Shifts Favor First-in-Class Product Innovation 9
3.5 Sustained Innovation 9
3.6 GBI Research Report Guidance 10

4 Clinical and Commercial Landscape 11
4.1 Disease Overview 11
4.2 Disease Symptoms 11
4.3 Disease Etiology 11
4.3.1 Genetics 11
4.3.2 Predisposing Medical Conditions and Risk Factors 12
4.4 Pathophysiology 13
4.4.1 Amyloidosis 13
4.4.2 Tau Hyperphosphorylation 14
4.4.3 Receptor for Advanced Glycation Endproducts Signaling 14
4.4.4 Oxidative Stress 14
4.4.5 Neuroinflammation 14
4.5 Comorbidities/Complications 15
4.6 Diagnosis 15
4.6.1 Tools for Screening Cognitive Function 15
4.6.2 Imaging Tests 16
4.6.3 Cerebral Spinal Fluid Testing 17
4.6.4 Blood Tests 17
4.7 Prognosis 18
4.8 Treatment Options 18
4.8.1 Treatment Algorithm 18
4.8.2 Non-Pharmacological Treatments 19
4.9 Current Unmet Needs 19

5 Assessment of Product Pipeline Innovation 21
5.1 Alzheimer's Disease Pipeline by Molecule Type, Phase and Therapeutic Target 21
5.2 Mechanisms of Action within the Alzheimer's Disease Pipeline 23
5.3 Comparative Distribution of Programs with First-in-Class and Established Molecular Targets 24
5.4 Pipeline Programs Targeting Established Molecular Targets 26
5.5 First-in-Class Pipeline Programs with Novel Molecular Targets 31

6 Signaling Network, Genetics and Innovation Alignment 35
6.1 The Complexity of Genetic Risk Factors in AD 35
6.2 Signaling Pathways, Disease-Causing Mutations and First-in-Class Molecular Target Integration 36
6.3 First-in-Class Target Matrix Assessment 38

7 First-in-Class Target Evaluation 39
7.1 Pipeline Programs Targeting Calpain 39
7.2 Pipeline Programs Targeting ? -Secretase 41
7.3 Pipeline Programs Targeting Brain-Derived Neurotrophic Factor 44
7.4 Pipeline Programs Targeting Apolipoprotein E 46
7.5 Pipeline Programs Targeting ?-Site Amyloid Precursor Protein Cleaving Enzyme 1 48
7.6 Pipeline Programs Targeting Amyloid Precursor Protein and Amyloid-Beta 50
7.7 Pipeline Programs Targeting Casein Kinase 56
7.8 Pipeline Programs Targeting Nerve Growth Factor 57
7.9 Pipeline Programs Targeting Kynurenine 3-Monooxygenase 59
7.10 Pipeline Programs Targeting Leucine -Rich Repeat Kinase -2 60
7.11 Pipeline Programs Targeting Insulin- Regulated Aminopeptidase 61
7.12 Pipeline Programs Targeting Tau 61
7.13 Pipeline Programs Targeting Cathepsin B 65
7.14 Pipeline Programs Targeting Receptor for Advanced Glycation End-products 67
7.15 Pipeline Programs Targeting Protein Phosphatase 2a 69
7.16 Pipeline Programs Targeting Caspase 69
7.17 Pipeline Programs Targeting Cyclin Dependent Kinase 5 71
7.18 Conclusion 73

8 Deals and Strategic Consolidations 75
8.1 Trends in Licensing Deals Across the Entire Pharmaceutical Industry 75
8.2 Deals and Strategic Consolidations in Alzheimer's Disease 76
8.2.1 Licensing Deals 76
8.2.2 Molecule type 78
8.2.3 Mechanism of Action 79
8.3 Co-development Deals 82
8.3.1 Molecule Type and Mechanism of Action 83

9 First-In-Class Molecules not Involved in Licensing or Co-development Deals 86

10 Appendix 89
10.1 References 90
10.2 Contact Us 101
10.3 Disclaimer 101

List of Tables

Table 1: Mini-Mental State Exam, 2005 15
Table 2: Alzheimer's Disease Assessment Scale, Cognitive Subscale, 1984 16

List of Figures

Figure 1: Innovation Trends in Product Approvals, 1987-2012 6
Figure 2: Sales Performance of First-in-Class and Non-First-in-Class Product post Marketing Approval, 2006-2013 8
Figure 3: Sales Performance of Central Nervous System First-in-Class and Non-First-in-Class Products post Marketing Approval, 2006-2013 8
Figure 4: Alzheimer's Disease, Global, Developmental Pipeline 22
Figure 5: Alzheimer's Disease, Global, Established and First-in-Class Pipeline 25
Figure 6: Alzheimer's Disease, Global, Established Developmental Pipeline Part 1, 2014 27
Figure 7: Alzheimer's Disease, Global, Established Developmental Pipeline Part 2, 2014 28
Figure 8: Alzheimer's Disease, Global, Established Developmental Pipeline Part 3, 2014 29
Figure 9: Alzheimer's Disease, Global, Established Developmental Pipeline Part 4, 2014 30
Figure 10: Alzheimer's Disease, Global, First-in-Class Developmental Pipeline Part 1, 2014 32
Figure 11: Alzheimer's Disease, Global, First-in-Class Developmental Pipeline Part 2, 2014 33
Figure 12: Alzheimer's Disease, Global, First-in-Class Developmental Pipeline Part 3, 2014 34
Figure 13:Signaling Networks of Functional Families in Alzheimer's Disease, 2014 37
Figure 14: First-in-Class Molecular Target Analysis Matrix 38
Figure 15: Data and Evidence for Calpain as a Therapeutic Target 40
Figure 16: Pipeline Programs Targeting Calpain 40
Figure 17: Data and Evidence for ? Secretase as a Therapeutic Target 42
Figure 18: Pipeline Programs Targeting ? Secretase 43
Figure 19: Data and Evidence for Brain-Derived Neurotrophic Factor as a Therapeutic Target 45
Figure 20: Pipeline Programs Targeting Brain-Derived Neurotrophic Factor 46
Figure 21: Data and Evidence for Apolipoprotein E as a Therapeutic Target 47
Figure 22: Pipeline Programs Targeting Apolipoprotein E 48
Figure 23: Data and Evidence for ?-secretase as a Therapeutic Target 49
Figure 24: Pipeline Programs Targeting ? Secretase 50
Figure 25: Data and Evidence for Amyloid Precursor Protein as a Therapeutic Target 53
Figure 26: Pipeline Programs Targeting Amyloid-Beta and Amyloid Precursor protein 55
Figure 27: Pipeline Programs Targeting Casein Kinases 56
Figure 28: Pipeline Programs Targeting Casein Kinases 57
Figure 29: Pipeline Programs Targeting Nerve Growth Factor 58
Figure 30: Pipeline Programs Targeting Nerve Growth Factor 59
Figure 31: Pipeline Programs Targeting Kynurenine 3-Monooxygenase 59
Figure 32: Pipeline Programs Targeting Kynurenine 3-Monooxygenase, 60
Figure 33: Pipeline Programs Targeting Leucine-Rich Repeat Kinase 2 61
Figure 34: Pipeline Programs Targeting Insulin-Regulated Aminopeptidase 61
Figure 35: Data and Evidence for Tau as a Therapeutic Target 63
Figure 36: Pipeline Programs Targeting Tau 64
Figure 37: Data and Evidence for Cathepsin B as a Therapeutic Target, xxxx 66
Figure 38: Pipeline Programs Targeting Cathepsin B 67
Figure 39: Data and Evidence for Receptor for Advanced Glycation End-products as a Therapeutic Target 68
Figure 40: Pipeline Programs Targeting Receptor for Advanced Glycation End-products 68
Figure 41: Data and Evidence for Receptor for Protein Phosphatase 2A as a Therapeutic Target 69
Figure 42: Pipeline Programs Targeting Protein Phosphatase 2A 69
Figure 43: Data and Evidence for Receptor for Caspase as a Therapeutic Target 70
Figure 44: Pipeline Programs Targeting Caspase 71
Figure 45: Data and Evidence for Cyclin-Dependent Kinase 5 as a Therapeutic Target 72
Figure 46: Pipeline Programs Targeting Cyclin-dependent kinase 5 73
Figure 47: Stage of Development of First-in-Class and Non-First-in-Class Programs at Deal Completion, 2006-2014 75
Figure 48: First-in-class and Non-First-in-Class Programs, Deal Valuations by Stage of Development, 2006-2014 76
Figure 49: Licensing Deal Trends, 2006-2014 77
Figure 50: Network of Licensing Deals, 2006-2014 78
Figure 51: Licensing Deals by Molecule Type, 2006-2014 78
Figure 52: Licensing Deals by Mechanism of Action, 2006-2014 79
Figure 53: Licensing Deals (Part 1), 2006-2014 80
Figure 54: Licensing Deals (Part 2), 2006-2014 81
Figure 55: Co-development Deal Trends, 2006-2014 82
Figure 56: Network of Co-development Deals, 2006-2014 83
Figure 57: Co-development Deals by Molecule Type, 2006-2014 83
Figure 58: Co-development Deals by Mechanism of Action, 2006-2014 84
Figure 59: Co-development Deals, Global, 2006-2014 85
Figure 60: First-in-Class Programs not Previously Involved in Licensing or Co-development Deals (Part 1) 87
Figure 61: First-in-Class Programs not Previously Involved in Licensing or Co-development Deals (Part 2) 88