Frontier Pharma: Schizophrenia - Diverse First-in-Class Pipeline Shows Promise for Treatment of Negative and Cognitive Symptoms

Abstract

• Frontier Pharma: Schizophrenia - Diverse First-in-Class Pipeline Shows Promise for Treatment of Negative and Cognitive Symptoms

Summary

• Schizophrenia is a severe chronic mental disorder affecting a person's mental, emotional and physical wellbeing. Patients appear out of touch with reality, preventing them from functioning at school, at work, in relationships and in society. Schizophrenia affects approximately 1% of the global population and is associated with a sizeable economic burden, estimated at between 0.02% and 1.65% of the global gross domestic product.
• In the 1960s, the antipsychotic drug Chlorpromazine entered the market for the treatment of schizophrenia, spurring the development of first-generation or 'typical' antipsychotics. Despite being effective, the exact mechanisms of action of antipsychotics are largely unknown. Both Chlorpomazine and Clozapine are dopamine-2 (D2) receptor antagonists, which are effective in treating the positive symptoms of schizophrenia, including psychosis, but also come with a plethora of side effects such as abnormal movements and hyperprolactinemia.
• The schizophrenia pipeline is relatively small, given the large patient population and well-defined unmet needs, with a total of 160 products in active development. This is indicative of a low level of R&D funding and investment, most likely due to a poor understanding of the underlying mechanisms of the disease, which acts as a strong barrier to the development of effective pharmaceutical products.
• Reflecting the situation in the market, the overwhelming majority of these products are small molecules, with a small but notable portion of the pipeline consisting of other molecule types such as cell therapies, peptides and vaccines - none of which are currently present in the schizophrenia market.
• From the research finding included in the report "Frontier Pharma: Schizophrenia - Diverse First-in-Class Pipeline Shows Promise for Treatment of Negative and Cognitive Symptoms"; First-in-class products have the greatest potential in terms of development and commercial prospects. In line with the overall pipeline, first-in-class innovation is dominated by products acting on neuromodulator targets with the strongest representation in the Discovery and Preclinical stages of development.

Scope

• Innovation within schizophrenia is relatively small. What are the unmet needs across this therapy area?
• There are 160 products in the pipeline for schizophrenia. What proportion of these products are first-in-class? How does first-in-class innovation vary by indication, development stage and molecular target class?
• Although the first-in-class pipeline is small in comparison with other CNS-related disorders, it is relatively diverse, with numerous molecular targets. Which first-in-class targets have been identified as most promising for schizophrenia?
• A total of 77 licensing deals and 44 development deals related to schizophrenia have been completed since 2006. Does schizophrenia attract high-value deals? Which first-in-class products have no prior deal involvement?

Reasons to buy

• Understand the current clinical and commercial landscape. This includes a comprehensive study of symptoms, epidemiology, etiology, pathophysiology, co-morbidities and complications, diagnosis and treatment options.
• Visualize the composition of the schizophrenia market in terms of dominant molecule types and molecular targets, highlighting what the current unmet needs are and how they can be addressed. This knowledge allows a competitive understanding of gaps in the market.
• Analyze the schizophrenia pipeline and stratify by stage of development, molecule type and molecular target.
• Assess the therapeutic potential of first-in-class targets. Using a proprietary matrix, first-in-class products have been assessed and ranked according to clinical potential. Promising first-in-class targets have been reviewed in greater detail.
• Recognize commercial opportunities in the schizophrenia deals landscape by analyzing trends in licensing and co-development deals, and identifying schizophrenia therapies that have not yet been involved in deals, and that may provide potential investment opportunities.

1 Table of Contents

1 Table of Contents 2

• 1.1 List of Tables 3
• 1.2 List of Figures 3

2 Executive Summary 5

• 2.1 A Complex and Poorly Understood Disorder with Numerous Unmet Needs 5
• 2.2 Development and Influence of Antipsychotics 5
• 2.3 Small Pipeline for Schizophrenia with Few Signs of Innovation 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 Innovation 8
• 3.5 Sustained Innovation in Schizophrenia 8

4 Clinical and Commercial Landscape 10

• 4.1 Overview of Schizophrenia 10
• 4.2 Symptoms 10
• 4.3 Diagnosis 11
• 4.4 Disease Etiology 12
• 4.5 Disease Pathophysiology 12
• 4.5.1 Susceptibility Genes 13
• 4.5.2 Neurotransmission Alterations 14
• 4.5.3 Phosphatidylinositol Signaling 16
• 4.6 Epidemiology 16
• 4.7 Co-morbidities and Complications 16
• 4.7.1 Anxiety 16
• 4.7.2 Depression 16
• 4.7.3 Post-Traumatic Stress Disorder 17
• 4.7.4 Obsessive Compulsive Disorder 17
• 4.7.5 Panic Disorder 17
• 4.7.6 Cognitive Impairment 17
• 4.8 Prognosis 17
• 4.9 Treatment 17
• 4.10 Overview of Marketed Products 18
• 4.10.1 Molecule Type and Target Analysis 18
• 4.11 Current Unmet Needs 19

5 Assessment of Pipeline Product Innovation 20

• 5.1 Overview 20
• 5.2 Pipeline by Stage of Development and Molecule Type 20
• 5.3 Pipeline by Molecular Target 21
• 5.4 Comparative Distribution of Programs between Schizophrenia Disease Market and Pipeline by Therapeutic Target Family 22
• 5.5 Comparative Distribution of First-in-Class and Non-First-in-Class Pipeline Programs by Molecular Target Class 23
• 5.6 Percentage Distribution of First-in-Class and Non-First-in-Class Pipeline Programs 24
• 5.7 Ratio of First-In-Class Programs to First-in-Class Molecular Targets within the Pipeline 25
• 5.8 List of All First-in-Class Pipeline Programs 25

6 Schizophrenia Pathophysiology and Innovation Alignment 30

• 6.1 Complexity of Signaling Networks in Schizophrenia 30
• 6.2 Signaling Pathways, Disease-Causing Mutations and First-in-Class Molecular Target Integration 31
• 6.3 First-in-Class Molecular Target Matrix Assessment 31

7 First-in-Class Molecular Target Evaluation 33

• 7.1 Pipeline Programs Targeting Metabotropic Glutamate Receptor 5 (GRM5) 33
• 7.2 Pipeline Programs Targeting Metabotropic Glutamate Receptor 3 (GRM3) 35
• 7.3 Pipeline Programs Targeting Metabotropic Glutamate Receptor 1 (GRM1) 36
• 7.4 Pipeline Programs Targeting 5-Hydroxytryptamine Receptor 5a (HTR5A) 38
• 7.5 Pipeline Programs Targeting Metabotropic Glutamate Receptor 2 (GRM2) 39
• 7.6 Pipeline Programs Targeting D-Amino Acid Oxidase (DAO) 41
• 7.7 Pipeline Programs Targeting Potassium Voltage-Gated Channel Subfamily C, Member 1 (KCNC1) 43
• 7.8 Pipeline Programs Targeting Microtubule Associated Protein Tau (MAPT) 44

8 Deals and Strategic Consolidations 47

• 8.1 Industry-Wide First-in-Class Deals 47
• 8.2 Licensing Deals 48
• 8.2.1 Deals by Region, Value and Year 48
• 8.2.2 Deals by Stage of Development and Value 49
• 8.2.3 Deals by Molecule Type and Molecular Target 50
• 8.2.4 List of Deals with Disclosed Deal Values 51
• 8.3 Co-development Deals 52
• 8.3.1 Deals by Region, Value and Year 52
• 8.3.2 Deals by Stage of Development and Value 53
• 8.3.3 Deals by Molecule Type and Molecular Target 54
• 8.3.4 List of Deals with Disclosed Deal Values 55
• 8.4 First-in-Class Programs with and without Prior Involvement in Licensing or Co-development Deals 55

9 Appendix 57

• 9.1 References 57
• 9.2 Abbreviations 65
• 9.3 Methodology 66
• 9.3.1 Data Integrity 66
• 9.3.2 Evidence Based Analysis and Insight 67
• 9.4 Secondary Research 67
• 9.4.1 Market Analysis 67
• 9.4.2 Pipeline Analysis 67
• 9.4.3 Licensing and Co-development Deals 68
• 9.5 Contact Us 68
• 9.6 Disclaimer 68

1.1 List of Tables

• Table 1: Schizophrenia, US, American Psychiatry Association Definition of Symptoms of Schizophrenia, 2018 11
• Table 2: Schizophrenia, US, American Psychiatry Association DSM-5 Schizophrenia Criteria, 2018 11
• Table 3: Schizophrenia, Global, World Health Organization ICD-10 Schizophrenia Criteria, 2018 12
• Table 4: Schizophrenia, Global, Key Features of Metabotropic Glutamate Receptor 5 (GRM5), 2018 34
• Table 5: Schizophrenia, Global, Evidence for Metabotropic Glutamate Receptor 5 (GRM5) as a Therapeutic Target, 2018 34
• Table 6: Pipeline Programs Targeting Metabotropic Glutamate Receptor 5 (GRM5), 2018 34
• Table 7: Schizophrenia, Global, Key Features of Metabotropic Glutamate Receptor 3 (GRM3), 2018 36
• Table 8: Schizophrenia, Global, Evidence for Metabotropic Glutamate Receptor 3 (GRM3) as a Therapeutic Target, 2018 36
• Table 9: Schizophrenia, Global, Pipeline Programs Targeting Metabotropic Glutamate Receptor 3 (GRM3), 2018 36
• Table 10: Schizophrenia, Global, Key Features of Metabotropic Glutamate Receptor 1 (GRM1), 2018 37
• Table 11: Schizophrenia, Evidence for Metabotropic Glutamate Receptor 1 (GRM1) as a Therapeutic Target, 2018 38
• Table 12: Schizophrenia, Pipeline Programs Targeting Metabotropic Glutamate Receptor 1 (GRM1), 2018 38
• Table 13: Schizophrenia, Global, Key Features of D-Amino Acid Oxidase (DAO), 2018 39
• Table 14: Schizophrenia, Global, Evidence for 5-Hydroxytryptamine Receptor 5A (HTR5A) as a Therapeutic Target, 2018 39
• Table 15: Schizophrenia, Global, Pipeline Programs Targeting 5-Hydroxytryptamine Receptor (HTR5A), 2018 39
• Table 16: Schizophrenia, Global, Key Features of Metabotropic Glutamate Receptor 2 (GRM2), 2018 40
• Table 17: Schizophrenia, Global, Evidence for Metabotropic Glutamate Receptor 2 (GRM2) as a Therapeutic Target, 2018 40
• Table 18: Pipeline Programs Targeting Metabotropic Glutamate Receptor 2 (GRM2), 2018 41
• Table 19: Schizophrenia, Global, Key Features of Potassium Voltage-Gated Channel Subfamily C, Member 1 (KCNC1), 2018 42
• Table 20: Schizophrenia, Global, Evidence for D-Amino Acid Oxidase (DAO) as a Therapeutic Target, 2018 42
• Table 21: Schizophrenia, Global, Pipeline Programs Targeting D-Amino Acid Oxidase (DAO), 2018 43
• Table 22: Schizophrenia, Global, Key Features of Potassium Voltage-Gated Channel Subfamily C, Member 1 (KCNC1), 2018 44
• Table 23: Schizophrenia, Global, Evidence for Potassium Voltage-Gated Channel Subfamily C, Member 1 (KCNC1) as a Therapeutic Target, 2018 44
• Table 24: Schizophrenia, Global, Pipeline Programs Targeting Potassium Voltage-Gated Channel Subfamily C, Member 1 (KCNC1), 2018 44
• Table 25: Schizophrenia, Global, Key Features of Tau Protein (MAPT), 2018 45
• Table 26: Schizophrenia, Global, Evidence for Tau Protein (MAPT) as a Therapeutic Target, 2018 45
• Table 27: Pipeline Programs Targeting Tau Protein (MAPT), 2018 46

1.2 List of Figures

• Figure 1: Schizophrenia, US, Innovation Trends in Product Approvals, 1987-2014 6
• Figure 2: Schizophrenia, US, Sales Performance of First-in-Class and Non-First-in-Class Products Post Marketing Approval, 2006-2013 8
• Figure 3: Schizophrenia, Global Market by Molecular Target and Molecule Type, 2018 19
• Figure 4: Schizophrenia, Global, Overall Pharmaceutical Industry Pipeline by Therapy Area, 2018 20
• Figure 5: Schizophrenia, Global, Pipeline by Stage of Development and Molecule Type, 2018 21
• Figure 6: Schizophrenia, Global, Pipeline by Molecular Target and Stage of Development, 2018 22
• Figure 7: Schizophrenia, Global, Distribution of Pipeline and Marketed Products by Molecular Target Class, 2018 23
• Figure 8: Schizophrenia, Global, Percentage Distribution of First-in-Class and Non-First-in-Class Products by Stage of Development and Molecular Target Class, 2018 25
• Figure 9: Schizophrenia, Global, Ratio of First-in-Class Products to First-in-Class Targets by Stage of Development and Molecular Target Class, 2018 25
• Figure 10: Schizophrenia, Global, All Pipeline Programs, 2018 (part 1) 26
• Figure 11: Schizophrenia, Global, All Pipeline Programs, 2018 (part 2) 27
• Figure 12: Schizophrenia, Global, All Pipeline Programs, 2018 (part 3) 28
• Figure 13: Schizophrenia, Global, All Pipeline Programs, 2018 (part 4) 29
• Figure 14: Schizophrenia, Global, All Pipeline Programs, 2018 (part 5) 29
• Figure 15: Schizophrenia, Global, First-in-Class Molecular Target Matrix Assessment, 2018 32
• Figure 16: Schizophrenia, Global, Industry-Wide Licensing Deals by Stage of Development, 2006-2014 47
• Figure 17: Schizophrenia, Global, Industry-Wide Deals by Stage of Development, 2006-2014 48
• Figure 18: Schizophrenia, Global Licensing Deals by Region, Value and Year 2006-2018 49
• Figure 19: Schizophrenia, Global, Licensing Deals by Deal Value, Upfront Payment Value and Stage of Development, 2006-2018 50
• Figure 20: Schizophrenia, Global, Number and Aggregate Deal Value of Licensing Deals by Molecule Type and Molecular Target Class, 2006-2018 51
• Figure 21: Schizophrenia, Global, Licensing Deals with Disclosed Deal Values, 2006-2018 52
• Figure 22: Schizophrenia, Global, Co-development Deals by Region, Value and Year 2006-2018 53
• Figure 23: Schizophrenia, Global, Number and Aggregate Deal Value of Co-development Deals By Stage of Development and Year, 2006-2018 54
• Figure 24: Schizophrenia, Global, Number and Aggregate Deal Value of Co-development Deals by Molecular Target Class, 2006-2018 55
• Figure 25: Schizophrenia, Global, Co-development Deals with Disclosed Deal Values, 2006-2018 55
• Figure 26: Schizophrenia, Global, First-in-Class Programs with and without Prior Involvement in Licensing or Co-development Deals, 2006-2018 56