PI3K Signaling Pathway Analysis: A Shifting Marketed and Pipeline Product Landscape, as Blockbusters Expire and Development Moves Towards Downstream Targets

GBI Research’s latest report, PI3K Signaling Pathway Analysis: A Shifting Marketed and Pipeline Product Landscape, as Blockbusters Expire and Development Moves Towards Downstream Targets, provides a comprehensive assessment of the marketed and pipeline products acting on various components of the phosphoinositide 3-kinase (PI3K) signaling network.

The PI3K pathway is a critical signal transduction pathway and plays important roles in the regulation of many cellular processes including protein synthesis, cell-cycle progression and cell survival. Additionally, numerous diseases are known to be associated with dysregulated PI3K signaling. Consequently, the PI3K signaling pathway has been extensively researched over recent decades and is widely recognized as a prime target for therapeutic intervention. Indeed, globally, 2,129 products that target components of the PI3K signaling network have gained market approval to date.

These include a number of highly clinically and commercially successful therapies such as the blockbuster drugs Herceptin (trastuzumab), Avastin (bevacizumab) and Lantus (insulin glargine). Despite this, PI3K signaling remains a focal point of drug discovery as many components of the pathway are yet to be targeted by currently available pharmaceuticals. There are 2,067 pipeline products in development that target components of the PI3K pathway, many of which act on first-in-class molecular targets.

The following report discusses the significance of the PI3K pathway, including its role in disease, and provides a comprehensive overview of the PI3K marketed and pipeline landscapes. The report provides a breakdown of the following key signaling pathways within the PI3K network in terms of marketed and pipeline activity: PI3K/AKT/mTOR pathway, Ras/Raf/MEK/ERK pathway, cell survival pathways downstream of AKT, cell-cycle progression pathways downstream of AKT, metabolism pathways downstream of AKT and kinases downstream of PDK1.

An analysis of the marketed and pipeline activity across various nodes (defined as groups of molecules which have the same role in response to a stimulus) within each of these pathways is provided. An examination of the marketed and pipeline products acting on each of these pathways in terms of molecule type and therapy area, and, in the case of pipeline products, novelty and stage of development, provides further granularity. Additionally, detailed product profiles of key marketed products are provided, which incorporate clinical and commercial perspectives and include historical and forecast annual sales revenues. The report concludes with a discussion of promising late-stage pipeline products.

Scope

– Which products that target components of the PI3K network are most commercially successful and which indications are these products approved for?

– What is the range of molecule types that act on components of the PI3K network?

– Which nodes across the various pathways are not currently targeted by marketed products and how many pipeline products act on these nodes?

– What is the distribution of pipeline products by stage of development across various nodes?

– Which late-stage pipeline products are projected to be the most commercially successful?

Reasons to buy

- Appreciate the significance and complexity of the PI3K signaling network, with visual schematics of the overall network, as well as breakdowns of the key signaling pathways, by node.

- Understand the current status of the PI3K marketed landscape, and the relative clinical and commercial success of currently marketed products.

- Analyze the PI3K pipeline landscape and gain insight into the pipeline products that act on novel molecular targets within the PI3K network.

Table of Contents

1 Table of Contents

1 Table of Contents 4

1.1 List of Tables 4

1.2 List of Figures 5

2 Introduction 7

2.1 Role of PI3K in Disease 9

2.1.1 Oncology 9

2.1.2 Central Nervous System 11

2.1.3 Ulcerative Colitis 12

3 Marketed Products Landscape 14

3.1 Overview 14

3.2 Key Signaling Pathways within the PI3K Marketed Product Landscape 14

3.2.1 PI3K/AKT/mTOR Pathway 14

3.2.2 Ras/Raf/MEK/ERK Pathway 18

3.2.3 Cell Survival Pathways Downstream of AKT 19

3.2.4 Cell Cycle Progression Pathways Downstream of AKT 22

3.2.5 Kinases Downstream of PDK1 24

3.3 Key Marketed Products 25

4 Pipeline Products Landscape 44

4.1 Overview 44

4.2 Key Signaling Pathways within the PI3K Pipeline Product Landscape 44

4.2.1 PI3K/AKT/mTOR Pathway 44

4.2.2 Ras/Raf/MEK/ERK Pathway 49

4.2.3 Cell Survival Pathways Downstream of AKT 52

4.2.4 Cell Cycle Progression Pathways Downstream of AKT 57

4.2.5 Metabolism Pathways Downstream of AKT 61

4.2.6 Kinases Downstream of PDK1 65

4.2.7 Clinical-Stage Pipeline Products 68

4.2.8 List of All Pipeline Products 81

5 Appendix 255

5.1 References 255

5.2 Abbreviations 258

5.3 List of PI3K Pathway Nodes 261

5.4 About GBI Research 265

5.5 Disclaimer 265

List of Tables

1.1 List of Tables

Table 1: PI3K Marketed and Pipeline Landscape, Most Commercially Successful Marketed Products Acting on Components of the PI3K Pathway, 2017-2024 36

Table 2: PI3K Marketed and Pipeline Landscape, Most Commercially Successful Pipeline Products Acting on the PI3K Signaling Network, 2024 69

Table 3: PI3K Marketed and Pipeline Landscape, All Pipeline Products Acting on the PI3K Signaling Network, 2018 81

List of Figures

1.2 List of Figures

Figure 1: PI3K Marketed and Pipeline Landscape, Global, PI3K Signaling Network, 2018 7

Figure 2: PI3K Marketed and Pipeline Landscape, Global, Marketed Activity for the PI3K/AKT/mTOR Pathway, 2018 15

Figure 3: PI3K Marketed and Pipeline Landscape, Global, Marketed Activity for the PI3K/AKT/mTOR Pathway by Molecule Type, 2018 16

Figure 4: PI3K Marketed and Pipeline Landscape, Global, Marketed Activity for the PI3K/AKT/mTOR Pathway by Therapy Area, 2018 17

Figure 5: PI3K Marketed and Pipeline Landscape, Global, Marketed Activity for the Ras/Raf/MER/ERK Pathway, 2018 18

Figure 6: PI3K Marketed and Pipeline Landscape, Global, Marketed Activity for the Ras/Raf/MER/ERK Pathway by Molecule Type, 2018 18

Figure 7: PI3K Marketed and Pipeline Landscape, Global, Marketed Activity for the Ras/Raf/MER/ERK Pathway by Therapy Area, 2018 19

Figure 8: PI3K Marketed and Pipeline Landscape, Gloal, Marketed Activity for Cell Survival Pathways Downstream of AKT, 2018 20

Figure 9: PI3K Marketed and Pipeline Landscape, Global, Marketed Activity for Cell Survival Pathways Downstream of AKT by Molecule Type, 2018 20

Figure 10: PI3K Marketed and Pipeline Landscape, Global, Marketed Activity for Cell Survival Pathways Downstream of AKT by Therapy Area, 2018 21

Figure 11: PI3K Marketed and Pipeline Landscape, Global, Marketed Activity for Cell Cycle Progression Pathways Downstream of AKT, 2018 22

Figure 12: PI3K Marketed and Pipeline Landscape, Global, Marketed Activity for Cell Cycle Progression Pathways Downstream of AKT by Molecule Type, 2018 23

Figure 13: PI3K Marketed and Pipeline Landscape, Global, Marketed Activity for Cell Cycle Progression Pathways Downstream of AKT by Therapy Area, 2018 23

Figure 14: PI3K Marketed and Pipeline Landscape, Global, Marketed Activity for Kinases Downstream of PDK1, 2018 24

Figure 15: PI3K Marketed and Pipeline Landscape, Global, Marketed Activity for Kinases Downstream of PDK1 by Molecule Type, 2018 24

Figure 16: PI3K Marketed and Pipeline Landscape, Global, Marketed Activity for Kinases Downstream of PDK1 by Therapy Area, 2018 25

Figure 17: PI3K Marketed and Pipeline Landscape, Global, Historical and Forecast Annual Revenues for Herceptin ($bn), 2006-2024 26

Figure 18: PI3K Marketed and Pipeline Landscape, Global, Historical and Forecast Annual Revenues for Avastin ($bn), 2006-2024 27

Figure 19: PI3K Marketed and Pipeline Landscape, Global, Historical and Forecast Annual Revenues for Lantus (insulin glargine) ($bn), 2006-2024 28

Figure 20: PI3K Marketed and Pipeline Landscape, Global, Historical and Forecast Annual Revenues for Eylea (aflibercept) ($bn), 2011-2024 29

Figure 21: PI3K Marketed and Pipeline Landscape, Global, Historical and Forecast Annual Revenues for Ibrance (palbociclib) ($bn), 2015-2024 30

Figure 22: PI3K Marketed and Pipeline Landscape, Global, Historical and Forecast Annual Revenues for Novolog ($bn), 2006-2024 31

Figure 23: PI3K Marketed and Pipeline Landscape, Global, Historical and Forecast Annual Revenues for Humalog ($bn), 2006-2024 32

Figure 24: PI3K Marketed and Pipeline Landscape, Global, Historical and Forecast Annual Revenues for Perjeta ($bn), 2012-2024 33

Figure 25: PI3K Marketed and Pipeline Landscape, Global, Historical and Forecast Annual Revenues for Avonex ($bn), 2006-2024 34

Figure 26: PI3K Marketed and Pipeline Landscape, Global, Historical and Forecast Annual Revenues for Levemir (insulin detemir) ($bn), 2006-2023 35

Figure 27: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for the PI3K/AKT/mTOR Pathway, 2018 44

Figure 28: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for the PI3K/AKT/mTOR Pathway by Novelty, 2018 46

Figure 29: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for the PI3K/AKT/mTOR Pathway by Stage of Development, 2018 47

Figure 30: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for the PI3K/AKT/mTOR Pathway by Molecule Type, 2018 48

Figure 31: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for the PI3K/AKT/mTOR Pathway by Therapy Area, 2018 49

Figure 32: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for the Ras/Raf/MEK/ERK Pathway, 2018 49

Figure 33: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for the Ras/Raf/MEK/ERK Pathway by Novelty, 2018 50

Figure 34: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for the Ras/Raf/MEK/ERK Pathway by Stage of Development, 2018 50

Figure 35: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for the Ras/Raf/MEK/ERK Pathway by Molecule Type, 2018 51

Figure 36: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for the Ras/Raf/MEK/ERK Pathway by Therapy Area, 2018 52

Figure 37: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for the Cell Survival Pathways Downstream of AKT, 2018 53

Figure 38: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for the Cell Survival Pathways Downstream of AKT by Novelty, 2018 54

Figure 39: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for the Cell Survival Pathways Downstream of AKT by Stage of Development, 2018 55

Figure 40: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for the Cell Survival Pathways Downstream of AKT by Molecule Type, 2018 56

Figure 41: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for the Cell Survival Pathways Downstream of AKT by Therapy Area, 2018 57

Figure 42: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for Cell-Cycle Progression Pathways Downstream of AKT, 2018 58

Figure 43: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for Cell-Cycle Progression Pathways Downstream of AKT by Novelty, 2018 58

Figure 44: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for Cell-Cycle Progression Pathways Downstream of AKT by Stage of Development, 2018 59

Figure 45: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for Cell-Cycle Progression Pathways Downstream of AKT by Molecule Type, 2018 60

Figure 46: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for Cell-Cycle Progression Pathways Downstream of AKT by Therapy Area, 2018 61

Figure 47: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for Metabolism Pathways Downstream of AKT, 2018 62

Figure 48: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity Metabolism Pathways Downstream of AKT by Novelty, 2018 62

Figure 49: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for Metabolism Pathways Downstream of AKT by Stage of Development, 2018 63

Figure 50: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for Metabolism Pathways Downstream of AKT by Molecule Type, 2018 64

Figure 51: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for Metabolism Pathways Downstream of AKT by Therapy Area, 2018 65

Figure 52: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for Kinases Downstream of PDK1, 2018 65

Figure 53: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for Kinases Downstream of PDK1 by Novelty, 2018 66

Figure 54: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for Kinases Downstream of PDK1 by Stage of Development, 2018 66

Figure 55: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for Kinases Downstream of PDK1 by Molecule Type, 2018 67

Figure 56: PI3K Marketed and Pipeline Landscape, Global, Pipeline Activity for Kinases Downstream of PDK1 by Therapy Area, 2018 68

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