Apoptosis 2009: Opportunities in Cancer and Other Diseases

Apoptosis 2009: Opportunities in Cancer and Other Diseases published by Biophoenix Limited in February, 2009. This report consists of 310 pages and the price starts from US $ 1000.

Introduction

Abstract

Executive Summary

Apoptosis is regarded as the major mode of cell death in cancer and should therefore be considered as a potential target when developing new antineoplastic drugs. An increasing number of companies are doing so, and we anticipate that this approach will pay substantial dividends, both therapeutically and commercially. This report reviews 370 apoptosis-modulating drug candidates (9% in Phase 3 or later) developed by 233 companies and having 148 molecular targets. The report reveals a transforming market offering growth potential in cancer and other indications. Apoptosis (programmed cell death) is a natural phenomenon and occurs via a tightly regulated complex signaling cascade. Several major classes of drugs on the market - cancer chemotherapeutics, anti-TNF therapies, glucocorticoids - are now known to work, at least partly and/or indirectly, via apoptosis modulation. In cancer and in other diseases, elements of the apoptotic process become dysregulated, offering many direct targets for drug discovery.

This report reveals that many drugs have been reported to induce cancer cell apoptosis in preclinical studies. Traditional chemotherapeutic agents impair cell division and induce apoptosis indirectly. Many of the second generation indirect apoptogens (IAs) in development are biotherapies. They include: monoclonal antibodies, peptides, oligonucleotides, oncolytic viruses, and immunotherapies. The prevalence of indirect apoptotic effects emphasises the importance of screening for apoptotic potential in new anticancer drugs. This is being enabled by the increasing availability of biomarker-based assays of apoptosis.

Cancer is characterized by the (at least) partial suppression of apoptosis, which in turn causes chemotherapy resistance. Of particular interest therefore are direct apoptogens (DAs) designed to overcome treatment resistance due to overexpression of anti-apoptotic genes or downregulation of pro-apoptotic genes. Over one hundred first-in-class DAs directed at one or more of over 40 genes with a direct involvement in apoptosis (identified using the Stanford Research Institute' s PANTHER database) are analyzed in this report. The targets include caspases, BCL2 family members, and TP53 (p53). Other targets which are gaining recognition are the proteasome and heat shock proteins (HSPs). Millenium Pharmaceuticals' Velcade is the first proteasome inhibitor (PI) on the US market, and represents the most cancer cell-selective apoptogen approved to date.

We forecast that the market for specific, direct, modulators of apoptosis in oncology will grow from $0.6 billion in 2008 to $12 billion in 2013, an average annual growth rate (AGR) of 64%, when it will represent about 22% of all oncology drug sales. This is well in excess of the AGR for oncology as a whole (which is expected to be almost 14% over the same period). Oncology will itself be the best performing major segment of the overall pharmaceutical market, which will grow at around 6% over the forecast period. Individual forecasts are presented for PIs and other DAs targeting caspases, BCL2 proteins, TP53, and HSPs.

We estimate that indirect modulators of apoptosis (which have varying apoptotic effects, but do not target known apoptotic pathways) comprise around half the oncology market by sales volume and will perform similarly to it, rising from $28 billion in 2008 to $57 billion in 2013, an average AGR of 12%. This corresponds to a fairly constant market share (51% of the oncology market in 2008, falling slightly to 48% by 2013). Forecasts are presented for first generation IAs and for the two main groups of second generation IAs (biologics and small moecules such as kinase inhibitors and hormone antagonists).

Various agents known or suspected to have apoptosis-modulating properties are also in development for indications other than cancer. The two main areas are: CNS disorders (in particular neurodegenerative diseases) and chronic inflammation/autoimmunity (in particular rheumatoid arthritis). Depending on cells being targeted, therapies seek to either promote or interfere with apoptosis. Some of the DAs currently in development for cancer may also find application in the treatment of other diseases.

This report also examines apoptosis-related patents and patent applications filed during the current decade to identify the most prolific filers of patents, technology trends and potential therapeutic applications of apoptosis

Table of Contents

Front Cover

List of Tables and Figures

About Biophoenix

About the Authors

Legal Notice

Executive Summary

Chapter 1 Apoptosis and its regulation

• 1.0 Chapter summary
• 1.1 Introduction to apoptosis
• 1.2 Apoptosis versus necrosis
• 1.3 Other modes of cell death
  • 1.3.1 Autophagy
  • 1.3.2 Mitotic catastrophe
  • 1.3.3 Anoikis
• 1.4 Mechanisms of apoptosis
• 1.5 Key molecular players in apoptosis
  • 1.5.1 TNF family and death receptors
  • 1.5.2 Apoptosis adaptor proteins
  • 1.5.3 Caspases and other proteases
  • 1.5.4 BCL2 family
  • 1.5.5 IAPs and other regulators of caspases
  • 1.5.6 Intracellular kinases
  • 1.5.7 Transcription factors and regulators
• 1.6 Apoptotic pathways
  • 1.6.1 Extrinsic pathway
  • 1.6.2 Intrinsic pathway
  • 1.6.3 The perforin/granzyme pathway
  • 1.6.4 Execution pathway
• 1.7 Targeting dysregulated apoptosis
• 1.8 Apoptosis pipeline audit

Chapter 2 Assays and biomarkers of apoptosis

• 2.0 Chapter summary
• 2.1 Introduction
• 2.2 Analysis of cytomorphological parameters
• 2.3 Analysis of mitochondrial parameters
• 2.4 Biomarker-based assays of apoptosis
  • 2.4.1 Commonly assayed biomarkers
    • 2.4.1.1 Externalized phosphatidylserine
    • 2.4.1.2 Nucleosomal DNA
    • 2.4.1.3 Caspases
    • 2.4.1.4 Cytochrome c
    • 2.4.1.5 Other protein biomarkers
    • 2.4.1.6 Cytokeratins (cancer)

Chapter 3 Indirect apoptogens in development for cancer

• 3.0 Chapter summary
• 3.1 Introduction to cancer
• 3.2 Overview of anticancer pharmacotherapies
• 3.3 Detecting apoptotic effects of new drugs
• 3.4 Drugs in development with apoptotic effects
• 3.5 First generation indirect apoptogens
  • 3.5.1 Radio- and chemo-sensitizers
  • 3.5.2 Alkylating and other DNA-binding agents
  • 3.5.3 Antimetabolites
  • 3.5.4 Topoisomerase inhibitors
  • 3.5.5 Antitumor antibiotics
  • 3.5.6 Microtubule-targeting agents
• 3.6 Second generation indirect apoptogens
  • 3.6.1 Hormone antagonists
  • 3.6.2 Biotherapies
    • 3.6.2.1 Monoclonal antibodies
    • 3.6.2.2 Ribonucleases
    • 3.6.2.3 Peptides
    • 3.6.2.4 Non-antisense oligonucleotides
    • 3.6.2.5 Oncolytic viruses
    • 3.6.2.6 Immunotherapies
  • 3.6.3 Focus on kinase inhibitors

Chapter 4 Direct apoptogens in development for cancer

• 4.0 Chapter summary
• 4.1 Promoting apoptosis of cancer cells
• 4.2 Gene targets of apoptogens in development
  • 4.2.1 TNF family and death receptors
    • 4.2.1.1 TNFRSF10A
      • 4.2.1.1.1 Description of target
      • 4.2.1.1.2 Drugs in development
    • 4.2.1.2 TNFRSF10B
      • 4.2.1.2.1 Description of target
      • 4.2.1.2.2 Drugs in development
    • 4.2.1.3 TNFSF10
      • 4.2.1.3.1 Description of target
      • 4.2.1.3.2 Drugs in development
    • 4.2.1.4 FAS
      • 4.2.1.4.1 Description of target
      • 4.2.1.4.2 Drugs in development
    • 4.2.1.5 FASLG
      • 4.2.1.5.1 Description of target
      • 4.2.1.5.2 Drugs in development
    • 4.2.1.6 TNFRSF1A
      • 4.2.1.6.1 Description of target
      • 4.2.1.6.2 Drugs in development
  • 4.2.2 Caspases
    • 4.2.2.1 CASP9
      • 4.2.2.1.1 Description of target
      • 4.2.2.1.2 Drugs in development
    • 4.2.2.2 CASP3
      • 4.2.2.2.1 Description of target
      • 4.2.2.2.2 Drugs in development
  • 4.2.3 BCL2 family
    • 4.2.3.1 BCL2
      • 4.2.3.1.1 Description of target
      • 4.2.3.1.2 Drugs in development
    • 4.2.3.2 BCL2L1
      • 4.2.3.2.1 Description of target
      • 4.2.3.2.2 Drugs in development
    • 4.2.3.3 MCL1
      • 4.2.3.3.1 Description of target
      • 4.2.3.3.2 Drugs in development
    • 4.2.3.4 BAD
      • 4.2.3.4.1 Description of target
      • 4.2.3.4.2 Drugs in development
  • 4.2.4 IAPs and regulators
    • 4.2.4.1 XIAP
      • 4.2.4.1.1 Description of target
      • 4.2.4.1.2 Drugs in development
    • 4.2.4.2 BIRC3
      • 4.2.4.2.1 Description of target
      • 4.2.4.2.2 Drugs in development
    • 4.2.4.3 BIRC5
      • 4.2.4.3.1 Description of target
      • 4.2.4.3.2 Drugs in development
    • 4.2.4.4 DIABLO
      • 4.2.4.4.1 Description of target
      • 4.2.4.4.2 Drugs in development
    • 4.2.4.5 CFLAR
      • 4.2.4.5.1 Description of target
      • 4.2.4.5.2 Drugs in development
  • 4.2.5 Transcription factors and regulators
    • 4.2.5.1 NFKB1
      • 4.2.5.1.1 Description of target
      • 4.2.5.1.2 Drugs in development
    • 4.2.5.2 TP53
      • 4.2.5.2.1 Description of target
      • 4.2.5.2.2 Drugs in development
    • 4.2.5.3 HDM2
      • 4.2.5.3.1 Description of target
      • 4.2.5.3.2 Drugs in development
    • 4.2.5.4 STAT3
      • 4.2.5.4.1 Description of target
      • 4.2.5.4.2 Drugs in development
  • 4.2.6 Kinases in the PI3K/AKT pathway
    • 4.2.6.1 PIK3CA/PIK3CD/PIK3CG
      • 4.2.6.1.1 Description of target
      • 4.2.6.1.2 Drugs in development
    • 4.2.6.2 AKT1
      • 4.2.6.2.1 Description of target
      • 4.2.6.2.2 Drugs in development
    • 4.2.6.3 BTK
      • 4.2.6.3.1 Description of target
      • 4.2.6.3.2 Drugs in development
    • 4.2.6.4 PRKD1
      • 4.2.6.4.1 Description of target
      • 4.2.6.4.2 Drugs in development
  • 4.2.7 Histone deacetylases
    • 4.2.7.1 HDAC (1-5, -7, -8, and -11)
      • 4.2.7.1.1 Description of target
      • 4.2.7.1.2 Drugs in development
  • 4.2.8 Other targets
    • 4.2.8.1 IL24
    • 4.2.8.2 AIFM1
    • 4.2.8.3 RLN1
• 4.3 Proteasome inhibitors
• 4.4 HSP inhibitors

Chapter 5 Other apoptosis modulators in development

• 5.0 Chapter summary
• 5.1 CNS diseases
  • 5.1.1 Apoptosis agents in development
    • 5.1.1.1 Apoptosis antagonists
    • 5.1.1.2 Apoptosis agonists
• 5.2 Chronic inflammation and autoimmunity
  • 5.2.1 Apoptosis agents in development
    • 5.2.1.1 Apoptosis agonists
    • 5.2.1.2 Apoptosis antagonists
• 5.3 Other apoptosis agents in development

Chapter 6 Commercial Outlook: Patent and Market Analysis

• 6.0 Chapter Summary
• 6.1 Patent Analysis
  • 6.1.1 Preamble
  • 6.1.2 Uses of Patent Information
  • 6.1.3 The Apoptosis Patent Dataset
  • 6.1.4 Apoptosis Patents by Filing and Publication Years
  • 6.1.5 Apoptosis Patents by Leading Assignees
  • 6.1.6 Focus on Cytovia / Maxim / EpiCept
  • 6.1.7 Apoptosis Patents by Forward Citations
  • 6.1.8 Apoptosis Patents by Activity
• 6.2 Market Analysis
  • 6.2.1 Preamble
  • 6.2.2 Cancer
    • 6.2.2.1 Disease burden
    • 6.2.2.2 Anticancer drug landscape
  • 6.2.3 Non-cancer apoptosis modulators
  • 6.2.4 World pharmaceutical market
  • 6.2.5 Market outlook for apoptotic drugs
    • 6.2.5.1 Drug and Target Types
    • 6.2.5.2 Focus on Velcade (bortezomib)
    • 6.2.5.3 Focus on Gendicine
    • 6.2.5.4 Direct apoptogens
    • 6.2.5.5 Indirect apoptogens

Chapter 7 Trends and opportunities

• 7.0 Chapter summary
• 7.1 Apoptosis modulation offers varied opportunities
• 7.2 New directions in cancer drug development
• 7.3 Combinatorial approaches to cancer drug resistance
• 7.4 Focus on apoptosis-resistant cancer stem cells
• 7.5 Key role for biomarkers of apoptosis in cancer
• 7.6 Prospects for apoptosis modulators in other areas

Appendix 1 Abbreviations and Acronyms

• A1.1 Key gene targets for apoptotic modulation
• A1.2 Other scientific/medical terms
• A1.3 Institutions

Appendix 2 Research Methodology

Appendix 3 List of Tables and Figures

List of Tables and Figures

• Figure 1.1 Apoptotic pathways
• Table 1.1 Genes involved in apoptotic processes or signalling pathways (according to the PANTHER database)
• Figure 1.2 Apoptotic genes by molecular function
• Table 1.2 Apoptosis pipeline audit: Pharmacology
• Table 1.3 Apoptosis pipeline audit: Indications
• Table 1.4 Apoptosis pipeline audit: Originating companies
• Table 1.5 Apoptosis pipeline audit: Development status
• Table 1.6 Apoptosis pipeline audit: Molecular targets
• Figure 1.3 Apoptosis drug target landscape
• Table 1.7 Apoptosis pipeline audit: Type of agent
• Table 3.1Anticancer agents in development with apoptotic effects by therapy
• Table 3.1b Anticancer agents in development with apoptotic effects by status
• Table 4.1 Anticancer agents in development with PANTHER-classified apoptotic targets by status
• Table 4.2 TNF family and death receptor agents in anticancer development with PANTHER-classified apoptotic targets
• Table 4.3 Caspase agents in anticancer development with PANTHER-classified apoptotic targets
• Table 4.4 BCL2 family agents in anticancer development with PANTHER-classified apoptotic targets
• Table 4.5 IAP and regulator agents in anticancer development with PANTHER-classified apoptotic targets
• Table 4.6 Transcription factor and regulator agents in anticancer development with PANTHER-classified apoptotic targets
• Table 4.7 PI3K/AKT kinase agents in anticancer development with PANTHER-classified apoptotic targets
• Table 4.8 Histone deacetylase agents in anticancer development with PANTHER-classified apoptotic targets
• Table 4.9 Other agents in anticancer development with PANTHER-classified apoptotic targets
• Table 4.10 Overview of proteasome inhibitors (PIs) by status
• Table 4.11 Overview of heat shock protein (HSP) inhibitors by status
• Table 5.1Non-cancer agents in development with apoptosis-modulating effects by therapy type
• Table 5.1b Non-cancer agents in development with apoptosis-modulating effects by status
• Table 5.2 TNF-related agents in development for the treatment of inflammation/autoimmunity
• Table 6.1 Apoptosis Patents by Filing and Publication Years
• Table 6.2 Leading Assignees for WIPO Patent Applications
• Table 6.3 Leading Assignees for US Published Patent Applications
• Table 6.4 Leading Assignees for Granted US Patents
• Table 6.5 Assignees with >6 Apoptosis Filings in both the US and WIPO
• Table 6.6 The 25 Most Frequently Cited Apoptosis Patents
• Table 6.7 Apoptosis Patent Activity among 10 Leading Assignees
• Table 6.8 Apoptosis Patent Activity Across the Entire Dataset
• Table 6.9 Cancer incidence and mortality for the regions of the world
• Table 6.10 The most common cancers worldwide
• Table 6.11 Global Pharma Market by Region in 2008 and 2013 ($USM)
• Table 6.12 Global Pharma Market by Application in 2008 and 2013 ($USM)
• Table 6.13 Apoptosis Market by Application in 2008 and 2013 ($USM)
• Table 6.14 Apoptosis Market by Region in 2008 and 2013 ($USM)

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