Market background
The main application of apoptosis research is presently in cancer treatment. It should be noted that this market is
one of the largest and fastest growing sectors of the pharma industry. Of the 370 pipeline agents identified in
Apoptosis 2009: Opportunities in Cancer and Other Diseases, 80% are anticancers. This report segments the
apoptosis-related cancer market into:
direct apoptogens (apoptosis-inducing drugs known, during their development, to have apoptosis-related
molecular targets)
a. first generation indirect apoptogens (established drugs such as cytotoxics which have turned out to rely on
apoptosis for part of their efficacy)
b. second generation indirect apoptogens (recently introduced and pipeline drugs with non-apoptotic targets
which nevertheless have apoptotic effects).
c. Opportunities for apoptosis modulators in indications such as CNS disorders and chronic
inflammation/autoimmunity are also explored.

Key Features
Examination of the molecular events in apoptosis which may become dysregulated, providing opportunities
for therapeutic intervention.
· Description of morphological criteria for detecting apoptosis, as well as recent methodologies based on
detecting specific biological aspects and biomarkers.
· Analysis of 370 apoptosis-modulating drug candidates (9% in Phase 3 or later) from 233 originating
companies. These drugs target 148 known gene targets, of which the top 15 are shown in Figure 1.3 from
the report, as reproduced below.
· Deployment of Stanford Research Institute's PANTHER Classification System to identify gene targets with
a validated role in apoptosis.
· Analysis of 4,872 apoptosis-related patents and patent applications to identify technology trends and
potential therapeutic applications.
· Forecasts for the overall oncology-based apoptosis market, and its individual sectors.

Key Benefits
Utilize biomarker and drug target information in this report to discover and develop drugs with
apoptosis-modulating properties.
· Identify emerging areas of opportunity for apoptosis modulators in cancer, CNS diseases, and chronic
inflammation/autoimmunity.
· Gain up-to-date competitive intelligence on apoptosis-modulating pipelines and identify the most promising
drugs under development.
· Identify the leading originator companies developing apoptosis-modulating drugs.
Use the patent analysis presented in this report to identify leading assignees, most influential patents and
unexploited indications for apoptosis modulation.
· Devise a commercial strategy leveraging apoptosis by utilizing market forecasts for the oncology-based
apoptosis market to 2013.

Key Issues raised
The ideal of cancer therapy is to promote apoptosis of cancer cells. Traditional chemotherapeutic agents
(first generation indirect apoptogens) trigger events which result in apoptosis of cancer cells. However,
they also kill normal cells. Second generation indirect apoptogens may be less toxic to normal cells.
· Wide prevalence of indirect apoptotic effects suggests that it is always worth screening for apoptotic effects
of new anticancer drugs. Wider application of validated biomarkers of apoptosis in preclinical and clinical
trials of new drugs is thus highly desirable.
· The utility of current anticancer therapies is limited by drug resistance, either intrinsic or acquired. Direct
apoptogens target overexpressed anti-apoptotic proteins or downregulated pro-apoptotic proteins
responsible for therapy resistance.
· Neurodegenerative diseases represent an area of unmet clinical need. No therapy for neuroprotection is
currently marketed, but new apoptosis-modulating drugs in development show promise.
· Existing treatments for rheumatoid arthritis and other autoimmune conditions (anti-TNF therapies and
glucocorticoids) may act partly via apoptosis modulation. However, new apoptosis- modulating therapies
with improved specificity are needed.

Key Findings
In our survey of the apoptosis drug landscape, we identified 370 drugs aimed at 148 known gene targets.
HSP90 (heat shock protein 90) is numerically the most popular target overall.

Seventy-six percent of all apoptosis-modulating drugs in development are anticancers, including 27
radio/chemosensitizers (7%). The overall apoptosis market is forecast to grow from $28 billion in 2008 to
$57 billion in 2013.
· Of particular interest are first-in-class direct apoptogens (over 100 agents identified) which target elements
of the apoptotic pathway (over 40 genes). The global market for direct apoptogens is forecast to grow from
$606 million in 2008 to $12 billion in 2013.
· The leading subgroups of the direct apoptogens market are: proteasome inhibitors; modulators of heat
shock proteins; TP53-targeted agents; caspase-targeted agents: BCL2-targeted agents; and multi-target
apoptogens.
· Eighteen percent (65) of all apoptosis-modulating drugs in development are anti-inflammatory, and 6% (24)
are CNS targeted. Our survey of apoptosis-related patents suggests that future drugs will also target
infectious disease.

· Key Questions answered
· What types of apoptosis-modulating drugs are on the market?
· Which companies are leading the way in the development of apoptosis- modulating drugs?
· Which assays and biomarkers are increasingly used to define apoptosis during drug development?
· Why should all new anticancer drugs be screened for apoptotic effects?
· How is the apoptosis drug target landscape shaping up?
· What are the most popular targets of direct apoptogens in development for the treatment of cancer?
· How is the global cancer apoptosis market segmented and how are these sectors expected to perform
over the period 2008-13?
· What progress is being made in developing apoptosis-modulating drugs for the treatment of CNS diseases
and inflammation/autoimmunity?
· What is the nature of the apoptosis-related patent landscape?

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

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
research.

MarketsandMarkets.com publishes about 120 report a year across 10 main industries. The reports are exhaustive reports with about 50 micro markets and product segments, about 80 to 100 market data summary tables, 50 short company profiles, market breakdown upto 5 levels, strategic and competitive landscape, patent overview of more than 300 patents.

MarketsandMarkets.com publishes about 120 report a year across 10 main industries. The reports are exhaustive reports with about 50 micro markets and product segments, about 80 to 100 market data summary tables, 50 short company profiles, market breakdown upto 5 levels, strategic and competitive landscape, patent overview of more than 300 patents.