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
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