IMMUNOMODULATORS: THERAPEUTIC NEEDS, PIPELINES AND PROSPECTS
EXECUTIVE SUMMARY
Chapter 1 Modulating the immune system
This Chapter begins with an overview of the human immune system. Various cells
and proteins that have roles in the immune system represent current and potential
drug targets.
Many significant medical conditions require therapeutic interventions to modulate
the activity of the patient's immune system.
In autoimmune diseases and allergies, the overactive immune system and chronic
inflammation needs to be suppressed. Immunostimulation is an approach relevant
to infections and cancers. In addition, transplant recipients usually require
immunosuppression.
The earliest immunomodulators to find clinical applications were orally-available
compounds developed from natural sources. Current treatments remain inadequate,
driving the development of improved and novel, often more specific
immunotherapies.
Some of the new immunomodulators in development are small synthetic molecules,
but many are biopharmaceuticals such as recombinant proteins and peptides,
vaccines, monoclonal antibodies and fusion proteins. Protein therapeutics are most
commonly delivered by subcutaneous injection.
Innovative protein products can be brought to the US marketplace via either the
New Drug Application (NDA) pathway and the Biological License Application
(BLA) pathway.
In preparing this Report, we have relied upon various databases, press releases, and
trade publications (in particular the US PhRMA's online database of drugs in
development, which is derived from ADIS' R&D Insight) for information on
pipeline immunomodulators.
Chapter 2 Inflammatory and Autoimmune Disorders
In autoimmune and inflammatory disorders (AIID) current treatments include
glucocorticoids, nonsteroidal anti-inflammatory drugs, therapies targeting
proinflammatory cytokines, and B cell-targeted therapeutics. These treatments
continue to be under investigation.
Development is proceeding of both broad anti-inflammatory strategies and more
targeted approaches.
In rheumatoid arthritis, protein therapeutics may be administered by injection to
inhibit the effects of TNFalpha and IL-1, to eliminate autoreactive B cells or to
prevent full T-cell activation.
This Chapter reviews immunomodulators in clinical development in the US for
rheumatoid arthritis, as well as other inflammatory conditions such as psoriasis,
multiple sclerosis, inflammatory bowel disease, systemic lupus erythematosus,
asthmaand atherosclerosis.
Most immunomodulators in development are either small molecule drugs or
monoclonal antibodies (mAbs). In addition, some immunomodulators are
recombinant proteins (for example, interferons for treatment of multiple sclerosis)
or other biopharmaceuticals (such as fusion proteins).
Current drug targets include GPCRs (in particular chemokine receptors), leukocyte
surface antigens, cytokines (interleukins, TNF family members, interferons), and
kinases.
Chapter 3 Infectious disease
In viral and bacterial infectious disease, prophylactic vaccines have traditionally
consisted of live attenuated or inactivated organisms or toxins, but safer and more
effective vaccines such as subunit vaccines and DNA vaccines have been
developed.
Many clinical trials involve prophylactic vaccines and other immunotherapies
directed at viral pathogens, in particular Influenza virus, HIV, Hepatitis viruses,
and Herpes simplex viruses.
Therapeutic vaccines are also in development, mainly for the treatment of HIV and
HCV infections.
Influenza vaccines are among the most widely used throughout the world, but new
candidates are being tested for improved vaccination efficacy. Influenza vaccines in
clinical trials include seasonal vaccines as well as vaccines based on strains that
may be related to an eventual pandemic strain.
In HIV, the initial rounds of viral replication establish a permanent reservoir of
infection. Approaches to this challenge include blocking HIV from entering cells or
inducing immune responses in mucosal surfaces. Non-vaccine immunomodulatory
agents may offer alternatives to current anti-retroviral therapies.
Vaccination is the most effective tool in preventing the transmission of HBV, but
HCV vaccine development remains at an earlier stage. Biopharmaceuticals such as
interferons and CpG oligonucleotides are also in clinical trials.
Although most basic research on herpes simplex viruses has focused on HSV-1,
there has been a greater interest in developing a vaccine for HSV-2 (which infects
genital tissues).
Almost all work in the field of bacterial vaccines has been for prophylactic
vaccines, largely driven by an increase in levels of microbial resistance to
antibiotics. Vaccines target Streptococcal and Staphylococcal bacteria as well as
the parasite Plasmodium.
Small peptide and peptidomimetics are in development, based on templates
provided by naturally-occuring cationic antimicrobial peptides.
Chapter 4 Cancer
Cancer immunotherapies use the body's immune system, either directly or
indirectly, to fight cancer. Some small molecule drugs may be used for this
purpose, but most agents in clinical development are biological response modifiers
(BRMs).
BRMs include cytokines (in particular interferons and interleukins), monoclonal
antibodies, and cancer vaccines; the first two are already a standard part of
treatment for certain types of cancer.
Monoclonal antibodies induce cytotoxic immune responses to antigen-expressing
tumor cells. Initially, mAbs targeted receptors such as antigens on tumor cells or
tumor neovasculature. Recently, immunostimulatory mAbs entered development
that work through specific immune system targets.
Prophylactic vaccines target cancer-causing viruses and are administered to healthy
individuals. Approved products in the US target HBV (associated with liver
cancer) and HPV (associated with cervical cancer).
As yet, there are no FDA-approved therapeutic vaccines but several product
candidates are in clinical trials in different types of cancer. Most use shared
antigens (overexpressed by tumor cells) to boost anti-tumor responses, but some
target unique tumor antigens.
Specific antigens may be presented to the body's immune system as
antigen/adjuvant vaccines, or a range of antigens may be presented as whole cell
vaccine preparations (which may be autologous). Vaccines based on idiotype
antibodies show particular promise in follicular lymphoma.
Dendritic cells (DCs) are responsible for the initiation of T cell and NK cell
responses to tumor antigens. An approach gaining increasing popularity is to
immunize cancer patients with their own DCs, loaded ex vivo with tumor antigens.
DCs have been shown to directly induce immunity in many clinical trials.
Other approaches under investigation include transfer of ex vivo expanded T cells
into cancer patients and use of immunostimulatory CpG oligodeoxynucleotides as
vaccine adjuvants.
Chapter 5 Transplantation
Many organs and tissues are now routinely transplanted. The activation of T cells in
response to the transplanted allograft is a central phenomenon of acute rejection.
Traditional immunosuppressants include calcineurin inhibitors, anti-proliferatives,
and glucocorticoids. They prevent acute rejection, but have adverse side effects and
increase the patient's susceptibility to infections and cancer. Improved small
molecule drugs are under development.
Induction therapy with antibodies to T cell antigens is initiated in transplant
recipients at the time of transplantation. T cell-targeting monoclonal antibodies
cause few side effects. Especially significant are the CD3 and CD25 directed
antibodies.
A new approach, use of protein blockers of the costimulatory signal needed to
activate immature T cells, promises to preserve patients' normal immune function.
Co-stimulation blockers may even eventually replace current therapies to become
the new standard of immunosuppression after transplantation.
Chapter 6 Market Considerations and Forecasts
The global pharmaceutical market was worth $643 billion in 2006.
Cancer/Immunology is the most dynamic of all major segments relevant to
immunomodulators, growing at almost 14% per annum.
The market for immunomodulators was worth $43 billion in 2006, and is expected
to grow at a CAGR of 13% to reach $80.8 billion in 2011. The North American and
European markets were worth respectively $19 billion and $12 billion in 2006, and
are forecast to rise to $40 billion and $21 billion respectively in 2011.
The immunomodulator market is divided approximately equally between agents
that suppress the immune response in autoimmunity, inflammation, and tissue
transplantation, and products (often immunostimulatory) which are targeted
towards infectious disease and cancer.
The leading immunomodulator drug classes in 2006 were the TNF blockers, used to
treat autoimmune disorders, and the recombinant interferons, used mainly in the
inflammatory CNS disorder multiple sclerosis and in infectious disease.
We predict that by 2010 the currently dominant classes will be rivaled or beaten by
cancer-specific monoclonal antibodies and vaccines. Growth in the latter category
will be driven particularly by prophylactic and therapeutic cancer vaccines.
Following imminently anticipated approvals, we expect a total cancer vaccine
market of $8 billion in 2011, dominated by Provenge, Gardasil, and Cervarix.
Prophylactic antiviral vaccines (not including prophylatic cancer vaccines) were
worth $8 billion in 2006, and sales are expected to grow slowly, reaching $12
billion in 2011.
Monoclonal antibodies for cancer are forecast to grow from $6.8 billion in 2006 to
$16.1 billion in 2011.
Sales of immunosuppressive agents for the treatment of
autoimmunity/inflammation and allergies were $14 billion in 2006, and are
expected to rise to $27 billion by 2011.
The use of immunosuppressant drugs in transplant recipients was worth $3 billion in
2006, and is forecast to reach $3.7billion in 2011.
Chapter 7 Trends and Opportunities
We identified 632 immunomodulators in active preclinical development worldwide.
Most of these agents are biologicals, reflecting the paradigm shift ongoing in the
pharmaceutical industry towards disease-modifying therapy.
The largest number of preclinical immunomodulator programs (265) are in
infectious disease. There is an equally large number of preclinical
immunomodulator programs in cancer (258). Other areas include arthritis (66),
other inflammation (21), and transplantation (22).
Immunostimulation is a well-established and evolving strategy in infection
prevention, but it marks a dynamic change in the way cancer is treated. In our
dataset of 231 preclinical vaccines, 37 were therapeutic cancer vaccines.
Monoclonal antibodies continue their march into the clinic. The three major areas
of therapeutic application are: cancer; diseases of the immune system; and
infectious diseases. A large number (111) are fully-human antibodies with a low
risk of immunogenicity.
Future players in immunomodulation are likely to include both large
pharmaceutical companies and smaller biotechnology companies. Medarex has the
greatest number of agents in preclinical programs, followed by AstraZeneca.
We carried out a survey of 8,562 immunomodulation-related US patents filed
between 1992 and mid-2007. Patents describing Vaccines formed the largest
segment, with 39% of the total, followed by Allergy (23%) and Autoimmunity
(18%).
We identified the most prominent assignees in various therapeutic categories.
Amongst the most prominent overall were the US government, Merck & Co, Pfizer,
GlaxoSmithKline/SmithKline Beecham, American Home Products/Wyeth, and the
University of California.
Many of the most prominent assignees were shown to be also the most influential
assignees, when ranked by the number of foward citations associated with their
patents, and were led by Merck & Co and AHP/Wyeth. It was also noted that AHP
patents were each cited three times as often as the survey average.
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