Chapter 1 Overview of biomarker diagnostics
Pathogenic disease processes, as well as pharmacologic
responses to therapeutic intervention may be analysed at the
molecular level by utilizing biomarkers.
Molecular diagnostics analyze key DNA, RNA or protein
biomarkers to identify a disease and/or determine its course,
evaluate response to therapy, or predict individual
susceptibility to disease or drug effects.
There is a growing concensus that multiple biomarkers provide
a better reflection of the multi-dimensional nature of a
disease state. Multivariate index assays are test systems
that employ data derived in part from one or more in vitro
assays, and an algorithm enabling their interpretation.
In new drug development, when the biomarker or combination of
biomarkers can be shown to be the single best measure of
efficacy, a combination drug-diagnostic product may be
developed.
Biomarkers can provide information about changes associated
with specific diseases or responses to treatment at the DNA,
RNA, protein, or metabolite level.
Established biomarker detection platforms are nucleic acid
testing and protein immunoassays.
Evolving biomarker detection platforms include DNA
microarrays that can perform parallel biomarker analyses and
mass spectrometry that can identify large numbers of proteins
or other components in complex mixtures.
In Europe CE marking of an in vitro diagnostic product (IVD)
is required before it can be launched in the market, in
accordance with Directive 98/79/EC. In the US the Food and
Drug Administration (FDA) operates with two main types of
applications: 510K and the more comprehensive PMA (Pre Market
Approval).
In the US, IVDs are marketed as complete test kits or as
analyte-specific reagents (ASRs). The Center for Medicaid and
Medicare Services (CMS) monitors the latter. In-house
developed (homebrew) tests are conducted by clinical
reference laboratories and do not require FDA approval.
A recent trend has been the coupling of in vivo imaging
techniques with molecular biomarkers. Developments in this
area are expected to accelerate progress in in vivo
diagnostics.
Chapter 2 Biomarker discovery and validation
New high-throughput omics technologies are yielding many
potential biomarkers and biomarker patterns, some of which
may prove useful for diagnostic use.
In the biomarker discovery phase a variety of omics
technologies may be applied. In the validation phase the
diagnostic performance of candidate biomarkers has to be
assessed. The final product development phase involves
transfer of the biomarker to a robust test platform.
Omics technologies which are enabling biomarker discovery
include genomics, pharmacogenomics, transcriptomics,
proteomics and metabolomics. In addition, systems biology
seeks to understand biomarkers and pathways in which they
participate at a whole systems level.
Plasma represents a rich source of potential biomarkers. In
order to increase the success rate in the discovery of
reliable protein biomarkers approaches such as use of protein
arrays and quantitative mass spectrometry are under
exploration.
The NCI's Early Detection Research Network has proposed five
conceptual phases of biomarker development and evaluation in
the cancer area: preclinical exploratory, clinical assay and
validation, retrospective longitudinal, prospective screening
and cancer control.
Companies have been establishing proprietary technology
platforms and applying them on a large scale for discovering
and validating novel biomarkers that may be used in
diagnostics.
Many bioinformatics companies are involved in, or support,
biomarker discovery. Bioinformatics platforms are used to
identify novel biomarkers and to place them into their
biological and clinical context.
BG Medicine's biomarker discovery platform involves the
integrated analysis of thousands of precise measurements of
proteins, metabolites and nucleic acids. Compugen also
discovers biomarkers at the DNA, RNA and protein levels.
PGxHealth can rapidly screen genetic variants for their
potential utility as genetic tests. Source MDx discovers RNA
biomarkers and has obtained the first known patent claim on a
normal range of gene expression.
Companies pursuing protein biomarker discovery such as
Monarch LifeSciences and Vermillion, Caprion Proteomics, and
Pronoma exploit a range of proprietary mass spectrometry
technologies and approaches. Digilab Peptidomics uses its
proprietary technologies to identify peptide biomarkers.
Metabolon discovers metabolite biomarkers.
Chapter 3 Opportunities in cancer
In cancer, biomarker-based tests are needed to diagnose
disease, monitor disease, determine prognosis and guide
treatment decisions. In the US, blood tests based on "tumor
associated antigens" have been approved by the FDA primarily
for monitoring patients with known cancer.
Breast cancer is the most common cancer among women in the
US. Tests for early cancer detection under development are
based on gene expression, alternative RNA splicing and
protein panels.
In February 2007, the FDA cleared the first InVitro
Diagnostic Multivariate Index Assay (IVDMIA), Agendia's
MammaPrint, a gene expression profiling test to assess the
risk of breast tumor recurrence.
A variety of prognostic tests for breast cancer is under
development, based on DNA, mRNA or protein biomarkers.
Companies are also investigating various biomarkers for
inclusion in tests to select patients for treatment with
specific anti-cancer agents.
Prostate cancer is the most common cancer among men in the
US. Current PSA screening test has many drawbacks. Other
individual biomarkers may offer better specificity and
sensitivity. In addition, a range of diagnostic and
prognostic tests under development is investigating DNA
methylation, gene expression, proteomic and peptidomic
patterns.
Diagnosis of colorectal cancer, the third most common cancer
in the US, is possible based on analysis of stool-associated
tumor DNA, but blood-based diagnosis may also be possible
based on a methylated DNA marker or gene expression patterns.
Tumor gene expression profiles may predict cancer recurrence
and distant metastases.
Third Wave Technologies' FDA-cleared Invader UGT1A1 Molecular
Assay can identify patients at risk of adverse reaction to
irinotecan and other genomic or protein-based tests are under
development to enable therapy selection in colorectal cancer.
Screening tests for lung cancer, the most common cancer in
the world, are urgently needed. Blood tests based on microRNA
biomarkers and a hybrid DNA/protein test are in development,
as well as a test based on DNA methylation markers. Abbott is
developing a peptide-based test to classify lung cancer.
Early detection is also key to successful treatment of
ovarian cancer but no standardized screening test exists.
Various combinations of protein markers in panels are being
tested. Correlogic Systems' OvaCheck is the first proteomic
pattern-based blood test developed for early cancer
detection. Proteomic profiling may also allow risk
stratification.
Chapter 4 Opportunities in cardiovascular disease
The processes that participate in the pathophysiology of
cardiovascular disease have been studied intensively and a
host of protein, lipid and metabolite biomarkers has emerged.
Tests based on several of these biomarkers have already been
approved by the FDA.
In atherosclerosis, several lipid and lipoprotein biomarkers
have well-established diagnostic use. Many emerging protein
and metabolite biomarkers are indicators of inflammation or
coronary artery plaque instability. Individually these
biomarkers are at best moderate predictors of acute coronary
events.
Current studies are applying transcriptomic, proteomic and
metabolomic profiling technology to atherosclerosis.
Commercial tests of susceptibility to coronary artery disease
are also in development by companies such as Interleukin
Genetics, deCODE genetics/Roche and Celera
Diagnostics/Abbott.
In patients presenting with chest pain rapid diagnosis of
acute myocardial infarction (AMI) and risk stratification has
enormous clinical importance. Currently the most specific
cardiac markers are the cardiac troponins, markers of
necrosis.
In addition to markers of necrosis, there are many potential
protein and metabolite markers of plaque rupture, thrombosis
and ischemia under investigation. Since many potential
biomarkers show poor clinical specificity, it is likely that
they will be best utilized as part of a multimarker panel for
early AMI diagnosis and risk stratification for near-term
cardiac events.
Congestive heart failure (CHF) presents a challenging
diagnosis, much aided by the availability of tests based on
B-type natriuretic peptide (BNP), a biomarker of hemodynamic
stress. Other neurohormonal, inflammatory and metabolic
markers may add complementary information to that provided by
currently available BNP assays.
A companion pharmacogenomic test is under development for
Arca Discovery's bucindolol, which promises to be the first
genetically-targeted drug for CHF.
There are currently no rapid in vitro diagnostic tests
commercially available in the US for helping to diagnose
stroke from a blood sample. Biomarker tests awaiting FDA
approval include Biosite's Triage Stroke panel, which
combines BNP with 3 other biomarkers, and CIS Biotech's
peptide-based test.
Chapter 5 Opportunities in other diseases
In infectious diseases, most tests are for pathogen-derived
nucleic acids and proteins, or for host-derived antibodies.
Although generally speaking pathogens may be viewed as causes
and not biomarkers of disease, tests can yield clinically
useful information about biologic responses to infection,
severity of disease, or response to treatment.
In HIV and hepatitis B and C viral infections, monitoring of
the viral load and genotyping can determine the effectiveness
of therapy. In human papillomavirus (HPV) infections,
gene-based diagnostic tests can detect high-risk HPV types
which cause cervical cancers.
Biomarkers enable early diagnosis of emerging viral diseases.
Gene expression profiling may lead to the design of new
diagnostics for severe acute respiratory syndrome (SARS).
Biomarker-based testing is especially useful for bacteria
that are hard to culture, for example Chlamydia trachomatis,
Neisseria gonorrhea and Mycobacterium tuberculosis.
For many years, researchers have searched for a diagnostic
biomarker that is specific to the diagnosis of sepsis. Two
biomarkers form the basis of tests cleared by the FDA. Gene
expression profiling represents a new approach to sepsis
diagnosis.
There are as yet few biomarker diagnostics for neurological
disorders but there is considerable biomarker R&D activity in
this area. In Alzheimer's disease controversial tests that
involve sampling the CSF are commercially available. Other
tests in development are based on proprietary biomarkers.
DiaGenic has identified a gene expression signature for
Alzheimer's disease, while proteomic profiling is being
carried out by an increasing number of companies. Biomarker
discovery projects are also underway in other
neurodegenerative diseases, multiple sclerosis and traumatic
brain injury.
The area of CNS therapeutics has been notorious for its lack
of robust and objective biomarkers of efficacy, but several
companies have initiated programs targeting therapy based on
genetics.
In diabetes, studies aim to elucidate biomarkers of
susceptibility. Defining the patient's genetic profile may
also have important implications for management.
Chapter 6 Market considerations and forecasts
In 2007, the world pharmaceutical market was worth about $700
billion at supplier wholesale prices, and is expected to
increase by 7% pa in real terms to $1,200 billion in 2012.
Overall, the regulation of in vitro diagnostics (IVDs) is
less stringent than for pharmaceuticals, partly because both
assay manufacturers and clinical laboratories are expected to
assume some responsibility for the correct performance of
assays.
The worldwide IVD market is currently worth around $51
billion, about 7% of the world pharma market, and is expected
to grow at an AGR of about 8% to $76 billion in 2012.
We forecast that the biomarker market will grow in real terms
at a compound annual growth rate (CAGR) of 17.6%, from $5.5
billion in 2007 to $12.4 billion in 2012.
Biomarker assays are deployed mainly in two end-user
segments: clinical diagnostics and research (including drug
development). Currently these two segments are
approximately equal in size, but therapeutic uses of
biomarkers are expected to predominate as the market grows.
Cancer biomarker asssays (including what used to be called
"tumor marker" assays) are forecast to grow at an AGR of 10%
from $1,662M in 2007 to $2,6767M in 2012.
Assays for cardiovascular biomarkers are forecast to grow at
an AGR of 23%, from $1,662M in 2007 to $4,500M in 2012
Viral and bacterial antigen tests are worth about $1,200M and
bacterial nucleic acid tests (NATs) are worth about $300M.
We expect these to grow together at a CAGR of about 12% to a
total of $2,658M in 2012.
Viral detection and load tests are worth $500M, and we expect
these to grow at a CAGR of 22% to $1,513M in 2012.
Genotyping tests (primarily for viral infections) are worth
about $104M, and we forecast that they will grow to $686M in
2012, an AGR of 45.8%.
We also predict a high AGR of 31% for the predisposition and
pharmacogenomic testing segment, which will grow from an
estimated $102M in 2007 to $392M in 2012 as more tests enter
widespread use.
Chapter 7 Trends and opportunities
Technological advances have shifted the paradigm for
identification of biomarkers from studies of pathophysiology
or epidemiology to studies utilizing genomic and proteomic
approaches.
With the increasing emphasis on personalized medicine,
biomarkers at the DNA level will have an increasingly
important role in healthcare delivery. Gene expression
profiling will continue to address areas of unmet diagnostic
need. Proteomic studies are set to provide a more accurate
reflection of the disease process itself.
Mass spectrometric instrumentation is currently not amenable
towards routine clinical analysis but protein biomarkers
discovered with this methodology may be developed into
immunoassays.
Acceptance of biomarkers will depend on perceived benefits,
some of which are easily quantified. The advent of companion
diagnostics will forge new links among diagnostic and
pharmaceutical companies, laboratory medicine, and academe.
We examined 571 biomarker-related patent documents in the
World Intellectual Property Organization (WIPO) database and
found cancer to be the predominant indication claimed. Of the
22 leading biomarker patent assignees, half were for-profit
organizations. The assignee with the largest estate (34
patents) was Novartis.
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