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C-Reactive
Protein: Cardiac Risk Marker and Potential Drug Target
By
Lucy
Sannes, Ph.D., Sannes
& Associates
Vicki Glaser, Contributing Editor to Pharma
DD, contributed to this article.
November 9, 2006
C-reactive
protein (CRP), a product of the liver that is secreted
into the bloodstream in response to inflammation, has
attracted considerable attention of late as a biomarker
for cardiovascular disease risk. In addition, interest in
CRP as a potential drug target continues to grow. At least
two biotech companies are currently exploring therapeutic
compounds that target CRP. The eventual impact of CRP as a
therapeutic target remains speculative, but there could be
multiple indications for a drug that affects CRP
expression and function--whether through direct
interaction with the protein or via a more indirect
mechanism--because inflammation plays a role in a number
of different disorders in addition to cardiovascular
disease. If clinical data ultimately demonstrate that CRP
is a reliable biomarker for cardiovascular disease and, as
a component of the inflammatory process, is a useful
therapeutic target, novel drugs developed to modulate CRP
levels and activity have the potential to be blockbuster
drugs with annual sales of multiple billions of dollars.
CRP is a
general marker for acute inflammation, and inflammation is
thought to have an important role in atherogenesis.
Diagnostic tests for CRP are broadly applicable for
monitoring inflammation and response to treatment for
inflammatory and autoimmune diseases such as rheumatoid
arthritis. In addition, a CRP measurement has diagnostic
value when acute viral or bacterial infection is
suspected.
Blood
levels of CRP that correlate with increased risk of
cardiovascular disease in apparently healthy individuals
are much lower than those detectable using standard CRP
tests. A high-sensitivity
CRP (hs-CRP) test is used for cardiac risk assessment.
Evolving
Role in Predicting Cardiac Risk
CRP tests
have been available for several years. Although an
elevated CRP level is known to be associated with an
increased risk of heart disease, no clear consensus exists
regarding when and on whom to use hs-CRP testing.
In January 2003, the Centers for Disease Control
and Prevention (CDC) and the American Heart Association
(AHA) published a joint scientific statement recommending
when this test might be useful.1 The CDC/AHA
recommendation states that the evidence supports the use
of hs-CRP as an independent predictor of cardiac risk when
evaluating individuals of intermediate or moderate risk
for cardiovascular disease. However, the statement does
not recommend use of hs-CRP testing for widespread
screening of adults to determine risk or to monitor
treatment.
The
CDC/AHA statement also defines risk groups (low, average,
and high) based on CRP levels in the blood. Patients at
high risk (CRP > 3 mg/L) have approximately a twofold
greater risk of cardiac disease compared to those in the
low risk group (CRP < 1 mg/L). At present, hs-CRP
testing is usually performed together with tests for other
cardiac risk markers such as total cholesterol,
low-density lipoprotein cholesterol, high-density
lipoprotein cholesterol, and triglycerides.
More
recently, clinical evidence to support a role for CRP
testing in risk assessment has been mixed. On the positive
side, a study published in July 2005 reported that people
with elevated CRP levels (> 3 mg/L) had a 45% increased
risk of having a heart attack in the next 10 years. 2
This study included 3,971 men and women aged 65 and older
who did not have a history of vascular disease and who
were enrolled in the Cardiovascular Health Study, a study
evaluating cardiac risk factors in the elderly.
In July
2006, Aaron R. Folsum, MD, MPH (
University
of
Minnesota
) and colleagues with the Atherosclerosis Risk in
Communities (ARIC) Study, published a paper describing the
association of 19 novel risk factors (including CRP) with
coronary heart disease (CHD). 3 The 15,792
participating adults were enrolled in the study between
1987 and 1989. At enrollment, the study population ranged
in age from 45 to 74 years; participants were subsequently
followed and monitored for development of CHD. The
findings indicated that several compounds, including CRP,
were associated with CHD risk, but assessment of these
novel risk factors did not improve the ability to predict
CHD compared to predictions based on traditional risk
factors. The authors did point out, however, that even if
compounds such as CRP are not useful additions to risk
assessment, they might still have important physiological
implications and be suitable treatment targets.
Numerous
other published studies, as well as ongoing studies, have
evaluated the role of CRP as a biomarker for cardiac risk.
Additional clinical trials have evaluated the impact of
drug classes such as statins on CRP levels. These drugs
are widely used to modify lipid levels and to reduce risk
of CHD. Several pharmaceutical companies recently reported
the results of clinical trials that demonstrated the
ability of statins to lower CRP levels. Selected examples
of these trials are presented in the accompanying table.
These represent just a small number of the many studies
that have been conducted by both pharmaceutical companies
and academic researchers.
Table:
Novel Therapies in Development Targeting C-Reactive
Protein (CRP) and Studies of Cardiovascular
Antihypertensive Drugs Using CRP as a Biomarker of
Inflammation
Company
|
Product
|
Comments
|
|
Novel
Therapies in Development
|
|
Isis
Pharmaceuticals
|
ISIS
353512
|
•Antisense
compound targeting CRP
•For
cardiovascular/inflammation
•In
preclinical development
|
|
Pentraxin
Therapeutics Ltd.
|
--
|
•Owns
patents and patent applications relating to research
on a CRP inhibitor developed at University College
London
|
|
Selected
Examples of Companies Conducting or Announcing
Trials Involving Elevated CRP Levels in
Cardiovascular Disease and Hypertension
|
|
AstraZeneca
|
Crestor
(rosuvastatin)
|
•Currently
conducting the JUPITER clinical trial to evaluate
the statin Crestor, 20 mg, for primary prevention of
cardiovascular events in subjects with reduced
low-density lipoprotein (LDL)-cholesterol levels and
elevated CRP levels (plan is to include 15,000
subjects)
|
|
Merck
and Schering-Plough
|
Vytorin
(ezetimibe/simvastatin)
|
•Combination
of the statin simvastatin and an inhibitor of
cholesterol absorption in the intestines (ezetimibe)
•March
2006: Announcements
by Merck and Schering-Plough of data analysis
presented at the
American
College
of Cardiology meeting demonstrating that Vytorin
lowers CRP and LDL-cholesterol more than Lipitor (atorvastatin)
and Zocor (simvastatin)
|
|
Novartis
|
Diovan
(valsartan)
|
•Angiotensin
II antagonist; Food and Drug Administration approved
for treatment of hypertension, heart failure, and
for reduction of mortality following myocardial
infarction
•May
2006: Novartis
announced at the American Society of Hypertension
meeting that Diovan reduces CRP levels (data from
the Val-MARC study)
|
|
Pfizer
|
Lipitor
(atorvastatin)
|
•January
2005: January
6 issue of the New England Journal of Medicine
included articles with data analyses from two trials
(the REVERSAL and PROVE-IT trials) evaluating roles
of LDL-cholesterol and CRP, showing that CRP
reduction may have clinical significance and that
the benefits of the statin Lipitor may not be
explained by lowering LDL-cholesterol alone.
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Source: Sannes & Associates
The
potential role of inflammation and of CRP as a biomarker
of inflammation in hypertension is also a focus of
increased interest. A
recent review article reported that inflammation may have
a role in the development of hypertension and that
elevated CRP levels are “predictive for the development
of hypertension in prehypertensive and normotensive
patients.” 4
In May
2006, Novartis announced that its blood pressure drug
Diovan (valsartan) lowers levels of CRP, based on the
results of hs-CRP testing. These findings were part of the
“Valsartan-Managing Blood Pressure Aggressively and
Evaluating Reductions in hs-CRP” (Val-MARC) trial and
were presented at the American Society of Hypertension’s
Annual Scientific Meeting and Exposition.
Exploring
CRP’s Role in Drug Discovery
Compared
to the body of evidence supporting CRP’s value as a
diagnostic biomarker, less data are available to support a
role for the protein as a therapeutic drug target.
In April 2006, researchers at University College
London, led by Professor Mark Pepys, published a report
describing a small molecule CRP inhibitor. 5
The authors proposed that targeting CRP might provide
cardioprotection for heart attack and possibly
neuroprotection for stroke. In a rat model of CHD, in
which the animals were given human CRP, this small
molecule (1,6-bis (phosphocholine)-hexane) bound to CRP
and blocked its damaging effects. The intellectual
property, including patents and patent applications,
relating to this research belongs to Pentraxin
Therapeutics Ltd., a spinout of University College London.
Mark Pepys is a director of Pentraxin.
Isis
Pharmaceuticals is in early stage development of a
potential drug that blocks production of CRP. The
experimental compound,
ISIS
353512, works via an antisense mechanism to inhibit CRP
synthesis.
Isis
has reported that the drug suppresses liver and serum
levels of CRP in monkeys (in which CRP production is
induced) and also reduces levels of human CRP in
transgenic mice.
ISIS
353512 is in preclinical development.
CRP has
definitely become a hot topic,
at least as a diagnostic marker and potentially as a
therapeutic target. The protein is an established
biomarker for cardiac risk, although the discussion in the
literature continues on how best to use this biomarker.
Further refinement of CRP’s use in risk assessment,
diagnosis, and treatment monitoring, together with a
clearer understanding of its role as a target for drug
discovery in a wide range of therapeutic areas with an
inflammatory component, including cardiovascular and
autoimmune disease, could lead to the development of
multiple drugs and therapeutic strategies aimed at
blocking CRP production and interfering in its actions in
inflammatory pathways. CRP’s potential therapeutic role
in coronary heart disease alone opens the door to enormous
market potential.
References
Boos CJ,
Lip GY. Is hypertension an inflammatory process? Curr Pharm Des
2006;12(13):1623–1635.
Cushman
M, Arnold AM, Psaty BM, et al. C-reactive protein and the
10-year incidence of coronary heart disease in older men
and women: the cardiovascular health study Circulation
2005;112:25–31.
Folsom
AR, Chambless LE, Ballantyne CM, et al. An
assessment of incremental coronary risk prediction using
C-reactive protein and other novel risk markers: the
atherosclerosis risk in communities study. Arch
Intern Med 2006;166:1368–1373.
Pearson
TA, Mensah GA, Alexander RW, et al. Markers of
inflammation and cardiovascular disease: application to
clinical and public health practice: A statement for
healthcare professionals from the Centers for Disease
Control and Prevention and the American Heart Association.
Circulation
2003;107:499–511.
Pepys MB,
Hirschfield GM, Tennent GA, et al. Targeting C-reactive
protein for the treatment of cardiovascular disease. Nature
2006;440(7088):1217–1221.
Copyright 2006, All Rights Reserved. Cambridge
Healthtech Institute.
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