deCODE genetics (Nasdaq:DCGN) today announced progress in
the development of DG041, the company’s Phase II developmental
compound for the prevention of arterial thrombosis. The results
of the Phase IIa and clinical pharmacology studies presented
today build upon previous findings demonstrating DG041’s
profile as an anti-platelet compound that deCODE expects
will make it possible to block the formation of blood clots
mediated through inflammation in atherosclerotic plaques
but without increasing bleeding risk. There is a large unmet
medical need for a drug with these characteristics, with
applicability to the prevention of heart attack, stroke and
the progression of peripheral artery disease (PAD). Drugs
such as Plavix™ and aspirin, the current mainstays of oral
anti-platelet therapy, significantly increase the risk of
bleeding by broadly blocking platelet activity.
Recent advances in deCODE’s therapeutic and diagnostics
pipeline will be discussed at the company’s annual R&D
event being held today in Reykjavik. The presentations will
be webcast live through the investors
page of the company’s
website at www.decode.com, starting at 9am GMT/5am EDT, and
will be archived on the site. Among the highlights to be
discussed are:
DG041 – Arterial thrombosis. DG041 is a novel, first in
class antagonist of the EP3 receptor for prostaglandins E2.
deCODE initially identified EP3 as a target by isolating
variants in the gene encoding the EP3 receptor for prostaglandins
E2 (PGE2) that approximately double the risk of PAD, a common
and debilitating atherosclerotic condition in which the flow
of blood to the legs is progressively constricted. The mechanism
through which EP3 modulates platelet aggregation is distinct
from those targeted by aspirin and Plavix™. Following deCODE’s
gene discovery, work by leading international scientists
has demonstrated in mice that PGE2 is produced in atherosclerotic
plaques, promoting the formation of clots immediately at
the sites of plaque but not over normal blood vessels. The
formation of these thrombi is dependent on signaling through
EP3. This pathway is left largely unaffected by existing
anti-platelet drugs such as aspirin and Plavix™.
deCODE’s medicinal chemistry group discovered DG041 as a
means to prevent arterial thrombosis by inhibiting the activity
of EP3. In animal studies and extensive Phase I clinical
testing completed in mid-2006, DG041 was shown to effectively
inhibit platelet aggregation through this pathway without
increasing bleeding time, and to be safe and well-tolerated
at all doses tested. Late last year, deCODE began a Phase
IIa randomized, placebo-controlled clinical trial of DG041
in 144 PAD patients, to examine safety and tolerability of
doses of 100mg twice a day and 400mg twice a day and their
effect on a range of biomarkers. Because a large proportion
of patients in this trial and subsequent trials would be
taking other anti-platelet compounds, the company simultaneously
began work to identify a sensitive biomarker of anti-platelet
activity that could discriminate between the effects of DG041
and these other agents. The vasodilator-stimulated protein
(VASP), which normally holds platelets in a quiescent state
when phosphorylated but causes platelets to bind when dephosphorylated
upon activation of EP3, was found to provide such a biomarker.
The company thus began a clinical pharmacology study to examine
DG041’s effectiveness in blocking VASP-mediated platelet
activation.
The results of these studies presented today provide a compelling
demonstration of DG041’s potential as a next-generation oral
anti-platelet therapy - an effective means of preventing
arterial thrombosis specifically at the sites of plaque lesions
in the vasculature. In the Phase IIa study, DG041 was found
to reduce several markers of inflammation – c-reactive protein
(CRP), monocyte chemotactic protein 1 (MCP1), and soluble
intracellular adhesion molecule (sICAM) – in a dose-dependent
manner.
Ankle-brachial
index (ABI) measurements – which gauge the strength of blood
flow to the legs and are a key measurement of the severity
of PAD – also showed improvement in both DG041 treatment
groups. There were no drug-related serious adverse events
in the study and no discernible difference in other adverse
events between the DG041 and matched placebo groups.
The results of the placebo-controlled clinical pharmacology
study also announced today demonstrate that in a concentration-dependent
manner DG041 dramatically inhibits platelet activation mediated
through VASP as well as platelet aggregation. DG041 also
reduced levels of another indicator of platelet activation,
p-selectin. Moreover, the desired effect on VASP appears
to be achievable at doses lower than previously anticipated.
deCODE is thus very encouraged that in targeting EP3, the
company is advancing a potentially major new approach to
anti-platelet therapy - one that acts specifically to prevent
arterial thrombi, targets a pathway not addressed by existing
drugs, with minimal impact on normal platelet function.
DG031 and DG051 – Heart attack
In its drug
development programs targeting the leukotriene pathway
for the prevention of heart attack, deCODE is advancing
the reformulation of its FLAP inhibitor DG031 for re-entry
into clinical trials. A lead formulation has been identified
and a 3-month accelerated stability study completed. The
company believes that a once-a-day dosing regimen may provide
even better pharmacodynamic effect than the previous twice-a-day
regimen. The company expects to be ready to restart Phase
III testing near year end. DG051, an inhibitor of leukotriene
A4 hydrolase (LTA4H), has successfully completed single-
and multiple-dose Phase I testing. It has demonstrated
potent, dose-dependent lowering of the production of leukotriene
B4, the end product of the leukotriene pathway which deCODE’s
genetics and biology work has pinpointed as a key means
of modulating risk of heart attack. DG051’s pharmacokinetic
profile supports its development with once-a-day dosing,
with a very satisfactory safety and tolerability profile.
The company plans to initiate Phase II clinical testing
of DG051 later this year.
Diagnostics and gene discovery
In April
deCODE launched deCODE T2™, the company’s first DNA-based,
reference laboratory test for gauging individual risk of
type 2 diabetes. The company will provide an update on
its marketing strategy for its diagnostic tests and will
discuss the upcoming launch of its deCODE AF™ test, which
detects a genetic variant that confers risk of atrial fibrillation,
the leading cause of cardiogenic stroke. The company is
also developing tests for sequence variants associated
with risk of heart attack, glaucoma and several other conditions
in which deCODE has recently isolated risk variants. Since
the beginning of the year, deCODE has dramatically accelerated
its gene discovery work, publishing major new risk variants
for heart attack, breast cancer, prostate cancer, type
2 diabetes, among others. The company expects to announce
many additional discoveries in the weeks and months ahead.
deCODE is underscoring its position as the global leader
in the identification of genetic risk factors for common
diseases, building on this leadership by bringing together
its human genetics resources and capabilities with the
power of genome-wide SNP association chips.
About deCODE
deCODE is
a biopharmaceutical company applying its discoveries in
human genetics to the development of drugs and diagnostics
for common diseases. deCODE is a global leader in gene
discovery — our population approach and resources have
enabled us to isolate key genes contributing to major public
health challenges from cardiovascular disease to cancer,
genes that are providing us with drug targets rooted in
the basic biology of disease. deCODE is also leveraging
its expertise in human genetics and integrated drug discovery
and development capabilities to offer innovative products
and services in DNA-based diagnostics, bioinformatics,
genotyping, structural biology, drug discovery and clinical
development. deCODE is delivering on the promise of the
new genetics.SM Visit us on the web at www.decode.com.
Any statements contained in this presentation that relate
to future plans, events or performance are forward-looking
statements within the meaning of the Private Securities Litigation
Reform Act of 1995. These forward-looking statements are
subject to a number of risks and uncertainties that could
cause actual results to differ materially from those described
in the forward-looking statements. These risks and uncertainties
include, among others, those relating to technology and product
development, integration of acquired businesses, market acceptance,
government regulation and regulatory approval processes,
intellectual property rights and litigation, dependence on
collaborative relationships, ability to obtain financing,
competitive products, industry trends and other risks identified
in deCODE’s filings with the Securities and Exchange Commission.
deCODE undertakes no obligation to update or alter these
forward-looking statements as a result of new information,
future events or otherwise.
