DG031
and DG051 for the prevention of heart attack (myocardial infarction)
Heart attack (also called myocardial infarction, or MI) is the
leading killer in the industrialized world. Nearly half of men
and one-third of women who reach the age of forty will suffer a
heart attack in their lifetime. Currently, there are effective
drugs for treating some of the contributing risk factors for heart
attack, such as high-cholesterol, diabetes and hypertension. However,
there are no existing drugs aimed at preventing the pathogenesis
of the disease itself.
We are working to meet this need by bringing our gene discoveries
to bear on the development of new drugs. The gene variants
we have linked to heart attack have pointed us to a major biological
mechanism increasing risk of the disease: the upregulation
of the leukotrine pathway leading to increased production of
the inflammatory mediator leukotriene B4. Our developmental
compounds are aimed at reducing the incidence of heart attack
by inhibiting the proteins made by these gene variants, and
have been shown in clinical trials to reduce the production
of leukotriene B4 in a dose-dependent manner. DG051, a first-in-class
compound developed by deCODE’s chemistry unit going into Phase
II clinical trials in 2H07, and DG031, which is currently being
reformulated for reentry into Phase
III
clinical
testing.
Read more
DG041
for the prevention of arterial thrombosis
DG041 is deCODE’s developmental anti-platelet compound
for the prevention of arterial thrombosis and its complications.
Thrombosis is a process that leads to the formation of
a blood clot that obstructs
the flow of blood through a vessel. Such clots can also
become detached from the sites where they originally
form - a process called embolization - and travel through
the bloodstream and lodge in vessels elsewhere in the
body.
Depending on where in the body such clots occur
they can contribute to a range of serious conditions,
including
peripheral artery disease (a common disorder involving
the narrowing of arteries in the legs by atherosclerotic
plaques), heart attack and stroke. Current anti-platelet
therapies broadly fight clot formation and as a side-effect
also increase the potential for bleeding events.
DG041 is a novel, first-in-class, orally-administered
small molecule developed by deCODE that the company
has shown to be a selective and potent antagonist of the
EP3 receptor for prostaglandins E2. deCODE identified
EP3 as a target through the company's population genetics
research linking variations in the gene encoding EP3
to increased risk of various vascular diseases.
Our aim with DG041 is to develop a novel anti-platelet compound that can prevent arterial thrombosis without increasing bleeding risk. In Phase I clinical trials, completed in early 2006, DG041 was found to be well tolerated, with no drug-related serious adverse events noted, and to provide a dose-dependent reduction in platelet aggregation with no significant changes in bleeding time observed between subjects on DG041 versus those on placebo.
In 2006, 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 such as Plavix™ and aspirin, 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 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 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.
PDE4 program in vascular disease, including stroke
Taken together, vascular diseases represent a major public
health challenge and a leading cause of death and disability.
Stroke alone is the third leading cause of death and
the leading cause of disability in the industrialized
world. There are currently few if any therapeutics designed
to prevent the onset, progression or recurrence of vascular
diseases by specifically targeting the underlying causes
of these conditions.
deCODE's population genetics work has linked versions
of the gene encoding the Phosphodiesterase 4D enzyme
(PDE4D) to a significantly increased risk of stroke.
Expression and functional analyses of the gene strongly
suggest that PDE4D plays an important role in atherosclerosis,
most likely by influencing the proliferation and migration
of smooth muscle cells within arteries that is central
to the biology of ischemic stroke.
In early 2005 deCODE and Roche began work under a three-year
collaboration to co-develop Phosphodiesterase 4 (PDE4)inhibitors
for vascular disease, including stroke. Under this collaboration,
deCODE has used its structure-based drug design capabilities
to generate novel PDE4D-specific inhibitors. deCODE is
currently optimizing lead series for clinical candidate
selection.
Inflammation
Employing its drug discovery assets in PDE4 inhibitors, deCODE has created novel
and selective inhibitors of PDE4B. Animal knock-out models have strongly implicated
PDE4B in TNFa-mediated pro-inflammatory response, suggesting that effective inhibition
of PDE4B may enable new approaches to the treatment of asthma, COPD, and other
conditions. deCODE’s biostructures unit has demonstrated that the company’s compounds
have a novel binding mode to PDE4B, and the company is optimizing these compounds
for lead series selection.
Pain
The recent identification of increased cardiovascular risk associated with
selective Cox-2 inhibitors and other non-selective anti-inflammatory drugs
(NSAIDs) has
created a need for new, non-opiate based drugs for treating acute and chronic
pain. deCODE is exploiting its drug discovery work on inhibitors of the EP3
receptor for prostaglandins E2 to pursue this opportunity. Utilizing compounds
discovered
in its program on arterial thrombosis (DG041), deCODE's drug discovery group
is focused on optimizing the pharmaceutical properties of potential lead candidates
and has discovered representative compounds with strong activity in relevant
pain models.
Obesity
Obesity is one of the fastest-growing public health challenges in the industrialized
world and a major risk factor in a number of other conditions from diabetes
to heart disease. deCODE has discovered several genes contributing to obesity
through our population-based studies employing genetic and clinical data from
some 17,000 participants in our obesity program in Iceland. These genes confer
increased risk of obesity through different biological pathways.
deCODE’s drug
discovery group is currently conducting lead optimization of a compound targeting
one of these pathways, and this work has demonstrated
encouraging activity in an animal model of obesity. Under our 2002 obesity
alliance with Merck, drug discovery work has also been undertaken against
another pathway identified through out gene discovery work.
Type 2 diabetes
Diabetes affects nearly 200 million people worldwide and an estimated
21 million in the United States - 7% of the population. In the United
States, the direct medical cost associated with diabetes is nearly $100
billion per year. The vast majority of diabetes patients have type 2
diabetes (T2D), a condition in which the cells in the body do not properly
use insulin and/or the body does not produce enough insulin.The incidence
of type 2 diabetes is increasing rapidly in the industrialized world,
in part due to the increase in obesity, one of the major risk factors
for developing the disease.
In January 2006, deCODE announced the discovery of the most significant inherited
risk factor for type 2 diabetes found to date. More than one third of individuals
in the study groups in Iceland, Denmark and the United States carry one copy
of the at-risk variant and are at an approximately 45% increased risk of the
disease compared to controls; 7% carry two copies and are at a 141% greater
risk. The company estimates that the at-risk variant of the gene - which is
located on chromosome 10 and encodes a protein called transcription factor
7-like 2 (TCF7L2) - accounts for some 20% of diabetes cases.
deCODE is applying these findings for diagnostic and drug discovery and development.
deCODE scientists have also isolated another gene associated with T2D that
encodes a target that appears to be involved in insulin secretion.
Schizophrenia
Schizophrenia is a debilitating psychiatric disorder and one of the most disabling
and emotionally devastating illnesses known to man. Approximately 0.5% to 1.0%
of people worldwide will develop schizophrenia during their lifetime. Its onset
usually occurs in early adulthood and it affects
its victims lifelong.
deCODE's
findings in schizophrenia provide a good example of how genetic
discoveries can shed light on the biological basis of complex diseases
about which little has been known. The disease gene the company
discovered through its population-based research, known by the name of
the protein it encodes, Neuregulin 1, is involved in the formation and
plasticity of neural synapses, the place where neurons communicate.
Experience is thought to affect the brain largely through the
remodelling of synapses, and Neuregulin may therefore represent a key
point at which the impact of nature and nurture meet to contribute to
the development of this serious mental illness.
deCODE's
extensive functional studies have provided an understanding of the role
of the Neuregulin 1 pathway in schizophrenia, yielding druggable
targets that have been taken into the drug discovery process.
deCODE has conducted a high-throughput screen against its most
promising target within the Neuregulin 1 pathway and found small
molecule compounds that restore ErbB4-dependent NMDA-R phosphorylation.
