DG-031-CV-301 Coronary Artery Disease and Leukotriene Gene Markers

Pioneering Research Study DG-031-CV-301 is a truly pioneering clinical trial To our knowledge it is the first example of a Phase III clinical trial in a common disease in which the drug is designed to affect a disease pathway that has been identified based on genetic/genomic research

Need for Better Treatments for Cardiovascular Disease CVD remains the leading cause of death in developed countries, and the problem is growing While effective preventive therapies exist, it is unfortunately the case that many events are not currently preventable Additional factors in the disease need to be discovered and then treated

deCODE’s Unique Scientific Approach In the development of DG031, deCODE has used population genetics studies in Iceland and replicated in Europe and the US to: Discover a basic biological pathway involved in heart attack and stroke, and Optimize the clinical development process for a compound aimed at blocking the pathway.

deCODE’s Unique Scientific Approach deCODE’s scientific staff has identified novel genetic markers associated with cardiovascular risk These genes are involved in “pathways” of inflammation and add to the evidence implicating inflammation as a key factor in heart disease and stroke deCODE now has a new drug to treat inflammation and will test whether this reduces heart disease and stroke beyond what can be accomplished with available therapies

deCODE’s target pathway: Leukotriene B4 (LTB4) LTB4 is a potent mediator of inflammation Individuals who have suffered a heart attack have increased LTB4 production by their white blood cells deCODE’s work has shown that variants of two genes encoding proteins that further up-regulate the production of LTB4 are associated with increased risk of heart attack and stroke

deCODE’s target pathway: Leukotriene B4 (LTB4) Overproduction of LTB4 by cells in the atherosclerotic plaque is associated with increased inflammation, plaque instability, and tendency to rupture, leading to clot formation and blockage of blood flow to tissues Two genes implicated by deCODE’s genetic work are: 5-lipoxygenase activating protein (FLAP) leukotriene A4 hydrolase (LTA4H)

Therapeutic Strategy By inhibiting the leukotriene pathway, reducing the production of LTB4, a reduced risk of heart attack and stroke is anticipated In Phase II studies, deCODE has demonstrated that DG031 is well-tolerated and can reduce LTB4 production in a dose-dependent manner On the basis of such studies they have selected a dose for the Phase III study

Identifying Patients Who Will Benefit Most From DG031 deCODE is also able to use genetics to make the clinical development process a more efficient and sensitive means for testing DG031 Specifically, by selecting patients with the genetic variants in the inflammatory pathway genes, deCODE can test the drug in patients they know are at an increased risk of the disease through the pathway targeted by the drug

Phase II Proof of Concept In a Phase IIa proof of concept study in Iceland, participants were drawn from highest risk group identified up to that time Icelanders with the at-risk variants of the FLAP and LTA4H genes Results were published in JAMA in May 2005

Replication in US Populations Late last year deCODE published the results of a large-scale replication study of the link between the at-risk variant of the LTA4H gene, called HapK, in 3 cohorts in the US Cleveland, Philadelphia, and Atlanta Striking result was that while in Icelanders and in Americans of European origin HapK is quite common and confers an approximately 20% increase in risk of the disease In African Americans HapK, carried by approximately 6% of the population, confers a 250% increase in risk of heart attack

Public Health Impact Important discovery from a public health perspective, as HapK is perhaps the single most powerful known risk factor for heart attack in African Americans Medically important to address this risk In DG031 we have a compound that is aimed at reducing risk of heart attack by targeting this pathway

DCV301 Trial In order to test whether DG031 is indeed effective in reducing heart attack and stroke risk, we have chosen to study the group at higher risk through the leukotriene pathway and also that which stands to derive the greatest immediate benefit from this new drug Phase III trial will focus on African Americans with the HapK variant and a history of CHD

A New Concept in Therapeutics: Pharmacogenomics Major advance in improving the risk/benefit ratio that currently exists today for pharmaceuticals Ability to tailor therapy with drugs to patients who are most likely to benefit by definition augments the ratio of benefit to risk Through genetics research and previous clinical trials, deCODE has shown that DG031 can effectively help correct the biological process through which a very common genetic predisposition to heart attack manifests itself

A New Concept in Therapeutics: Pharmacogenomics The power of pharmacogenomics to improve the therapeutic potential of other compounds targeting disordered pathways in common disease is immense

Broad Potential for Disease Treatment In our work in heart attack, as in virtually all of the programs in which we have identified genes, genetic susceptibility appears to act primarily by either up- regulating or down-regulating the activity of an important biological pathway The genetic variants associated with common diseases appear to push individuals to one extreme or other of what is probably a normal distribution of the activity of a given biological pathway

Broad Potential for Disease Treatment Important from a therapeutic perspective because it means that while it is most efficient and of greatest immediate medical benefit to first develop such treatments for those at highest risk, in order to bring them down the risk spectrum, the eventual therapeutic goal from a public health perspective may be much broader: Perhaps to bring everyone, even those at "average" risk, down to the risk profile of those who are least likely to suffer the disease

DG-031 Experience Veliflapon (DG-031) has been given to over 2000 people and has a very good safety and tolerability profile It has been studied in a wide dose range from 5 mg/day to up to 1500 mg/day and has been studied in efficacy and safety trials for up to 1 year in duration

Regulatory Issues Study protocol has been submitted and reviewed by the FDA under a procedure known as a Special Protocol Assessment (SPA) deCODE has worked with a number of clinicians and statisticians at the FDA to finalize the study protocol to a version that is complete and thorough in defining the objectives, endpoints and analyses to be performed

SNP Testing LTA4 HapK variant assay is referred to as haplotype testing Haplotype is a DNA sequence, defined by 2 or more single nucleotide polymorphisms (SNPs) or microsatellite markers SNPs are single base pair positions in genomic DNA at which different sequence alternatives (alleles) exist in normal individuals in some population(s) wherein the least frequent allele has an abundance of 1% or more

SNP Testing These markers should be perceived purely as a risk factor, much like the presence of elevated LDL and glucose, or high blood pressure This test is required to participate in the study and requires a simple blood draw as with many of the other biomarkers that are important in determining disease risk

SNP Testing Will evaluate approximately 5-8 SNPs The assay used to identify the high-risk individuals in the LTCAD study will evaluate only 5-8 SNPs out of 3 billion SNPs in the human genome Sole purpose is to ascertain whether the individual has the at-risk variant in the LTA4H gene No additional genetic information can be gleaned from this test

Study Support Has excellent academic support from both the cardiology and genetics community Using human genetics to develop better drugs and design better clinical studies is being advocated by academic and regulatory scientists All of these groups agree with the strategy of testing this drug in an intelligent manner by studying it in the patients that are at the highest risk of developing the disease through the pathway altered by this drug

Study Logistics Slightly over 20% of African Americans with heart attack are anticipated to have this variant Once the blood sample has been obtained, it will take approximately 5 working days to perform the simple test and to get information on eligibility and randomization back to the site

Risk HapK in African-Americans° HapK in Caucasians° Race (AA vs. C) High hsCRP* Hypertension † Smoking Diabetes High LDL cholesterol ‡ Low HDL cholesterol ± Risk Factor