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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 upregulating 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
Risk Factor
HapK in African-Americans°
HapK in Caucasians°
Race (AA vs. C)
High hsCRP*
Hypertension†
Smoking
Diabetes
High LDL cholesterol‡
Low HDL cholesterol±
3.57
1.16
1.09
2.00
1.73
1.71
1.47
1.74
1.46