Through our population genetics work in Iceland
we identified the first genetic variants ever linked to the common
form of heart attack. Our work has shown that at-risk variants
of two genes contribute to risk of the disease by increasing the
production of a pro-inflammatory molecule called leukotriene B4
(LTB4). LTB4 contributes to inflammation of plaques that build
up inside arteries, increasing the propensity of the plaques to
rupture. This is the event that directly precedes most heart attacks.
These findings have given us a novel, direct and potentially powerful therapeutic
approach for preventing heart attack: inhibiting the synthesis of LTB4. This
is the basic biological effect our two developmental compounds are designed
to achieve. DG051, a first-in-class small molecule developed by deCODE’s
chemistry unit in Chicago, is an inhibitor of leukotriene A4 hydrolase (LTA4H).
LTA4H is the protein encoded by one of the genes deCODE has linked to risk
of heart attack, and is directly involved in the synthesis of LTB4. DG031,
which we are currently reformulating for Phase III clinical testing, we in-licensed
from Bayer AG and is an inhibitor of the 5-lipoxygenase activating protein,
or FLAP. FLAP is encoded by the other gene deCODE isolated in its heart attack
genetics work and regulates the first step in the biochemical pathway that
leads to the synthesis of LTB4. In Phase II clinical trails concluded last
year, DG031 was shown to be well tolerated at all doses tested and to reduce
the production of LTB4 in a dose-dependent manner.
The goal of both compounds is to safely and effectively rein
in the activity of the leukotriene pathway and LTB4 production,
and in so doing demonstrate that we can reduce the occurrence
of heart attack and cardiac events. We are also applying our
genetics discoveries to optimize mid- and late-stage clinical
development. We have firmly established the link between the
at-risk variants in the genes we have isolated in a variety
of populations. By focusing trial enrollment on patients with
these at-risk variants, we can test compounds on those at high
risk through the pathway targeted by the compounds. We believe
that this enables more compact and sensitive trials with the
highest possible likelihood of success, at the same time targeting
pathways our research has shown modulate risk of the disease
in many populations.
