angiopoietin-like 3 protein, or ANGPTL3. Lp(a) is another independent risk factor for cardiovascular disease.
ANGPTL3 is a genetically validated target shown to play a significant role in regulating lipid levels. Humans
who do not produce a functional ANGPTL3 protein due to a genetic mutation have extremely low levels of
cholesterol, LDL-C, and very low levels of triglycerides and HDL-cholesterol. Currently available lipid-lowering
therapies do not significantly lower apoC-III, triglycerides, Lp(a), or ANGPTL3. We believe that reducing levels
of apoC-III, Lp(a) andANGPTL3 could provide a complimentary approach to lipid-lowering therapies, including
KYNAMRO. We are also developing follow-on LICAantisense drugs for the three drugs in our lipid franchise.
In order to maximize the value of our lipid franchise, while also maintaining control over the development
and commercialization of these assets, we have created a wholly owned subsidiary, Akcea Therapeutics. Akcea is
focused on the development and commercialization of our lipid franchise drugs and their follow on compounds.
In addition to our lipid franchise drugs, we have a promising anticoagulant agent, ISIS-FXI
Rx
, in
development in our cardiovascular disease franchise. We recently reported Phase 2 data on ISIS-FXI
Rx
showing
that ISIS-FXI
Rx
-treated patients experienced a seven-fold lower incidence of venous thromboembolism and
numerically fewer bleeding events compared to patients treated with enoxaparin, a commonly used anticoagulant.
These data demonstrate that for the first time, an anticoagulant, ISIS-FXI
Rx
, can prevent clotting without
increasing bleeding, two biological events that were previously inseparable. Our latest drug to enter the franchise,
ISIS-AGT-L
Rx
, offers a novel approach to treating patients with high blood pressure.
ISIS-APO(a)
Rx
—ISIS-APO(a)
Rx
is an antisense drug we designed to reduce apolipoprotein(a) in the liver
to offer a direct approach for reducing Lp(a), an independent risk factor for cardiovascular disease. Scientists
associate high levels of Lp(a) with an increased risk of atherosclerosis, coronary heart disease, heart attack and
stroke. Lp(a) levels in blood can vary greatly between individuals due primarily to genetic variations between
individuals. Lp(a) levels are genetically determined, reached by the age of two and remain constant throughout
the life of the individual. Diet and lifestyle changes have little impact on Lp(a) levels and current therapies do
not adequately reduce Lp(a) to acceptable levels in patients with elevated Lp(a). As a general guideline for ideal
Lp(a) levels, the EuropeanAtherosclerosis Society recommends that Lp(a) be less than or equal to 50 mg/dL.
Even patients who can control their LDL-C remain at high-risk of cardiovascular events if they have high levels
of Lp(a). There is a significant need for a highly specific drug that can lower Lp(a).
ISIS-APO(a)
Rx
is part of our lipid franchise and, as such, we plan to transition development activities
associated with ISIS-APO(a)
Rx
toAkcea, our wholly owned lipid subsidiary. We are developing ISIS-APO(a)
Rx
to treat patients with high Lp(a) levels who have either coronary heart disease or aortic stenosis. Both of these
groups of patients are at high risk of cardiovascular events.
We completed a Phase 1 study evaluating ISIS-APO(a)
Rx
in healthy volunteers with incoming Lp(a) levels
ranging from 10 mg/dL to 98 mg/dL. In this study, we reported dose-dependent reductions of up to 95 percent in
Lp(a). In addition to Lp(a) activity, subjects treated with 300 mg of ISIS-APO(a)
Rx
experienced an up to
59 percent reduction in oxidized phospholipids, lipids that play an important role in proinflammatory and
proatherogenic processes believed to be associated with Lp(a). In this study, ISIS-APO(a)
Rx
was generally well
tolerated.
We are currently evaluating ISIS-APO(a)
Rx
in a Phase 2 study in patients with elevated levels of Lp(a)
(greater than 50 mg/dL). We plan to report data from this study in late 2015 or early 2016.
ISIS-FXI
Rx
—ISIS-FXI
Rx
is an antisense drug we designed to treat clotting disorders. It targets Factor XI,
a clotting factor produced in the liver that is an important component of the coagulation pathway. High levels of
Factor XI increase the risk of thrombosis, a process involving aberrant blood clot formation that can be
responsible for heart attacks and strokes. Elevated levels of Factor XI also increase the risk of venous
thrombosis, a common problem after surgery, particularly major orthopedic procedures, such as knee or hip
replacement. People who are deficient in Factor XI have a lower incidence of thromboembolic events with
minimal increase in bleeding risk. Although currently available anticoagulants reduce the risk of thrombosis,
physicians associate these anticoagulants with increased bleeding, which can be fatal. Given the mechanism of
Factor XI inhibition, we believe that doctors could use our drug broadly as an anti-thrombotic in many different
therapeutic settings for which additional safe and well tolerated anti-thrombotic drugs are needed.
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