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Cardiovascular

Cardiovascular disease is the leading cause of death in the United States. A common cause of cardiovascular disease is atherosclerosis, or premature plaque buildup, which occurs when cholesterol and inflammatory cells accumulate in blood vessels. Researchers have shown a strong correlation between high cholesterol levels and subsequent cardiovascular diseases. As such, lowering cholesterol is a key component in preventing and managing cardiovascular disease.

Cardiovascular disease is an area of focus for us. We have created a cardiovascular disease franchise comprised of drugs that target all the key components of cardiovascular disease, including various atherogenic lipids, inflammation and thrombosis, an aberrant blood clot formation responsible for most heart attacks and strokes. We have designed the majority of the drugs in our cardiovascular franchise to target cardiovascular risk factors. These drugs make up our lipid franchise and include ISIS-APO(a)Rx and ISIS-ANGPTL3Rx. Recent additions to our lipid franchise are our drugs that lower Lp(a) and 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) and ANGPTL3 could provide a complimentary approach to lipid-lowering therapies, including KYNAMRO®. We are also developing follow-on LICA antisense 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-FXIRx, in development in our cardiovascular disease franchise. We recently reported Phase 2 data on ISIS-FXI Rx showing that ISIS-FXIRx-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-FXIRx, can prevent clotting without increasing bleeding, two biological events that were previously inseparable. Our latest drug to enter the franchise, ISIS-AGT-LRx, offers a novel approach to treating patients with high blood pressure.

KYNAMRO® (mipomersen sodium)

NOW APPROVED

Kynamro

KYNAMRO® (mipomersen sodium) is an oligonucleotide inhibitor of apolipoprotein B-100 synthesis indicated as an adjunct to lipid-lowering medications and diet to reduce low density lipoprotein-cholesterol (LDL-C), apolipoprotein B (apo B), total cholesterol (TC), and non-high density lipoprotein-cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH).

KYNAMRO is approved for use in patients with HoFH in the United States, Mexico, Argentina and South Korea.

U.S. Product Web Site

U.S. Prescribing Information (PDF)

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 European Atherosclerosis 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 to Akcea, 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)Rxin a Phase 2 study in patients with elevated levels of Lp(a) (greater than 50 mg/dL).

ISIS-FXIRx

ISIS-FXIRx 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.

In preclinical studies, ISIS-FXIRx demonstrated potent antithrombotic activity with no increase in bleeding compared with standard anti-clotting agents, including low molecular weight heparin, warfarin and Factor Xa inhibitors, all of which increase bleeding.

We have completed a Phase 2 comparator-controlled study evaluating the incidence of venous thromboembolic events, or VTE, in patients treated with ISIS-FXIRx undergoing total knee replacement surgery, or total knee arthroplasty, or TKA. In December 2014, we reported these data at the American Society of Hematology meeting and also published these data in the New England Journal of Medicine. In this study, we showed that ISIS-FXIRx-treated patients experienced a dose-dependent decrease in venous thromboembolic events. Patients treated with 300 mg of ISIS-FXIRx experienced a seven-fold lower rate of VTE as compared with those treated with enoxaparin (4.2% and 30.4%, respectively; p<0.001). Patients treated with 200 mg of ISIS-FXIRx had a rate of VTE comparable to that in patients treated with enoxaparin (26.9% and 30.4%, respectively). The rate of VTE in patients given enoxaparin is within the range documented in previous studies in this therapeutic setting. ISIS-FXIRx treatment was associated with a dose-dependent and sustained reduction in Factor XI activity that correlated with the lower rate of VTE. The rate of bleeding was low with ISIS-FXIRx and enoxaparin. We also reported that in this study, ISIS-FXIRx was generally well tolerated. There were no observed differences in safety outcomes compared with enoxaparin. In particular, there were no flu-like symptoms, and injection site reactions were infrequent and mild. There have been no drug-related serious adverse events reported to date.

We believe that there are a number of opportunities to develop ISIS-FXIRx as an antithrombotic for patients who require a safer and more effective agent. We plan to evaluate ISIS-FXIRx in patient populations with an unmet need in which relatively small studies can be conducted such as patients with atrial fibrillation, or AF, and end-stage renal disease. We also believe that ISIS-FXIRx can potentially be used in broader indications, including in patients with mechanical heart valves and to prevent secondary cardiovascular events in patients with acute coronary syndrome.

ISIS-ANGPTL3Rx

ISIS-ANGPTL3Rx is an antisense drug we designed to reduce angiopoietin-like 3 protein, or ANGPTL3, an independent risk factor for cardiovascular disease. ANGPTL3 is produced in the liver and regulates lipid, glucose and energy metabolism. Humans with elevated levels of ANGPTL3 have hyperlipidemia that is associated with an increased risk of premature heart attacks, increased arterial wall thickness as well as multiple metabolic abnormalities, such as insulin resistance. In contrast, humans with lower levels of ANGPTL3 have lower LDL-C and triglyceride levels and a lower risk of cardiovascular disease. In preclinical studies, antisense inhibition of ANGPTL3 resulted in robust reductions of multiple lipid parameters, including total-cholesterol, LDL-C and triglycerides.

ISIS-ANGPTL3Rx is part of our lipid franchise and, as such, we plan to transition development activities associated with ISIS-ANGPTL3Rx to Akcea.

ISIS-AGT-LRx

ISIS-AGT-LRx is in preclinical development. We are currently conducting studies on ISIS-AGT-LRx to support clinical development.

ISIS-APOCIII-LRx

ISIS-APOCIII-LRx is in preclinical development. We are currently conducting studies on ISIS-APOCIII-LRx to support clinical development.

ISIS-TMPRSS6-LRx

ISIS-TMPRSS6-LRx is in preclinical development. We are currently conducting studies on ISIS-TMPRSS6-LRx to support clinical development.

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