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. For example, we are developing a drug that lowers apoC-III and triglycerides, which are both independent risk factors for cardiovascular disease. Our most recent addition to our cardiovascular franchise is our drug that lowers Lp(a), another independent risk factor for cardiovascular disease. Currently available lipid-lowering therapies do not significantly lower apoC-III, triglycerides, or Lp(a). We believe that targeting apoC-III and Lp(a) could provide a complementary approach to lipid-lowering therapies, including KYNAMRO. We are also developing a drug that lowers C-reactive protein, or CRP, a protein that scientists associate with cardiovascular disease. And finally, we expanded our cardiovascular franchise to include two anti-thrombotic agents, which could offer safer more effective alternatives to anti-clotting agents currently on the market.

We believe antisense drugs could have a significant positive effect in patients with high cardiovascular risk. Because there are many liver-produced targets that affect the production of cholesterol particles, clotting factors and other factors that contribute to the inflammatory components of cardiovascular disease, the liver is an ideal target organ for cardiovascular disease therapies, and antisense drugs in particular. Our antisense drugs distribute to the liver and inhibit the production of many targets associated with cardiovascular risk, creating an opportunity for us to develop many complementary and effective antisense drugs for cardiovascular disease.

• KYNAMRO™ (High Risk/High Cholesterol)
• ISIS-CRP_Rx (Coronary Artery Disease)
• ISIS-APOCIII_Rx (High Triglycerides)
• ISIS-FXI_Rx (Clotting Disorders)
• ISIS-APOA_Rx (Atherosclerosis)
• ISIS-FVII_Rx (Clotting Disorders)

KYNAMRO™ (mipomersen sodium)

KYNAMRO is the most advanced drug in our pipeline. We and Genzyme are developing KYNAMRO to treat patients with severe forms of FH, at high cardiovascular risk and who cannot reduce their LDL-C sufficiently with currently available lipid-lowering therapies. KYNAMRO is a novel, first-in-class, apo-B synthesis inhibitor in development for the reduction of LDL cholesterol, or LDL-C. It is a second-generation antisense drug we discovered and licensed to Genzyme in 2008. KYNAMRO acts by decreasing the production of apolipoprotein-B, or apo-B. Apo-B provides the structural core for atherogenic lipids, including LDL-C, which carry cholesterol through the bloodstream. KYNAMRO reduces LDL-C and other key atherogenic lipids linked to cardiovascular disease by preventing their formation.

In March 2012, Genzyme submitted a marketing application for KYNAMRO in the United States for patients with hoFH. In July 2011, Genzyme submitted a marketing application for KYNAMRO in Europe for patients with hoFH and severe heFH. Together with Genzyme, we completed the largest clinical study conducted to date in hoFH patients to support the regulatory submissions in the United States and Europe. In all of our Phase 3 studies, patients treated with KYNAMRO experienced significant reductions in all measures of atherogenic lipids, including LDL-C, Lp(a), and apoB.

Genzyme estimates that there are approximately 40,000 patients with hoFH and severe heFH in Europe and the United States. Due to the large size of the severe heFH population in the United States, the FDA requested additional 12 month clinical data before the KYNAMRO filing for severe heFH in the United States. To address this request, Genzyme is conducting a study titled 'evaluating the saFety and atherOgeniC lipoprotein redUction of mipomerSen in FH (FOCUS FH)', which began in 2011. Genzyme designed the study to support potentially broadening the FH patient population beyond the first indication and to support an alternative dosing regimen. Genzyme is also preparing to file for marketing approval in markets beyond the United States and Europe.

Commercialization Strategy

Genzyme is executing a comprehensive plan to address a global commercial market that consists of patients who are in desperate need of new treatment options. Genzyme has substantial expertise in successfully marketing drugs in the U.S. and internationally for severe and rare diseases and plans to leverage its infrastructure in these markets to rapidly launch KYNAMRO upon approval. Along with preparing for an efficient marketing and sales effort for KYNAMRO, Genzyme has made significant progress raising awareness of FH and the importance of family screening to identify patients earlier. These activities include conducting continued medical educational programs to inform physicians about FH and partnering with key advocacy groups, such as the National Lipid Association, American College of Cardiology, European Atherosclerosis Society Congress, International Symposium on Atherosclerosis and the American Heart Association.

Genzyme plans to concentrate marketing and sales efforts on lipid specialists and physicians who refer patients to these specialists to quickly reach the initial patient populations for KYNAMRO in the United States and Europe. Genzyme has also established the foundation for market access and reimbursement in the United States and Europe to accelerate market penetration after launch. Genzyme is planning to launch KYNAMRO with a prefilled syringe that will provide a convenient form of administration. We believe that Genzyme has the commercial infrastructure and aptitude to successfully commercialize KYNAMRO worldwide making the drug available for patients in need. In 2011, Sanofi acquired Genzyme, and we believe that Sanofi and its global presence will aid in the rapid market expansion of KYNAMRO throughout the world.

Familial Hypercholesterolemia

Physicians diagnose patients as having FH if they have very high cholesterol, are at high cardiovascular risk and cannot reduce their LDL-C sufficiently with currently available lipid-lowering therapies. FH is a genetic disease that causes elevated LDL-C levels and family patterns of increased risk of premature heart disease and heart disease-related death. FH patients have inherited abnormalities in liver cells that are responsible for clearing LDL particles from the blood. FH is autosomal dominant, which means that all first-degree relatives of FH patients have a 50 percent chance of having the disease as well, making early detection through early screening critically important. Patients with untreated FH have a 50 percent mortality rate by age 60.

The most severe FH patients have LDL-C levels that are two to four times higher than recommended levels, even when taking multiple cholesterol-lowering medications. These people, who clinicians characterize as having severe FH, include: those who have inherited the disease from both parents, hoFH, and those who have inherited the disease from only one parent and have a severe form of the disease, severe heFH. HoFH is a rare form of FH. HoFH patients can have untreated LDL-C levels greater than 600 mg/dL or treated LDL-C levels greater than 300 mg/dL and are at very high risk for early coronary events and sudden death. Severe heFH patients comprise a small subset of heterozygous FH patients and these patients have LDL-C levels greater than 200 mg/dL with coronary artery disease or more than 300 mg/dL without coronary artery disease despite maintaining a regimen of maximally tolerated lipid-lowering therapy. For these severe FH patients, remaining options are limited and may include apheresis and liver transplant. Apheresis is a two to four hour process administered two to four times a month that mechanically separates LDL-C from the blood and it is the only therapy available on top of maximally tolerated lipid-lowering therapy.

Phase 3 Summary

Together with Genzyme, we have evaluated KYNAMRO in four Phase 3 studies, which met all primary, secondary and tertiary endpoints. In all four Phase 3 studies, treatment with KYNAMRO lowered LDL-C and reduced other atherogenic lipids, including apo-B, Lp(a), triglycerides and very-low density lipoprotein, or VLDL. These key lipids are generally accepted risk factors for cardiovascular disease. Two of our Phase 3 studies evaluated KYNAMRO in patients with hoFH and severe hypercholesterolemia who were on substantial lipid lowering therapy. In both of these studies, the average reduction of LDL-C was greater than 100 mg/dL.

In the two additional Phase 3 studies, we evaluated KYNAMRO in patients with heFH and in patients with high cholesterol at high risk for coronary heart disease who were on substantial lipid lowering therapy.

In all studies, frequently observed adverse events were injection site reactions, flu-like symptoms and elevations in liver transaminases. In our Phase 3 experience eight percent of patients treated with KYNAMRO had persistent ALT elevations above three times the upper limit of normal. We believe the lipid-lowering profile together with the emerging safety profile of KYNAMRO will support our initial plan for KYNAMRO to treat patients who, despite using maximally tolerated lipid-lowering therapies, are far from their recommended LDL-C goal. We now have treated more than 110 patients with KYNAMRO for longer than a year and more than 50 patients for two years, in an long-term extension study. In this study, we observed sustained robust reductions in LDL-C and all other ApoB containing atherogenic lipoproteins with a safety profile consistent with our Phase 3 experience. Data from the long-term extension study suggest liver fat may stabilize or decline in patients who continue treatment beyond a year. In general, increases in ALT levels and liver fat appear to be associated with rapid and larger drops in LDL-C.

In summary, the performance of KYNAMRO has been consistent across the entire Phase 3 program, supporting our initial market focus in patients, who despite treatment with maximally tolerated lipid-lowering therapies, are far from their recommended LDL-C goal and as a result are at high risk of a cardiovascular event or death.

ISIS-CRP_Rx

ISIS-CRP_Rx is an antisense drug that targets CRP, a protein produced in the liver. CRP levels increase dramatically during inflammatory disorders, and scientists have linked excessive amounts of CRP to coronary artery disease. Furthermore, a growing body of evidence from clinical trials implicates CRP in cardiovascular disease progression. These results suggest that it may be therapeutically beneficial to significantly decrease CRP levels in patients who are at risk for coronary events. In addition, clinicians have associated elevated CRP levels with a worsening of overall outcomes in conditions such as end-stage renal disease and multiple myeloma, suggesting that lowering CRP could help these patients. CRP elevation is also evident in many other major inflammatory diseases such as Crohn's disease and rheumatoid arthritis.

In preclinical studies, we observed that our antisense inhibitor of CRP suppressed liver and serum CRP levels. We evaluated ISIS-CRP_Rx in a Phase 1 study in which ISIS-CRP_Rx produced statistically significant reductions in CRP in the cohort of subjects that entered the study with elevated levels of CRP. All subjects tolerated ISIS-CRP_Rx well. Our Phase 2 plan for ISIS-CRP_Rx is to evaluate the drug in diseases with elevated CRP that could provide early proof-of-concept.

We are currently evaluating ISIS-CRP_Rx in a Phase 2 study in patients with rheumatoid arthritis and plan to initiate an additional Phase 2 study in patients with atrial fibrillation in 2012. Atrial fibrillation involves an irregular heart rate that commonly causes poor blood flow to the body.

ISIS-APOCIII_Rx

ISIS-APOCIII_Rx is an antisense drug we designed to reduce apolipoprotein C-III, or apoC-III, protein production and lower triglycerides. ApoC-III is responsible for triglyceride transport in the blood and is an independent cardiovascular risk factor. People who do not produce apoC-III have lower levels of triglycerides and lower instances of cardiovascular disease. ApoC-III is elevated in patients with dyslipidemia, or an abnormal concentration of lipids in the blood, and is frequently associated with multiple metabolic abnormalities, such as insulin resistance and/or metabolic syndrome. In human population studies, lower levels of apoC-III and triglycerides correlated with a lower rate of cardiovascular events. In certain populations, apoC-III mediates insulin resistance, which can make metabolic syndrome worse.

We are pursuing a staged development plan for ISIS-APOCIII_Rx designed to shorten the time to bring this medicine to patients at high-risk of cardiovascular disease and pancreatitis. These are the patients with the highest unmet medical need who have severely high triglyceride levels despite currently available therapies and are at the greatest risk. Our plan is to complete the ongoing Phase 2 study in patients with very high triglyceride levels (>500 mg/dL) and initiate a Phase 3 program that will include evaluating ISIS-APOCIII_Rx in patients with severely elevated triglyceride levels (>1,000 mg/dL). Patients with triglycerides greater than 1,000 mg/dL are at a higher risk of developing pancreatitis, a painful and sometimes fatal disease that requires hospitalization and close monitoring. In these patients who cannot reduce their triglycerides to acceptable levels, the primary therapy, requiring strict adherence and often unsuccessful, is diet. Our plan is to initially develop ISIS-APOCIII_Rx to treat patients with triglyceride levels greater than 1,000 mg/dL and as we gain additional experience in these patients, expand to include other less severe patient populations.

In preclinical studies, ISIS-APOCIII_Rx diminished symptoms of metabolic syndrome and reduced atherosclerosis in mice. We have completed a Phase 1 study evaluating the safety and activity of ISIS-APOCIII_Rx in healthy volunteers. In this study, ISIS-APOCIII_Rx produced rapid, dose-dependent median reductions of up to 78 percent in apoC-III protein and up to 44 percent in blood triglycerides. All subjects tolerated ISIS-APOCIII_Rx well.

We are currently evaluating ISIS-APOCIII_Rx in a Phase 2 study in patients with hypertriglyceridemia. In this study, we expect to enroll approximately 100 patients who have triglyceride levels of 500 mg/dL or higher, and evaluate ISIS-APOCIII_Rx as a monotherapy and in combination with fibrates.

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 responsible for most 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.

In preclinical studies, ISIS-FXI_Rx 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 1 study evaluating the safety and activity of ISIS-FXI_Rx in healthy volunteers. In this study, ISIS-FXI_Rx produced dose-dependent statistically significant reductions of greater than 80 percent in Factor XI protein. Subjects tolerated ISIS-FXI_Rx well with no increase in bleeding.

We plan to initiate a Phase 2 study evaluating the efficacy of ISIS-FXI_Rx in 2012 in patients undergoing total knee replacement surgery.

ISIS-APOA_Rx

ISIS-APOA_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. Commonly prescribed lipid-lowering drugs have little or no effect on Lp(a) levels. Even patients who can control their LDL-C levels 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). We plan to develop ISIS-APOA_Rx to treat patients with high Lp(a) levels who are at severe risk of experiencing cardiovascular events.

We plan to conduct preclinical studies to support an investigational new drug application for ISIS-APOA_Rx in 2012.

ISIS-FVII_Rx

ISIS-FVII_Rx is an antisense drug we designed to reduce Factor VII, a key component of the tissue factor coagulation pathway, for the treatment or prevention of thrombotic diseases. Clinicians have linked elevated levels of Factor VII activity with poor prognosis in several thrombotic diseases, such as heart attacks, and with cancer-associated thrombosis, which is the second leading cause of death in cancer patients.

In preclinical studies, antisense inhibition of Factor VII rapidly reduced Factor VII activity by more than 90 percent in three days, suggesting that physicians could use ISIS-FVII_Rx in acute clinical settings, such as following surgery, to prevent patients from developing harmful blood clots. In addition, we observed no increase in bleeding with ISIS-FVII_Rx, which is a common side effect of currently available anti-thrombotic drugs. ISIS-FVII_Rx is the second drug to enter development as part of our strategy to create more potent and safer anti-thrombotic drugs that do not increase bleeding.

We plan to conduct preclinical studies to support an investigational new drug application for ISIS-FVII_Rx in 2012.