Cardiovascular

Cardiovascular disease is the leading cause of death in the United States. A common cause of cardiovascular disease is atherosclerosis, or hardening of the arteries, 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. Lowering cholesterol is a key component in preventing and managing cardiovascular disease. Another independent risk factor for cardiovascular disease is high levels of C-reactive protein, or CRP, which clinicians associate with significantly worse outcomes in patients with cardiovascular disease.

Cardiovascular disease is an area of focus for us. We believe that antisense drugs could have a significant impact in patients with high cardiovascular risk. These are patients who are on a regimen of cardiovascular disease therapies and who are still at high risk for a cardiac event or death. The liver is an ideal target organ for cardiovascular disease therapies, and antisense drugs in particular, because there are many liver-produced targets that affect the production of cholesterol particles, clotting factors and factors that contribute to the inflammatory components of cardiovascular disease. 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 effective antisense drugs for cardiovascular disease.

We continue to build our cardiovascular disease franchise by evaluating potential drug targets that influence the onset and progression of cardiovascular disease, and we intend to expand our franchise with additional drugs to treat various aspects of cardiovascular disease through complementary mechanisms.

• Mipomersen (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)

Mipomersen (Kynamro™)

Mipomersen is a novel first-in-class apo-B synthesis inhibitor in development for the reduction of LDL cholesterol (LDL-C). Mipomersen is a second-generation antisense drug we discovered and licensed to Genzyme in 2008. In 2011 Sanofi acquired Genzyme. Mipomersen 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. Mipomersen reduces LDL-C and other key atherogenic lipids linked to cardiovascular disease by preventing their formation.

Mipomersen is being developed to treat patients with very high cholesterol, at high cardiovascular risk and who cannot reduce their LDL-C sufficiently with currently available lipid-lowering therapies. These patients can be diagnosed as having familial hypercholesterolemia, or FH. FH is a genetic disease that results in 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 are characterized as having severe FH, include: those who have interited the disease from both parents (homozygous FH (hoFH)) and those who have inherited from only on parent and have a severe form of the disease, severe heterozygous FH (severe heFH). HoFH is a rare form of FH. HoFH patients can have untreated LDL-C levels greater than 600 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, a more common form of the disorder. Severe heFH 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.

In July 2011, Genzyme submitted a marketing application for mipomersen in Europe for patients with hoFH and severe heFH. Genzyme plans to file for marketing approval for mipomersen in the United States in the first quarter of 2012 for patients with hoFH. Sanofi estimates that there are approximately 40,000 patients in Europe and the U.S. with hoFH and severe heFH. Due to the larger size of the severe heFH population, the FDA requested an additional 12 month clinical data before the mipomersen filing for severe heFH in the United States. This study, titled ‘evaluating the saFety and atherOgeniC lipoprotein redUction of mipomerSen in FH (FOCUS FH)’, is designed to support potentially broadened indications in the United States and Europe, and to support an alternative dosing regimen. The FOCUS FH study will begin in 2011. Genzyme is also preparing for filings in markets beyond the United States and Europe. Pending regulatory approval, mipomersen will be marketed under the brand name Kynamro™.

Together with Genzyme, we have evaluated mipomersen in four Phase 3 studies in which all primary, secondary and tertiary endpoints were met. In all four Phase 3 studies, treatment with mipomersen 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 mipomersen 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 mipomersen in patients with heterozygous FH and in patients with high cholesterol at high risk for coronary heart disease who were on substantial lipid lowering therapy. As with the two previous studies, all primary, secondary and tertiary endpoints were met, including reduction in apo-B, Lp(a), triglycerides, total cholesterol, non HDL-C and VLDL.

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 mipomersen had persistent ALT elevations above 3XULN. We believe the lipid-lowering profile together with the emerging safety profile of mipomersen will support our initial plan for mipomersen to be used in patients who, despite being treated with maximally tolerated lipid-lowering therapies, are far from their recommended LDL-C goal. We now have treated more than a 100 patients in an open label extension study who have been dosed with mipomersen for more than a year, with some of these patients dosed for more than two years. In this study, we observed sustained reductions in LDL-C and all other measured atherogenic lipids with no evidence of liver toxicity, consistent with our Phase 3 experience. Preliminary data from the open label 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 mipomersen has been consistent across the entire Phase 3 program, supporting our initial market focus in patients, who despite being treated 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.

Genzyme is implementing a comprehensive plan to address the initial commercial market that consists of patients who are in desperate need of new treatment options. Genzyme plans to concentrate marketing and sales efforts on lipid specialists and physicians who refer patients to these specialists, using its expertise to quickly reach the initial patient populations for mipomersen in the U.S. and Europe. We believe Genzyme has the commercial infrastructure and aptitude to successfully commercialize mipomersen worldwide making the drug available for patients in need.

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 excessive amounts of CRP have been linked 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. Initially we plan to evaluate ISIS-CRP_Rx in patients with multiple myeloma and rheumatoid arthritis. The data from these initial Phase 2 studies will inform the development path for ISIS-CRP_Rx, in which we could expand into cardiovascular and other diseases.

ISIS-APOCIII_Rx

ISIS-APOCIII_Rx is an antisense drug we designed to reduce apolipoprotein C-III (apoC-III) protein production and lower triglycerides. ApoC-III is a protein that is responsible for triglyceride transport in the blood and is a pro-inflammatory protein and an independent cardiovascular risk factor. Humans who do not produce apoC-III have lower levels of triglycerides and lower instances of cardiovascular disease. ApoC-III is increased in patients with dyslipidemia associated with multiple metabolic abnormalities, such as insulin resistance and/or metabolic syndrome. In clinical studies, lower levels of apoC-III and triglycerides correlates with lower cardiovascular event rates. In addition, apoC-III mediates insulin resistance, leading to worsening of the metabolic syndrome.

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 reductions of up to 78 percent in apoC-III protein and up to 44 percent in blood triglycerides. In all subjects, ISIS-APOCIII_Rx was shown to have a good safety profile and was well tolerated. We plan to initiate a Phase 2 study evaluating the efficacy of ISIS-APOCIII_Rx in treatment-naïve patients with elevated triglycerides in 2012.

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, aberrant blood clot formation that is 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. Humans 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 venous thrombosis, these anticoagulants are associated with increased bleeding that 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 increased 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 up to 78 percent in Factor XI activity. In all subjects, ISIS-FXI_Rx was safe and well tolerated with no increase in bleeding. We plan to initiate a Phase 2 study evaluating the efficacy of ISIS-FXI_Rx in 2012.

ISIS-APOA_Rx

ISIS-APOA_Rx reduces apolipoprotein(a) in the liver and is designed to offer a direct approach to reducing Lp(a), an independent risk factor for cardiovascular disease. High levels of Lp(a) are associated with an increased risk of atherosclerosis, coronary heart disease, heart attack and stroke. Lp(a) promotes premature plaque buildup, or atherosclerosis, in arteries. Commonly prescribed lipid-lowering drugs have little or no effect on Lp(a) levels. Patients who are able to control their LDL-C levels, but still have high levels of Lp(a) remain at high-risk of cardiovascular events. There is a significant need for a highly specific drug that can lower Lp(a).

We are developing ISIS-APOA_Rx as part of our strategy to create a cardiovascular disease franchise comprised of drugs that target all the key components of cardiovascular disease, including various atherogenic lipids, inflammation and thrombosis. 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 investigational new drug enabling studies on ISIS-APOA_Rx in 2012.

ISIS-FVII_Rx

ISIS-FVII_Rx is designed to reduce Factor VII, a key component of the tissue factor coagulation pathway, for the treatment or prevention of thrombotic diseases, without causing bleeding, which is a common side effect of currently available anti-thrombotic drugs. Elevated levels of Factor VII activity are indicative of poor prognosis in several thrombotic diseases, such as heart attacks. Furthermore, elevated levels of Factor VII activity are strongly linked to 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 ISIS-FVII_Rx has the potential to be used in acute clinical settings, such as following surgery, in which patients are at high-risk for developing blood clots. ISIS-FVII_Rx is the second drug to enter development as part of Isis’ strategy to create more potent and safer anti-thrombotic drugs that do not increase bleeding.

We plan to conduct preclinical investigational new drug enabling studies on ISIS-FVII_Rx in 2012.