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, our cardiovascular franchise includes 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™ (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).
ISIS-APOCIIIRx is an antisense drug we designed to reduce apolipoprotein C-III, or apoC-III, protein production and lower triglycerides. ApoC-III regulates triglyceride metabolism in the blood and is an independent cardiovascular risk factor. This approach is validated by the fact that humans who have certain mutations in the gene for apoC-III that result in lower levels of apoC-III have lower levels of triglycerides and lower instances of cardiovascular disease. Also, humans with elevated levels of apoC-III have increased dyslipidemia associated with multiple metabolic abnormalities, such as insulin resistance and/or metabolic syndrome. In addition, patients with elevated triglycerides are at increased risk for type 2 diabetes, and patients with severely elevated triglycerides are at high risk for acute pancreatitis and other serious conditions.
We are developing ISIS-APOCIIIRx for patients with familial chylomicronemia syndrome, or FCS, and patients with severely high triglycerides. FCS is a rare orphan disease that affects an estimated one to two people per a million people. FCS patients often have triglyceride levels higher than 2,000 mg/dL and experience a number of health problems such as abdominal pain, enlargement of the liver and spleen, and recurrent acute pancreatitis that often requires hospitalization. We believe that the significant unmet medical need for an effective triglyceride-lowering drug for patients with FCS and the robust, consistent effects we observe with ISIS-APOCIIIRx should enable us to rapidly move this program forward toward the market.
We are also developing ISIS-APOCIIIRx for the treatment of patients with severely high triglycerides. These are patients with triglyceride levels greater than 880 mg/dL who are also at a higher risk of pancreatitis and other serious conditions. For all patients who cannot reduce their triglycerides to acceptable levels, the primary therapy is diet, which requires strict adherence and is often unsuccessful.
In preclinical studies, ISIS-APOCIIIRx diminished signs of metabolic syndrome and reduced atherosclerosis in mice. In a Phase 1 study in healthy volunteers, ISIS-APOCIIIRx produced rapid, dose-dependent median reductions in blood of up to 78 percent in apoC-III protein levels and up to 44 percent in triglyceride levels.
We completed a broad Phase 2 program evaluating ISIS-APOCIIIRx in patients with high, very high, and severely high triglycerides, in patients with type 2 diabetes and in patients with FCS. We also evaluated ISIS-APOCIIIRx both as a monotherapy and in combination with fibrates. Patients in our Phase 2 program entered with baseline triglyceride levels ranging from moderately high to very severely high. In all patient groups studied, irrespective of their incoming triglyceride levels, treatment with ISIS-APOCIIIRx consistently reduced apoC-III, triglycerides and apoC-III-associated VLDL complexes, and increased HDL, with a positive effect on non-HDL. Data from these studies are summarized in the table below. We highlight the 300 mg/week dose, as this is the dose that we have decided to use in our Phase 3 program, which we plan to begin next year.
Table 1: Comparison of the effects on key lipids for patients treated with 300 mg/week of ISIS-APOCIIIRx
|Mean % Change from Baseline|
|Lipid Parameter||Single agent in diabetics||Single agent in very high TG*||In addition to fibrates in very high TB||Single agent in FCS patients|
Consistent across the Phase 2 program, ISIS-APOCIIIRx demonstrated a good safety profile and was well tolerated. The most common adverse event was injection site reactions, which were predominantly mild and typically resolved rapidly. There were no flu-like symptoms, no treatment-related elevations in liver enzymes greater than three times the upper limit of normal, no abnormalities in renal function and no clinically meaningful changes in other laboratory values.
ISIS-CRPRx is an antisense drug that targets C-reactive protein (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.
In preclinical studies, we observed that our antisense inhibitor of CRP suppressed liver and serum CRP levels. We evaluated ISIS-CRPRx 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. We also evaluated ISIS-CRPRx in healthy volunteers who were subjected to an endotoxin challenge, which caused an increase in CRP and other inflammatory markers. In this study, we showed that pretreatment with ISIS-CRPRx was able to blunt the acute increase in CRP. In our Phase 2 program, we are evaluating ISIS-CRPRx in different disease settings where elevated levels of CRP are associated with a worsening of disease symptoms. The first of these Phase 2 studies evaluated ISIS-CRPRx in patients with rheumatoid arthritis (RA) with chronically elevated CRP. In this study, patients treated with ISIS-CRPRx achieved rapid, dose-dependent mean reductions of up to 67 percent in CRP. Patients also showed improvements in signs and symptoms of RA, which correlated with reductions in CRP, but were not sufficiently greater than improvements observed in the placebo group to justify further development of ISIS-CRPRx for RA.
We are also evaluating ISIS-CRPRx in a Phase 2 study in patients with atrial fibrillation, or AF. AF involves an irregular heart rate that commonly causes poor blood flow to the body. In this study, we are evaluating the effect of lowering CRP on the frequency and duration of AF.
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 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-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 1 study evaluating the safety and activity of ISIS-FXIRx in healthy volunteers. In this study, ISIS-FXIRx produced dose-dependent statistically significant reductions of greater than 80 percent in Factor XI protein. In this study, subjects tolerated ISIS-FXIRx well with no increase in bleeding.
In 2012, we initiated a Phase 2 study evaluating ISIS-FXIRx in patients undergoing knee replacement surgery, also referred to as total knee arthroplasty, or TKA. This study is a comparator-controlled study, in which we will compare the safety and activity of ISIS-FXIRx to a commonly used anti-coagulant, enoxaparin. In this study, we are evaluating the effectiveness of ISIS-FXIRx in reducing the number of thrombotic events in patients following TKA without increasing bleeding. 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.
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. As a result, 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 currently therapies are not able to adequately reduce elevated levels of 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) levels be less than or equal to 50 mg/dL. 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-APO(a)Rx to treat patients with high Lp(a) levels who are at severe risk of experiencing cardiovascular events. We are currently evaluating ISIS-APO(a)Rx in a Phase 1 study in healthy volunteers.
ISIS-FVIIRx 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-FVIIRx 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-FVIIRx, which is a common side effect of currently available anti-thrombotic drugs. ISIS-FVIIRx 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.
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. We are currently evaluating ISIS-ANGPTL3Rx in IND-enabling studies to support clinical development.