The aim of this study is to assess the safety of varying doses of ISIS 301012 in subjects on Stable statin therapy.

Inclusion Criteria:

• On a stable dose of >/= 40 mg Simvastatin or atorvastatin daily for >/= 3 months prior to baseline and expected to remain on this dose for the remainder of the study
• LDL-cholesterol between 2.60 and 5.70 mmol/L (100 and 220 mg/dL), inclusive at screening
• Females not of childbearing potential.

Exclusion Criteria:

• History of CHD or CHD-equivalent (such as diabetes mellitus, or another clinical form of atherosclerotic disease, e.g., peripheral arterial disease, abdominal aortic aneurysm, or symptomatic carotid artery disease)
• Fasting triglyceride >2.26 mmol/L (200 mg/dL) at screening
• Any uncontrolled medical/surgical/psychiatric condition, including conditions that may predispose to secondary hypercholesterolemia
• Current diagnosis or known history of complement deficiency or abnormality
• A positive hepatitis B surface antigen or hepatitis C antibody, or a known positive HIV status
• Current diagnosis or known history of liver disease, or has an ALT >ULN at screening
• Known history of fibromyalgia, myopathy, myositis, rhabdomyolysis, any unexplained muscle pain, or has a CPK >ULN at screening
• Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin that has been adequately treated
• The advisability of a subject taking any prescription medication (apart from simvastatin or atorvastatin) within 6 weeks prior to screening should be discussed with the Isis Medical Monitor
• Subject unwilling to discontinue taking alternative/herbal medication for the duration of the study
• History of drug abuse within 2 years of screening
• Subject unwilling to limit alcohol consumption for the duration of the study: male subjects to a maximum of 3 drinks (30 g) per day, and <12 drinks (120 g) per week; female subjects to a maximum of 2 drinks (20 g) per day, and <8 drinks (80 g) per week
• Known allergy or hypersensitivity to simvastatin
• Undergoing or has undergone treatment with another investigational drug, biologic agent, or device within 3 months, or 3 half lives, prior to screening, whichever is longer