Lipoprotein(a), also known as Lp(a), is a protein that carries cholesterol and proteins in your blood. People with high Lp(a) have a higher risk for heart disease. The main purpose of the study is to investigate how lepodisiran, compared to a placebo, affects the amount and type of plaque in the heart's vessels using an imaging technology known as Coronary Computed Tomography Angiography (CCTA) in adults who have high levels of Lp(a).

Participation will last about 120 weeks.

Inclusion Criteria:

• Have an Lp(a) ≥175 nmol/L
• Have established cardiovascular (CV) disease or are at risk for a first CV event
• Have angiographic evidence of coronary artery disease on screening CCTA
• If taking lipid-lowering medications, inclusive of statins or prescription strength niacin and PCSK9 inhibitors, these should be stable for 8 weeks

Exclusion Criteria:

• Have had a major CV event less than 60 days before measurement of the Lp(a) level used for eligibility or uncontrolled high blood pressure at screening
• Have moderate to severe renal dysfunction
• Have severe heart failure
• Have a history of coronary artery bypass graft surgery (CABG)
• Have a planned coronary angiography, percutaneous coronary intervention (PCI), coronary artery bypass graft, or valvular intervention
• Have had a procedure to remove lipoproteins from the blood or received therapy specifically targeting Lp(a)
• Are unable to safely undergo CCTA due to medication intolerance, contrast allergies, or anatomical/technical factors

Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.

Data are available 6 months after the primary publication or approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.

A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.