The purpose of this study is to evaluate the efficacy of lepodisiran in reducing cardiovascular risk in participants with high lipoprotein(a) who have cardiovascular disease or are at risk of a heart attack or stroke. The study drug will be administered subcutaneously (SC) (under the skin). Approximately 1700 additional participants will be enrolled in an addendum to explore Lp(a) lowering with an alternative dosing schema.

Inclusion Criteria:

• Have Lipoprotein(a) [Lp(a)] ≥175 nanomoles per liter (nmol/L).

• Meet criteria of either 2a or 2b:

  2a: Individuals 18 years of age or older with established atherosclerotic cardiovascular disease (ASCVD) with an event or revascularization.

  2b: Individuals 55 years of age or older who are at risk for a first cardiovascular (CV) event and either: Documented coronary artery disease (CAD), carotid stenosis, or peripheral artery disease (PAD) without history of event or revascularization; known familial hypercholesteremia; or a combination of high-risk factors.

Exclusion Criteria:

• Have had a major cardiovascular event or surgery, such as myocardial infarction (MI), stroke or coronary or peripheral revascularization, < 60 days before screening

• Have uncontrolled hypertension

• Have New York Heart Association class IV heart failure.

• Have lipoprotein apheresis within 90 days of screening, or planned lipoprotein apheresis during the study.

• Have severe renal failure, defined as

  • Estimated glomerular rate (eGFR) <15 milliliters per minute per 1.73 meters squared (mL/min/1.73m2) at screening Visit 1, or ongoing dialysis.

• Have a diagnosis of active nephrotic syndrome, or urine albumin-creatinine ratio (UACR) of ≥5000 mg/g at screening Visit 1.

• Have acute or chronic hepatitis, known cirrhosis, signs and symptoms of any other liver disease other than metabolic-associated steatotic liver disease, or exclusionary laboratory results as determined by the central laboratory during screening.

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 and 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.