A Double-blind, Randomized, Placebo-controlled, Multi-center Study Evaluating the Safety, Tolerability, and Effect of Olpasiran on Coronary Artery Plaque Burden Assessed by Coronary Computed Tomography Angiography in Participants With Stable Atherosclerotic Cardiovascular Disease and Elevated Lipoprotein(a)

The primary objective of this study is to evaluate the effect of olpasiran compared to placebo on non-calcified plaque volume as measured by Coronary Computed Tomography Angiography (CCTA). This assessment is clinically relevant for understanding the potential of olpasiran to modify atherosclerotic plaque composition in patients with stable atherosclerotic cardiovascular disease and elevated lipoprotein(a), as non-calcified plaque is associated with higher vulnerability and risk of acute coronary events.

The secondary objectives include evaluating the effect of olpasiran compared to placebo on changes in different plaque types and morphologies as measured by CCTA:

• Low attenuation plaque volume change
• Total plaque volume change
• Calcified plaque volume change

These secondary endpoints provide additional characterization of olpasiran's impact on the overall coronary artery plaque burden and composition, which may offer insights into the mechanism of plaque stabilization and regression in this patient population.

The clinical trial enrolled a total of **220 participants** diagnosed with **cardiovascular disease**. The study population included both **male and female subjects** aged **35 to 80 years**. Participants were selected based on specific clinical characteristics, including a screening **lipoprotein(a)** level of **≥ 200 nmol/L** and a documented history of **atherosclerotic cardiovascular disease**, defined as prior **myocardial infarction** (presumed type 1 event due to plaque rupture or erosion) and/or **coronary revascularization** by **percutaneous coronary intervention**. Additionally, participants were required to have a baseline **Coronary Computed Tomography Angiography** scan that met specific imaging criteria as determined by the central imaging laboratory. The trial population represented patients with established cardiovascular pathology rather than healthy volunteers. No vulnerable populations were included in this study.

This is a double-blind, randomized, placebo-controlled, multi-center clinical trial designed to evaluate the safety, tolerability, and effect of olpasiran on coronary artery plaque burden in participants with stable atherosclerotic cardiovascular disease and elevated lipoprotein(a). The study is classified as a Phase III trial. Olpasiran is an antisense oligonucleotide administered as a solution for injection in pre-filled syringe via subcutaneous route. The comparator is a matching placebo for AMG 890. The trial aims to assess coronary artery plaque characteristics using Coronary Computed Tomography Angiography (CCTA) as the primary imaging modality.

The primary objective of the trial is to evaluate the effect of olpasiran compared to placebo on non-calcified plaque volume as measured by CCTA. The primary endpoint is the change in non-calcified plaque volume from baseline to week 72. Secondary endpoints include changes in the following plaque volume types from baseline to week 72: low attenuation plaque volume, total plaque volume, and calcified plaque volume. These endpoints will provide comprehensive assessment of the impact of olpasiran on different components of coronary atherosclerotic plaque.

Eligible participants must be between 35 and 80 years of age. Key inclusion criteria require screening lipoprotein(a) levels of 200 nmol/L or greater and a documented history of atherosclerotic cardiovascular disease, defined as a history of either myocardial infarction (presumed type 1 event due to plaque rupture or erosion) and/or coronary revascularization by percutaneous coronary intervention. Additionally, the screening baseline imaging scan must meet specific CCTA imaging criteria as determined by the central imaging laboratory to ensure adequate image quality for plaque volume assessment.

The trial involves a structured series of study visits throughout the participation period. The screening visit serves as the baseline assessment and includes CCTA imaging to establish initial plaque measurements and verify eligibility criteria. Follow-up visits are scheduled at regular intervals during the treatment period to monitor safety, tolerability, and compliance with the investigational medicinal product administration. A key imaging assessment visit occurs at week 72, where repeat CCTA is performed to measure changes in plaque volume parameters. The end-of-study visit marks the completion of participant involvement in the trial.

The estimated duration of participant involvement extends to week 72, corresponding to the timepoint of the primary endpoint assessment. The overall trial duration is anticipated from the estimated recruitment start date of March 21, 2026, to the estimated end date of May 27, 2028. Conditions that may lead to early termination from the study include withdrawal of consent, safety concerns, protocol deviations, or investigator decision based on participant's best interest. The trial protocol includes provisions for monitoring participant safety throughout the study period.

**Olpasiran** (AMG 890) is administered as the experimental treatment in this clinical trial. The active substance, olpasiran, is an **antisense oligonucleotide** of nucleic acid origin. The investigational medicinal product is formulated as a **solution for injection** supplied in a **pre-filled syringe**. The route of administration is **subcutaneous injection**. The pre-filled syringe delivery system is utilized to ensure accurate dosing and ease of administration. The manufacturer of olpasiran is Amgen Inc.

**Placebo for AMG 890** serves as the comparator treatment in this double-blind, randomized, placebo-controlled study. The placebo is designed to match the experimental treatment to maintain blinding throughout the trial. Participants randomized to the placebo arm will receive the comparator treatment according to the same administration schedule as those receiving the active investigational product.

Efficacy will be assessed through the evaluation of coronary artery plaque burden using **Coronary Computed Tomography Angiography (CCTA)**. The primary endpoint is the change in **non-calcified plaque (NCP) volume** from baseline to week 72. Secondary endpoints include changes in low attenuation plaque volume, total plaque volume, and calcified plaque volume, all measured from baseline to week 72. The screening baseline imaging scan must meet the CCTA imaging criteria as determined by the central imaging laboratory to ensure standardized assessment of plaque parameters throughout the trial.