Long-term Safety and Tolerability Evaluation of Pelacarsen in Patients with Elevated Lipoprotein(a) and Established Atherosclerotic Cardiovascular Disease

The primary objective of this study is to evaluate the long-term **safety** and tolerability of pelacarsen (TQJ230) in participants with elevated lipoprotein(a) [Lp(a)] and established atherosclerotic cardiovascular disease (ASCVD) who have completed the parent Lp(a)HORIZON study. This is clinically relevant as it aims to ensure that the therapeutic use of pelacarsen is safe and well-tolerated over an extended period, which is crucial for chronic conditions like ASCVD.

Secondary objectives include:

• Evaluating the long-term efficacy of pelacarsen on 4P-MACE, which encompasses cardiovascular death, nonfatal myocardial infarction, non-fatal stroke, and urgent coronary revascularization requiring hospitalization. This is important for understanding the potential of pelacarsen to reduce major adverse cardiovascular events.
• Assessing the long-term efficacy of pelacarsen in lowering Lp(a) levels, which is significant as elevated Lp(a) is a known risk factor for cardiovascular diseases, and its reduction could potentially mitigate associated risks.

The clinical trial involves a total of **2945 participants** who have been selected based on their completion of the parent Lp(a)HORIZON study. The study population includes both **male and female** subjects, encompassing an **age range** that corresponds to categories 3 and 4, which typically represent adults and older adults. Participants are individuals with **atherosclerotic cardiovascular disease (ASCVD)** and elevated lipoprotein(a) levels. The trial aims to assess the long-term safety and tolerability of pelacarsen (TQJ230). The population includes a vulnerable group, indicating that special considerations are in place to ensure their safety and well-being throughout the study. Participants were required to provide informed consent and must have completed the parent study's end-of-study visit while still on the assigned investigational product. Lifestyle factors such as diet, physical activity, and habits are not specified in the available data.

The clinical trial is designed as a **single arm, multicenter, open-label extension** study to evaluate the long-term safety and tolerability of **pelacarsen** (TQJ230) in participants with elevated lipoprotein(a) and established **atherosclerotic cardiovascular disease** (ASCVD) who have completed the parent Lp(a)HORIZON trial. The trial will involve the administration of pelacarsen via **subcutaneous use** in the form of a solution for injection in a pre-filled syringe. The trial is expected to commence recruitment on September 1, 2025, and is estimated to conclude by March 31, 2029, with a maximum treatment period of 36 months.

Participants will be required to attend several study visits throughout the trial. The initial visit will serve as the inclusion (screening) visit, where eligibility will be confirmed based on the completion of the parent study's end-of-study visit while still on the assigned investigational product. Subsequent follow-up visits will be scheduled to monitor the occurrence of treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs), as well as to assess safety laboratory measures and vital signs. The end-of-study visit will mark the conclusion of the participant's involvement in the trial.

The expected length of participant involvement is up to 36 months, contingent upon the absence of any conditions that may necessitate early termination from the study. Such conditions include the occurrence of TEAEs or TESAEs that lead to treatment discontinuation. The primary endpoints of the trial include the occurrence of TEAEs, TESAEs, and treatment discontinuations due to these events. Secondary endpoints will evaluate the time to the first occurrence of major adverse cardiovascular events (4P-MACE) and changes in lipoprotein(a) levels from both the parent and open-label extension study baselines.

The clinical trial involves the administration of **pelacarsen**, an experimental medication identified by the sponsor product code TQJ230. Pelacarsen is formulated as a **solution for injection in a pre-filled syringe** and is classified as an **antisense oligonucleotide**. The active substance, pelacarsen, is derived from **nucleic acid**. The pharmaceutical form is specifically designed for **subcutaneous use**. The maximum daily dose of pelacarsen is 80 mg, with a total maximum dose of 2880 mg over a treatment period of up to 36 months. The administration of pelacarsen is facilitated by a pre-filled syringe equipped with a needle safety device, although it does not possess a CE mark.

In this open-label extension trial, pelacarsen is the primary investigational product, and no additional non-experimental treatments such as placebo or comparator treatments are utilized. The trial aims to evaluate the long-term safety and tolerability of pelacarsen in participants with elevated lipoprotein(a) and established cardiovascular disease who have completed the parent Lp(a)HORIZON study. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

The efficacy of the clinical trial will be assessed through both primary and secondary endpoints. The primary endpoints include the occurrence of **Treatment Emergent Adverse Events (TEAEs)**, **Treatment Emergent Serious Adverse Events (TESAEs)**, and treatment discontinuations due to TEAEs or TESAEs. Additionally, TEAEs of special interest will be monitored, with observed values or changes from baseline in safety laboratory measures and vital signs being recorded.

Secondary endpoints focus on cardiovascular outcomes and changes in lipoprotein(a) levels. These include the time to the first occurrence of 4-point major adverse cardiovascular events (4P-MACE) from both the parent study baseline and the open-label extension (OLE) study baseline. The cumulative number of 4P-MACE over time from both baselines will also be evaluated. Furthermore, observed values and changes in lipoprotein(a) from the parent study baseline and the OLE study baseline will be assessed.