Long-Term Safety and Efficacy Evaluation of ARO-APOC3 in Adults with Mixed Dyslipidemia: A Phase 2 Open-Label Extension Study

The primary objective of this Phase 2 open-label extension study is to evaluate the **safety** and **efficacy** of long-term treatment with ARO-APOC3 in adults with **mixed dyslipidemia**. This is clinically relevant as mixed dyslipidemia, characterized by abnormal levels of lipids in the blood, is a significant risk factor for cardiovascular diseases. The study aims to assess whether ARO-APOC3, a synthetic double-stranded siRNA oligonucleotide directed against apolipoprotein C-III mRNA, can effectively manage lipid levels over an extended period, thereby potentially reducing cardiovascular risk.

The clinical trial involves a total of **264 participants** diagnosed with **mixed dyslipidemia**. The study population includes both male and female adults aged 18 years and older. Participants are required to be nonpregnant and nonlactating, with no plans to become pregnant during the study period. The selection process for the trial population included individuals who completed a 48-week study treatment period in a parent study, ensuring a consistent baseline of prior treatment exposure. The trial does not specify particular lifestyle considerations such as diet or physical activity, but it does include a vulnerable population, indicating a need for careful monitoring and ethical considerations. The participants were selected based on their ability and willingness to provide written informed consent, ensuring that all individuals are fully aware of the study's requirements and implications.

The clinical trial is designed to evaluate the long-term safety and efficacy of **ARO-APOC3** in adults with **mixed dyslipidemia**. This is a Phase 2 open-label extension study, which follows a non-randomized, open-label design. The trial is expected to last until September 2025, with recruitment having commenced in July 2022. Participants eligible for this study are adults aged 18 years or older who have completed a prior 48-week study treatment period. The primary endpoint is the incidence of treatment-emergent adverse events (TEAEs), while secondary endpoints include changes in fasting triglycerides, apolipoprotein C-III, non-high-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total apolipoprotein B, and low-density lipoprotein cholesterol over time.

Participants will receive **ARO-APOC3** via subcutaneous injection, with a maximum daily dose of 25 mg and a total dose not exceeding 200 mg over the course of the study. The maximum treatment period is 104 weeks. Study visits are structured to include an initial screening visit to confirm eligibility, followed by regular follow-up visits to monitor safety and efficacy parameters. The end-of-study visit will conclude the participant's involvement, ensuring all necessary data is collected and any adverse events are addressed. The expected length of participant involvement is approximately two years, contingent upon adherence to study protocols and absence of any conditions necessitating early termination, such as significant adverse reactions or withdrawal of consent.

The clinical trial involves the administration of the experimental medication **ARO-APOC3**, which is a **solution for injection**. The active substance in ARO-APOC3 is a **synthetic double-stranded siRNA oligonucleotide** directed against **apolipoprotein C-III mRNA** and is covalently linked to a ligand containing three N-acetylgalactosamine residues. This formulation is designed for subcutaneous injection. The dosing regimen for ARO-APOC3 involves a maximum daily dose of 25 mg, with a total maximum dose of 200 mg over the course of the treatment period. The maximum treatment period is 104 weeks. The administration of the drug is conducted under controlled conditions to ensure participant compliance and to monitor any potential adverse effects.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the long-term safety and efficacy of ARO-APOC3 in adults with mixed **dyslipidemia**. Participant compliance is monitored through regular follow-ups and assessments to ensure adherence to the dosing schedule and to evaluate the therapeutic outcomes of the treatment. The trial is conducted in accordance with regulatory standards and guidelines to ensure the safety and well-being of all participants.

The efficacy of the clinical trial evaluating ARO-APOC3 in adults with **dyslipidemia** will be assessed through several secondary endpoints. These include the change and percent change from baseline over time in fasting triglycerides (TG), apolipoprotein C-III (ApoC-III), fasting non-high-density lipoprotein cholesterol (non-HDL-C), fasting high-density lipoprotein cholesterol (HDL-C), fasting total apolipoprotein B (ApoB), and fasting low-density lipoprotein cholesterol (LDL-C) using ultracentrifugation. These parameters will be measured at specified intervals throughout the study to evaluate the long-term efficacy of the treatment. The data collected will be analyzed to determine the impact of ARO-APOC3 on these lipid and lipoprotein levels, providing insights into its therapeutic potential in managing dyslipidemia.