Evaluation of Efficacy and Safety of ARO-APOC3 in Adults with Familial Chylomicronemia Syndrome: A Phase 3 Randomized Controlled Trial

The primary objective of this Phase 3 study is to evaluate the **efficacy** and **safety** of ARO-APOC3 in adults diagnosed with **Familial Chylomicronemia Syndrome (FCS)**. This investigation is clinically relevant as FCS is a rare genetic disorder characterized by extremely high levels of triglycerides, leading to recurrent episodes of pancreatitis and other serious complications. The study aims to determine whether ARO-APOC3, a synthetic double-stranded siRNA oligonucleotide directed against apolipoprotein C-III mRNA, can effectively reduce triglyceride levels and improve patient outcomes. No secondary objectives are specified for this study.

The clinical trial involves a total of **55 participants** diagnosed with **Familial Chylomicronemia Syndrome (FCS)**. The study population includes both men and nonpregnant women aged 18 years and older, with the age requirement adjusted to 19 years where local regulations apply. Participants were selected based on their fasting triglyceride levels of 10 mmol/L (880 mg/dL) or higher, which are refractory to standard lipid-lowering therapy. The trial includes individuals from a vulnerable population, ensuring a comprehensive evaluation of the efficacy and safety of ARO-APOC3 in adults with FCS. Both male and female subjects are included, reflecting a diverse gender representation. The selection criteria emphasize the need for a confirmed diagnosis of FCS, ensuring that the study population is appropriately targeted for the investigation of this specific condition.

The clinical trial is designed to evaluate the efficacy and safety of **ARO-APOC3** in adults diagnosed with **Familial Chylomicronemia Syndrome (FCS)**. This is a Phase 3, randomized, double-blind, controlled study. Participants will be randomly assigned to receive either the investigational product, ARO-APOC3, or a placebo, administered via subcutaneous injection. The trial is expected to last approximately 36 months, with the estimated end date in May 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (≥18 years), fasting triglyceride levels (≥10 mmol/L), and a confirmed diagnosis of FCS. Following successful screening, participants will be enrolled and randomized into the study. The primary endpoint is the percent change from baseline in fasting triglycerides at Month 10, with secondary endpoints including changes in fasting triglycerides and APOC3 at Months 10 and 12.

Study visits will occur at regular intervals to monitor safety and efficacy, including follow-up visits at Months 10 and 12. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted. Participants are expected to remain in the study for the full duration unless they meet conditions for early termination, such as adverse events, withdrawal of consent, or non-compliance with study procedures.

The clinical trial involves the administration of **ARO-APOC3**, a **solution for injection** containing a **synthetic double-stranded siRNA oligonucleotide** directed against **apolipoprotein C-III mRNA**. This active substance is covalently linked to a ligand containing three **N-acetylgalactosamine** residues. The pharmaceutical form is a solution for injection, and it is administered via **subcutaneous injection**. The maximum daily dose is 50 mg, with a total maximum dose of 200 mg over a treatment period of 36 weeks. The administration schedule and participant compliance are monitored throughout the study to ensure adherence to the dosing regimen.

Additionally, the trial includes the use of **ARO-APOC3 PFS**, which is a **solution for injection in a pre-filled syringe**. This formulation also contains the same active substance as ARO-APOC3 and is administered via subcutaneous injection. The dosing schedule mirrors that of ARO-APOC3, with a maximum daily dose of 50 mg and a total maximum dose of 200 mg over 36 weeks. The pre-filled syringe is utilized to facilitate accurate dosing and ease of administration.

The study also employs **0.9% Normal Saline for injection** as a comparator treatment. This is used as a placebo in the trial to evaluate the efficacy and safety of the experimental medication. The saline solution is administered in a manner consistent with standard clinical practices for placebo administration, ensuring blinding and maintaining the integrity of the study design.

The efficacy of ARO-APOC3 in adults with Familial Chylomicronemia Syndrome (FCS) will be assessed through a series of primary and secondary endpoints. The primary endpoint is the percent change from baseline in fasting triglycerides (TG) at Month 10. Secondary endpoints include the percent change from baseline in fasting TG at Months 10 and 12 (averaged), as well as the percent change from baseline in fasting **APOC3** at Months 10 and 12. These endpoints will be measured to evaluate the therapeutic impact of ARO-APOC3 on lipid levels in the target population.

Data collection will occur at specified timepoints, with fasting TG and **APOC3** levels being the primary biomarkers of interest. The study will utilize validated laboratory tests to ensure the accuracy and reliability of the measurements. The analysis will focus on the changes in these biomarkers from baseline, providing insights into the efficacy of the treatment over the course of the trial. The trial is designed to follow participants for a maximum treatment period of 36 months, with the final data collection expected by May 2026.