Phase 3 Double-Blind, Placebo-Controlled Study on the Efficacy and Safety of Plozasiran in Adults with Hypertriglyceridemia

The primary objective of this study is to evaluate the **efficacy** of plozasiran in reducing fasting serum triglyceride (TG) levels in adults with **hypertriglyceridemia**. This is clinically relevant as elevated TG levels are associated with an increased risk of cardiovascular diseases, and effective management of TG levels can potentially reduce this risk.

Secondary objectives include:

• To demonstrate the proportion of subjects who achieve the attainment goal of reduction in TG levels.
• To demonstrate the efficacy of plozasiran on reducing remnant cholesterol, specifically very low-density lipoprotein cholesterol (VLDL-C), and non-high-density lipoprotein cholesterol (non-HDL-C).

The clinical trial involves a total of **939 participants** diagnosed with **hypertriglyceridemia**. The study population includes both male and female subjects who are 18 years of age or older. Participants were selected based on specific inclusion criteria, including a documented history of hypertriglyceridemia with fasting triglyceride levels between 150 mg/dL and 499 mg/dL, and a fasting LDL-C level of less than 130 mg/dL at screening. Additionally, participants must have a screening HbA1c of less than 9.0% and be willing to adhere to diet counseling, maintaining a stable low-fat diet. All subjects are required to be on standard lipid and triglyceride-lowering medications unless documented as intolerant. The trial does not exclude vulnerable populations, and the selection process ensures a representative sample of the target demographic. The study aims to evaluate the efficacy of plozasiran in reducing fasting serum triglyceride levels.

The clinical trial is a **randomized**, **double-blind**, placebo-controlled, Phase 3 study designed to evaluate the efficacy and safety of Plozasiran in adults with **hypertriglyceridemia**. The primary objective is to demonstrate the efficacy of Plozasiran in reducing fasting serum triglyceride (TG) levels. The trial is expected to commence recruitment on October 15, 2024, and conclude by October 21, 2026. Participants will be involved in the study for a maximum treatment period of 12 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, established diagnosis of hypertriglyceridemia, and specific fasting TG and LDL-C levels. The screening period will involve two separate visits at least 7 days apart to collect fasting TG levels. Following successful screening, participants will be randomized to receive either the investigational product, ARO-APOC3 PFS, a **synthetic double-stranded siRNA oligonucleotide**, or a placebo, both administered via subcutaneous injection.

Throughout the trial, participants will attend regular follow-up visits to monitor safety and efficacy endpoints. The primary endpoint is the percent change in fasting serum TG levels from baseline to Month 12, with secondary endpoints including changes in remnant cholesterol and non-HDL-C levels. The study will also assess the proportion of subjects achieving fasting TG levels below 150 mg/dL at Month 12. The end-of-study visit will occur at the conclusion of the 12-month treatment period, where final assessments will be conducted.

Participant involvement may be terminated early if they experience adverse reactions, fail to adhere to the study protocol, or withdraw consent. The trial will adhere to rigorous scientific and ethical standards to ensure the integrity of the data and the safety of the participants.

The clinical trial involves the administration of **ARO-APOC3 PFS**, an experimental medication formulated as a **solution for injection in a pre-filled syringe**. The active substance in ARO-APOC3 PFS is a **synthetic double-stranded siRNA oligonucleotide** directed against apolipoprotein C-III mRNA, covalently linked to a ligand containing three N-acetylgalactosamine residues. This nucleic acid-based therapeutic is designed to be administered via the **subcutaneous route**. The dosing regimen specifies a maximum daily dose of 25 mg, with a total maximum dose of 100 mg over a treatment period of up to 12 weeks. The administration device is a NeoPak® SCF® syringe barrel equipped with a 29-gauge ½” needle, ensuring compliance with Type I closure requirements per Ph.Eur. and USP standards.

In addition to the experimental treatment, the study includes a **placebo** control, referred to as **Plozasiran Injection Placebo**. The placebo is utilized to maintain the double-blind nature of the trial, ensuring unbiased assessment of the efficacy and safety of the experimental medication. The placebo is administered in a manner consistent with the experimental treatment, although specific details regarding its pharmaceutical form and active substances are not applicable. The inclusion of a placebo group is critical for evaluating the true therapeutic effect of ARO-APOC3 PFS in reducing fasting serum triglyceride levels in adults with hypertriglyceridemia.

The efficacy of Plozasiran in the treatment of **hypertriglyceridemia** will be assessed in a double-blind, placebo-controlled, Phase 3 clinical trial. The primary endpoint for evaluating efficacy is the percent change in fasting serum triglyceride (TG) levels from baseline to Month 12, with measurements taken at visits V10 and V11, compared to placebo. Secondary endpoints include the percent change in fasting serum TG levels from baseline to Month 10 (V8 and V9), the proportion of subjects achieving fasting TG levels of less than 150 mg/dL at Month 12, and the percent change in remnant cholesterol (VLDL-C) and non-HDL-C from baseline to Month 12, all compared to placebo.

Fasting serum TG levels will be collected at specified timepoints throughout the trial to ensure accurate assessment of the drug's efficacy. The trial aims to demonstrate the efficacy of Plozasiran in reducing fasting serum TG levels in adults with hypertriglyceridemia. The study will involve the administration of Plozasiran in a solution for injection in pre-filled syringes, with a maximum treatment period of 12 months. The trial is designed to provide robust data on the efficacy of Plozasiran in achieving clinically meaningful reductions in serum TG levels and other lipid parameters.