A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Plozasiran in Adults with Severe Hypertriglyceridemia

The primary objective of this study is to demonstrate the efficacy of **plozasiran** in reducing fasting serum triglyceride (TG) levels in adults with severe hypertriglyceridemia. This is clinically relevant as elevated TG levels are associated with an increased risk of cardiovascular diseases and pancreatitis, making effective management crucial for patient outcomes.

Secondary objectives include:

• Demonstrating the proportion of subjects who achieve the attainment goal of reduction in TG levels.
• Demonstrating 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).
• Evaluating the efficacy of plozasiran on the adjudicated abdominal clinical event rate, including emergency room visits or hospitalizations for abdominal pain attributed to hypertriglyceridemia and events of documented pancreatitis.

The clinical trial involves a total of **251 participants** diagnosed with **severe hypertriglyceridemia (SHTG)**. 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 fasting triglyceride (TG) levels of 500 mg/dL (5.65 mmol/L) or higher, and a mean fasting TG level of 500 mg/dL (5.65 mmol/L) or higher collected at two separate visits. Additionally, participants must have a fasting LDL-C level of 130 mg/dL (3.37 mmol/L) or lower and an HbA1c level of 9.0% or lower at screening. The trial population is required to follow diet counseling and maintain a stable low-fat diet. Subjects are also expected to be on standard lipid and TG-lowering medications unless they are documented as intolerant. The study includes a vulnerable population, and the participants are required to adhere to the outlined lifestyle considerations to ensure the integrity of the trial outcomes.

The clinical trial is designed to evaluate the **efficacy** and safety of Plozasiran in adults with severe hypertriglyceridemia. This is a Phase 3, double-blind, placebo-controlled study. Participants will be randomly assigned to receive either the active treatment, ARO-APOC3 PFS, or a placebo, both administered as a solution for injection in pre-filled syringes. The trial is expected to last approximately two years, with an estimated recruitment start date in October 2024 and an estimated end date in October 2026.

The study will include several key visits: an initial screening visit, multiple follow-up visits, and an end-of-study visit. During the screening visit, eligibility will be assessed based on criteria such as age, diagnosis of severe hypertriglyceridemia, and specific laboratory values, including fasting triglyceride levels. Participants must also be willing to adhere to dietary counseling and maintain a stable low-fat diet. Follow-up visits will occur at regular intervals to monitor the primary endpoint, which is the percent change in fasting serum triglyceride levels from baseline to Month 12. Secondary endpoints include changes in other lipid parameters and the occurrence of abdominal clinical events related to hypertriglyceridemia.

Participants are expected to be involved in the study for a maximum of 12 months of treatment, with the possibility of early termination if they experience adverse events, fail to comply with the study protocol, or withdraw consent. The trial aims to provide robust data on the potential benefits of Plozasiran in reducing triglyceride levels and improving clinical outcomes in this patient population.

The clinical trial involves the administration of **Plozasiran**, an experimental medication, in the form of a **solution for injection in a pre-filled syringe**. The active substance, Plozasiran, is a nucleic acid-based compound developed by Arrowhead Pharmaceuticals Inc. The medication is administered subcutaneously, with a maximum daily dose of 25 mg and a total maximum dose of 100 mg over a treatment period of 12 weeks. The pre-filled syringe is equipped with a NeoPak® SCF® syringe barrel, a 29-gauge ½” needle, and a BD260 rigid needle shield, ensuring compliance with Ph.Eur. and USP requirements for Type I closures. The dosing schedule is designed to evaluate the efficacy of Plozasiran in reducing fasting serum triglyceride levels in adults with severe hypertriglyceridemia.

In addition to the experimental treatment, a **placebo** is utilized as a comparator in this double-blind, placebo-controlled study. The placebo is administered in the same pharmaceutical form and via the same route as the active treatment, ensuring blinding and maintaining the integrity of the study design. The placebo is referred to as Plozasiran Injection Placebo and is used to assess the efficacy and safety of the active treatment by providing a baseline for comparison. Participant compliance with the dosing regimen is monitored throughout the study to ensure accurate and reliable results.

The efficacy of Plozasiran in the treatment of severe hypertriglyceridemia will be assessed through 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, compared to placebo. Secondary endpoints include the percent change in fasting serum TG levels from baseline to Month 10, the proportion of subjects achieving fasting TG levels of less than 500 mg/dL and less than 150 mg/dL at Month 12, the percent change in remnant cholesterol (VLDL-C) and non-HDL-C from baseline to Month 12, and the adjudicated abdominal clinical event rate, including emergency room visits or hospitalizations for abdominal pain attributed to hypertriglyceridemia and events of documented pancreatitis during the treatment period, compared to placebo at Month 12.

Measurements will be collected at specified timepoints, including baseline, Month 10, and Month 12, using validated laboratory tests to ensure accuracy and reliability. The trial will involve the administration of Plozasiran as a solution for injection in a pre-filled syringe, with a maximum treatment period of 12 months. The data collected will be analyzed to determine the efficacy of Plozasiran in reducing fasting serum TG levels and improving related lipid parameters in adults with severe hypertriglyceridemia.