Phase 3 Double-Blind, Placebo-Controlled Trial Evaluating Plozasiran Efficacy and Safety 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:

• 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).
• To evaluate 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 **151 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 a screening HbA1c of 9.0% or lower. All subjects are required to follow diet counseling and maintain a stable low-fat diet. They must also be on standard lipid- and TG-lowering medications unless documented as intolerant. The trial includes a vulnerable population, and the selection process ensures that participants meet the necessary health and lifestyle criteria to assess the efficacy of plozasiran in reducing fasting serum TG 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 severe 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 1, 2024, and conclude by October 21, 2026. Participants will be involved in the study for a maximum treatment period of 12 months, during which they will receive either the active drug, ARO-APOC3 PFS, or a placebo, both administered as a **solution for injection in pre-filled syringes** via the **subcutaneous** route.

The study will include several key visits: an initial screening visit to confirm eligibility, followed by regular follow-up visits to monitor progress and collect data. The inclusion criteria require participants to be adults aged 18 years or older with a confirmed diagnosis of severe hypertriglyceridemia, evidenced by fasting TG levels of ≥500 mg/dL. Participants must also have a fasting LDL-C ≤130 mg/dL and a screening HbA1c ≤9.0%. They should be willing to adhere to diet counseling and maintain a stable low-fat diet. 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, as well as the proportion of subjects achieving specific TG level thresholds.

Study visits will be scheduled at baseline, followed by monthly visits to assess the primary and secondary endpoints. The end-of-study visit will occur at Month 12, where final assessments will be conducted. Participants may be withdrawn from the study early if they experience adverse events, fail to comply with the study protocol, or withdraw consent. The trial is not categorized as low intervention, given that it involves a drug not currently authorized for the population involved. The study aims to provide robust data on the efficacy and safety of plozasiran, contributing to the understanding and management of severe hypertriglyceridemia.

The clinical trial involves the administration of **Plozasiran**, an investigational medication formulated as a **solution for injection in 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 dose not exceeding 100 mg over the course of the treatment. The maximum treatment period is 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. The plunger stopper is a PremiumCoat™ Plunger Stopper, BSCF, made of bromobutyl and ETFE coated, ensuring compliance with Ph.Eur. monograph 3.2.9 and USP requirements for Type I closures.

The study also includes a **placebo** group, where participants receive a placebo injection designed to mimic the appearance and administration of the plozasiran injection. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered following the same subcutaneous route and schedule as the active medication, ensuring consistency in the administration process across all study participants.

The efficacy of **plozasiran** in the treatment of severe 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, 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 of fasting serum TG levels will be collected at specified timepoints, including baseline, Month 10, and Month 12. The analysis will compare these measurements to placebo to determine the efficacy of **plozasiran**. The trial is designed to ensure rigorous assessment of the drug's impact on lipid parameters and related clinical outcomes in adults with severe hypertriglyceridemia. The study will utilize validated laboratory tests to measure these parameters, ensuring the reliability and accuracy of the data collected throughout the trial duration.