Phase 3 Open-Label Extension Study on Long-Term Safety and Efficacy of Plozasiran in Adults with Hypertriglyceridemia Using Synthetic siRNA Oligonucleotide

The primary objective of this study is to demonstrate the long-term **safety** of plozasiran in subjects with hypertriglyceridemia (HTG) and severe hypertriglyceridemia (SHTG). This is clinically relevant as it addresses the potential risks associated with prolonged use of plozasiran, ensuring that the treatment does not lead to adverse health outcomes over time.

Secondary objectives include:

• Evaluating the efficacy of plozasiran on the reduction of fasting triglyceride (TG) levels over time, which is crucial for understanding its impact on lipid metabolism and cardiovascular risk.
• Demonstrating the effects of plozasiran on fasting apolipoprotein C-III (APOC3), remnant cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (Apo B), and low-density lipoprotein cholesterol (LDL-C) over time, providing insights into its broader lipid-modifying effects.
• Evaluating adjudicated major adverse cardiovascular event (MACE) rate, which is important for assessing the cardiovascular safety profile of the treatment.
• Evaluating the immunogenicity, specifically the presence of anti-drug antibodies (ADAs), of the investigational medicinal product (IMP), which is essential for understanding potential immune responses that could affect treatment efficacy or safety.

The clinical trial involves a total of **468 participants** diagnosed with **hypertriglyceridemia (HTG)**. The study population includes both adult males and nonpregnant, nonlactating adult females, who have completed all required study visits in the parent study. Participants are within the age range of 18 to 64 years, encompassing both genders. The trial population was selected based on their ability and willingness to provide written informed consent, and adherence to specific contraceptive measures if of childbearing potential. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial aims to demonstrate the long-term safety of plozasiran in subjects with HTG and severe hypertriglyceridemia (SHTG). The inclusion of a vulnerable population is noted, although specific details are not provided.

The clinical trial is designed to evaluate the long-term safety and efficacy of **plozasiran** in adults with **hypertriglyceridemia**. This is a Phase 3, open-label extension study, which involves a non-randomized, controlled trial design. The trial is expected to commence recruitment on June 17, 2025, and conclude by July 27, 2028. Participants will receive **plozasiran** via subcutaneous injection, with a maximum daily dose of 25 mg and a total dose not exceeding 200 mg over a 24-month treatment period.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will confirm eligibility based on criteria such as completion of prior related studies and agreement to use effective contraception. Follow-up visits will occur at regular intervals to assess primary and secondary endpoints, including the incidence of treatment-emergent adverse events and changes in fasting triglyceride levels, among other lipid parameters. The end-of-study visit will finalize data collection and ensure participant safety post-treatment.

Participant involvement is anticipated to last up to 24 months, with conditions for early termination including withdrawal of consent, non-compliance with study procedures, or adverse events that compromise safety. The trial aims to provide valuable insights into the long-term impact of **plozasiran** on lipid profiles and overall safety in the target population.

The clinical trial involves the administration of **ARO-APOC3 PFS**, a **solution for injection in pre-filled syringe**. This experimental medication contains a **synthetic double-stranded siRNA oligonucleotide** directed against **apolipoprotein C-III mRNA**. The active substance is covalently linked to a ligand containing three **N-acetylgalactosamine residues**. The pharmaceutical form is designed for **subcutaneous** administration. The maximum daily dose is 25 mg, with a total maximum dose of 200 mg over a treatment period of 24 weeks. The medication is provided by Arrowhead Pharmaceuticals Inc. and is not a pediatric formulation.

The device used for administration is the NeoPak® SCF® syringe barrel, equipped with a 29 gauge ½” needle and a BD260 rigid needle shield. The syringe includes a PremiumCoat™ Plunger Stopper, BSCF, made from Bromobutyl and ETFE coated. The formulation complies with the requirements for Type I closures as per Ph.Eur. monograph 3.2.9 and USP section 381.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

The efficacy of the investigational product, plozasiran, in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the subject incidence of treatment-emergent adverse events (TEAEs). Secondary endpoints include the evaluation of changes and percent changes from baseline over time in various lipid parameters, such as fasting triglyceride (TG) levels, **APOC3**, remnant cholesterol, fasting non-HDL-C, fasting HDL-C, fasting total Apo B, and fasting LDL-C using ultracentrifugation. Additionally, changes from baseline over time in hemoglobin A1c (HbA1c) will be measured. The incidence of emergent apheresis, adjudicated major adverse cardiovascular event (MACE) rates during the treatment period, and the incidence and titers of anti-drug antibodies (ADA) to plozasiran in those receiving the treatment over time will also be assessed.