Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Plozasiran in Adults with Severe Hypertriglyceridemia at High Risk of Acute Pancreatitis (SHASTA-5 Study)

The primary objective is to evaluate the efficacy of plozasiran on adjudicated acute pancreatitis events during the double-blind treatment period. This objective addresses the critical clinical need to prevent acute pancreatitis in patients with severe hypertriglyceridemia, a condition associated with significantly elevated risk of this serious complication.

The secondary objectives include:

• To demonstrate the efficacy of plozasiran on reducing fasting serum triglyceride levels

• To demonstrate the proportion of participants receiving plozasiran who achieve the attainment goal of reduction in triglyceride levels

• To evaluate the efficacy of plozasiran on major abdominal pain events

• To evaluate the effect of plozasiran on patient-reported outcomes

• To evaluate the safety and tolerability of plozasiran administered subcutaneously every 3 months

• To evaluate adjudicated major adverse cardiovascular event rate

This clinical trial enrolled a total of **233 participants** diagnosed with **severe hypertriglyceridemia (SHTG)** who had experienced at least one prior episode of **acute pancreatitis** not attributed to other etiologies such as gallstones or alcohol within the last 5 years. The study population included both **male and female participants** aged **18 years and older** at the time of screening. Eligible participants were required to have an established diagnosis of SHTG with prior documented fasting **triglyceride levels** of ≥880 mg/dL (≥10 mmol/L) and screening fasting triglyceride levels of ≥500 mg/dL (≥5.65 mmol/L). Additional selection criteria included fasting **LDL cholesterol** ≤130 mg/dL (≤3.37 mmol/L), screening **HbA1c** ≤9.5%, and the requirement that participants be on standard of care lipid- and triglyceride-lowering medications per local guidelines unless documented as intolerant. Female participants were required to be nonpregnant, not planning to become pregnant, and nonlactating. All participants were expected to follow diet counseling and maintain a stable **low-fat diet** throughout the study duration.

This is a **Phase 3**, **double-blind**, **placebo-controlled** clinical trial designed to evaluate the efficacy and safety of **plozasiran** (ARO-APOC3 PFS) in adults with **severe hypertriglyceridemia** at high risk of **acute pancreatitis**. The investigational medicinal product is a synthetic double-stranded **siRNA oligonucleotide** directed against **apolipoprotein C-III mRNA** covalently linked to a ligand containing three N-acetylgalactosamine residues, formulated as a solution for injection in a pre-filled syringe for **subcutaneous** administration. The trial employs a randomized design comparing plozasiran with placebo during the double-blind treatment period. The maximum daily dose is 25 mg, with a maximum total dose of 425 mg over a treatment period of 48 weeks.

The primary objective is to evaluate the efficacy of plozasiran on adjudicated acute pancreatitis events occurring more than 10 days after the first dose during the double-blind treatment period. Secondary objectives include assessment of percent change in fasting serum **triglyceride** levels from baseline to Month 12, proportion of participants achieving average fasting triglyceride levels below 880 mg/dL and below 500 mg/dL from Month 3 to the end of the double-blind treatment period, time to first occurrence of major abdominal pain events, changes in patient-reported productivity and activity impairment, health status assessment, frequency and severity of **treatment-emergent adverse events**, and adjudicated **major adverse cardiovascular event** rates. The trial is expected to commence recruitment in September 2025 and conclude in November 2029.

Eligible participants include males and nonpregnant, nonlactating females aged 18 years or older at screening with an established diagnosis of severe hypertriglyceridemia and prior documented evidence of fasting triglyceride levels of at least 880 mg/dL. Participants must have fasting triglyceride levels of at least 500 mg/dL during the screening period and documented evidence of at least one prior acute pancreatitis event not attributed to other etiologies such as gallstones or alcohol, occurring within the last 5 years prior to screening. Additional inclusion criteria include fasting **LDL-cholesterol** levels of 130 mg/dL or less at screening, screening **HbA1c** of 9.5% or less, willingness to follow diet counseling and maintain a stable low-fat diet, and adherence to standard of care lipid- and triglyceride-lowering medications per local guidelines unless documented as intolerant.

The trial involves a structured sequence of study visits beginning with a screening visit to assess eligibility criteria. Following enrollment, participants undergo baseline assessments before receiving the first dose of study drug. Follow-up visits are scheduled at Month 3 and Month 12, with additional visits as specified in the protocol to monitor efficacy parameters including fasting serum triglyceride levels, occurrence of acute pancreatitis events, and safety assessments. The end-of-study visit occurs upon completion of the double-blind treatment period or upon early termination. Participant involvement extends throughout the double-blind treatment period of up to 48 weeks, with continued monitoring for treatment-emergent adverse events and major adverse cardiovascular events until the end of study. Early termination from the study may occur due to participant withdrawal of consent, investigator decision, safety concerns, protocol violations, or other conditions as specified in the protocol.

The experimental medication utilized in this clinical trial is **plozasiran**, also known as **ARO-APOC3 PFS**. This investigational product contains a **synthetic double-stranded siRNA oligonucleotide** directed against **apolipoprotein C-III mRNA** and covalently linked to a ligand containing three **N-acetylgalactosamine residues**. The active substance is of **nucleic acid** origin. The medication is formulated as a **solution for injection** supplied in a **pre-filled syringe**. The delivery system consists of a NeoPak SCF syringe barrel equipped with a 29 gauge ½ inch needle and BD260 rigid needle shield, meeting Type I closure requirements per Ph.Eur. monograph 3.2.9 and USP section 381. The product has been designated as an **orphan drug** under the designation number EU/3/21/2459 and is manufactured by Arrowhead Pharmaceuticals Inc.

Plozasiran is administered via the **subcutaneous route**. The **maximum daily dose** is **25 mg**, with a **maximum total dose** of **425 mg** over the course of treatment. The **maximum treatment period** is **48 weeks**. The dosing schedule and administration protocol are designed to evaluate the efficacy of the investigational product in reducing adjudicated acute pancreatitis events in adults with **severe hypertriglyceridemia** at high risk of acute pancreatitis.

The **placebo** comparator used in this double-blind, placebo-controlled Phase 3 study is designated as **Plozasiran Injection Placebo**. This comparator is administered to the control group to enable assessment of the experimental medication's efficacy and safety profile relative to an inactive treatment. The placebo is matched to the active treatment to maintain blinding throughout the study duration. Participant compliance monitoring and adherence to the dosing schedule are integral components of the trial protocol to ensure the validity and reliability of efficacy and safety data collected during the double-blind treatment period.

Efficacy will be assessed through multiple parameters evaluating clinical outcomes and biochemical markers in participants with severe hypertriglyceridemia. The primary efficacy endpoint is the time to first occurrence of positively adjudicated acute pancreatitis event occurring more than 10 days after the first dose of study drug compared with placebo during the double-blind treatment period. Secondary efficacy endpoints include the percent change in fasting serum triglyceride levels from baseline to Month 12 compared with placebo. Additional secondary endpoints assess the proportion of participants who achieve average fasting triglyceride levels of less than 880 mg/dL (10 mmol/L) from Month 3 to the end of the double-blind treatment period, and the proportion achieving average fasting triglyceride levels of less than 500 mg/dL (5.65 mmol/L) during the same timeframe. The time to first occurrence of major abdominal pain event, defined as positively adjudicated acute pancreatitis, positively adjudicated presentation to emergency room and/or hospitalization with abdominal pain for which no other etiology has been identified, or need to initiate apheresis to decrease triglyceride levels, will also be evaluated compared with placebo. Patient-reported outcomes will be measured through changes from baseline in productivity and activity impairment as assessed by the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem score, and changes from baseline in health status as assessed by the EuroQol 5-dimension instrument (EQ-5D-5L) score. Safety will be evaluated through the frequency and severity of treatment-emergent adverse events from baseline to end of study, and adjudicated major adverse cardiovascular event rates will be assessed.