Study of Plozasiran (ARO-APOC3) in Adults With Severe Hypertriglyceridemia (SHASTA-3)

Double-blind, Placebo-controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Plozasiran in Adults With Severe Hypertriglyceridemia

This Phase 3 study will evaluate the safety and efficacy of plozasiran injection (ARO-APOC3) in adult participants with severe hypertriglyceridemia (SHTG). After providing informed consent eligible participants will be randomized to receive 4 doses (once every 3 months) of plozasiran or placebo, and be evaluated for efficacy and safety. After month 12, eligible participants will be offered an opportunity to continue in an optional open-label extension under a separate protocol.

Study Overview

• Status: Recruiting
• Conditions: Severe Hypertriglyceridemia
• Intervention / Treatment: Drug: Placebo; Drug: Plozasiran Injection

• Study Type: Interventional
• Enrollment (Estimated): 405
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Medical Monitor; Phone Number: 626-304-3400; Email: plozasiran@arrowheadpharma.com

Study Locations

• United States
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73111
      • Recruiting
      • Lynn Health Science Institute
      • Contact: Aquilla Smith; Phone Number: 405-602-3938; Email: asmith@lhsi.net
      • Principal Investigator: Charles Lunn, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Established diagnosis of severe hypertriglyceridemia (SHTG) and prior documented evidence (medical history) of fasting TG levels of ≥ 500 mg/dL (≥5.65mmol/L)
• Mean fasting TG level ≥500 mg/dL (≥5.65 mmol/L) collected at 2 separate and consecutive visits at least 7 days apart and no more than 17 days apart during the screening period
• Fasting low density lipoprotein-cholesterol (LDL-C) ≤130 mg/dL (≤3.37 mmol/L) at screening
• Screening HbA1C ≤8.5%
• Willing to follow diet counseling and maintain a stable low-fat diet
• Must be on standard of care lipid-lowering medications per local guidelines (unless documented as intolerant as determined by the Investigator)

Exclusion Criteria:

• Use of any hepatocyte-targeted small interfering ribonucleic acid (siRNA) that targets lipids and/or triglycerides within 365 days before Day 1 (except inclisiran, which is permitted). Administration of investigational drug and inclisiran must be separated by at least 4 weeks
• Use of any other hepatocyte-targeted siRNA or antisense oligonucleotide molecule within 60 days or within 5-half-lives before Day 1 based on plasma pharmacokinetics (PK), whichever is longer
• Known diagnosis of familial chylomicronemia syndrome (FCS) (type 1 Hyperlipoproteinemia) by documentation of confirmed homozygote or double heterozygote for loss-of-function mutations in type 1-causing genes
• Acute pancreatitis within 4 weeks prior to screening
• Body mass index >45kg/m^2

Note: Additional Inclusion/Exclusion criteria may apply per protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; calculated volume to match active treatment by sc injection	Drug: Placebo; sterile normal saline (0.9% NaCl)
Experimental: Plozasiran Injection; 4 doses of plozasiran (ARO-APOC3) by subcutaneous (sc) injection	Drug: Plozasiran Injection; ARO-APOC3 Injection; Other Names: ARO-APOC3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percent Change in Fasting Serum Triglyceride (TG) Levels from Baseline to Month 12 Compared to Placebo	Baseline, Month 12

Secondary Outcome Measures

Outcome Measure	Time Frame
Percent Change in Fasting Serum TG Levels from Baseline to Month 10 Compared to Placebo	Baseline, Month 10
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	Month 12
Incidence Rates of New-Onset Diabetes Mellitus (NODM) Throughout the Course of Treatment	From first dose of study drug through Month 12
Incidence Rates of Impaired Glucose Tolerance Throughout the Course of Treatment	From first dose of study drug through Month 12
Incidence Rates of Worsening of Existing Diabetes Throughout the Course of Treatment	From first dose of study drug through Month 12
Change from Baseline in Fasting Blood Glucose During the Treatment Period Compared to Placebo	From first dose of study drug through Month 12
Change from Baseline in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) During the Treatment Period Compared to Placebo	From first dose of study drug through Month 12
Adjudicated Major Adverse Cardiovascular Events (MACE) Rates During the Treatment Period Compared to Placebo	From first dose of study drug through Month 12
Proportion of Participants Who Achieve Fasting TG Levels of <500 mg/dL (<5.65 mmol/L) at Month 10 and Month 12 Compared to Placebo	Month 10, Month 12
Proportion of Participants Who Achieve Fasting TG Levels of <150 mg/dL (<1.69 mmol/L) at Month 10 and Month 12 Compared to Placebo	Month 10, Month 12
Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) Over Time through Month 12 as Compared to Placebo	From first dose of study drug through Month 12
Change from Baseline in Hemoglobin A1c (HbA1c) During the Treatment Period Compared to Placebo	From first dose of study drug through Month 12
Change from Baseline in C-peptide During the Treatment Period Compared to Placebo	From first dose of study drug through Month 12
Incidence Rates of Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs) Associated with Worsening Glycemic Control During the Treatment Period Compared to Placebo	From first dose of study drug through Month 12
Initiation of New Medication for Hyperglycemia Among Study Participants Not Known to Have Pre-existing Diabetes Mellitus During the Treatment Period Compared to Placebo	From first dose of study drug through Month 12
Incidence of Anti-drug Antibodies (ADA) to Plozasiran in Participants Receiving Plozasiran Over Time Through Month 12	From first dose of study drug through Month 12
Titers of Anti-drug Antibodies (ADA) to Plozasiran in Participants Receiving Plozasiran Over Time Through Month 12	From first dose of study drug through Month 12

Collaborators and Investigators

• Sponsor: Arrowhead Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: March 29, 2024
• First Submitted That Met QC Criteria: March 29, 2024
• First Posted (Actual): April 4, 2024

Study Record Updates

• Last Update Posted (Estimated): April 30, 2024
• Last Update Submitted That Met QC Criteria: April 27, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Hypertriglyceridemia
• Other Study ID Numbers: AROAPOC3-3003; 2023-509300-14 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No