Study of Plozasiran in Adults With Severe Hypertriglyceridemia at Risk of Acute Pancreatitis (SHASTA-5)

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)

This study will evaluate the efficacy and safety of plozasiran in approximately 288 adult participants with severe hypertriglyceridemia (SHTG) and history of at least two prior acute pancreatitis (AP) events not attributed to other etiologies, with at least one occurring within the last 12 months prior to screening. Eligible participants will be randomly assigned in a double-blind manner to either receive plozasiran 25 mg by subcutaneous (SC) injection every three months (Q3M) or matching placebo. Enrolled participants will be counseled to remain on the specified low-fat diet and background medications throughout the study. Following completion of the double-blind treatment period, or if the participant has a positively adjudicated AP event (whichever occurs first), participants will transition to the 12-month Open-Label Extension (OLE) treatment period receiving plozasiran 25 mg by SC injection Q3M.

Study Overview

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

• Study Type: Interventional
• Enrollment (Estimated): 288
• Phase: Phase 3

Contacts and Locations

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

Study Locations

• Argentina
  • Ciudad Autonoma Buenos Aires, Argentina, C1430CKE
    • Recruiting
    • Research Site
  • Buenos Aires
    • Ramos Mejía, Buenos Aires, Argentina, 1704
      • Recruiting
      • Research Site
  • Córdoba Province
    • Córdoba, Córdoba Province, Argentina, 5000
      • Recruiting
      • Research Site
    • Córdoba, Córdoba Province, Argentina, X5003DCE
      • Recruiting
      • Research Site
  • Santa Fe Province
    • Rosario, Santa Fe Province, Argentina, 2000
      • Recruiting
      • Research Site
• Austria
  • Graz, Austria, 8036
    • Recruiting
    • Research Site
• Brazil
  • Ceará
    • Fortaleza, Ceará, Brazil, 60430-370
      • Recruiting
      • Research Site
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil, 30150-274
      • Recruiting
      • Research Site
    • Belo Horizonte, Minas Gerais, Brazil, 30150-320
      • Recruiting
      • Research Site
    • Belo Horizonte, Minas Gerais, Brazil, 30220-140
      • Recruiting
      • Research Site
  • Rio Grande do Sul
    • Porto Alegre, Rio Grande do Sul, Brazil, 90035-903
      • Recruiting
      • Research Site
    • Pôrto Alegre, Rio Grande do Sul, Brazil, 90050-170
      • Recruiting
      • Research Site
  • São Paulo
    • São Paulo, São Paulo, Brazil, 05403-900
      • Recruiting
      • Research Site
• Bulgaria
  • Burgas, Bulgaria, 8000
    • Recruiting
    • Research Site
  • Pleven, Bulgaria, 5800
    • Recruiting
    • Research Site
  • Plovdiv, Bulgaria, 4003
    • Recruiting
    • Research Site
  • Plovdiv, Bulgaria, 4002
    • Recruiting
    • Research Center
  • Rousse, Bulgaria, 7013
    • Recruiting
    • Research Site
  • Sofia, Bulgaria, 1431
    • Recruiting
    • Research Site
  • Sofia, Bulgaria, 1404
    • Recruiting
    • Research Site
  • Stara Zagora, Bulgaria, 6000
    • Recruiting
    • Research Site
• China
  • Beijing, China, 100053
    • Recruiting
    • Research Site
  • Nanjing, China, 210002
    • Recruiting
    • Research Site
  • Beijing Municipality
    • Beijing, Beijing Municipality, China, 100730
      • Recruiting
      • Research Center
  • Guizhou
    • Guiyang, Guizhou, China, 550000
      • Recruiting
      • Research Site
  • Heilongjiang
    • Harbin, Heilongjiang, China, 150040
      • Recruiting
      • Research Site
  • Inner Mongolia
    • Baotou, Inner Mongolia, China, 014010
      • Recruiting
      • Research Center
    • Chifeng, Inner Mongolia, China, 024099
      • Recruiting
      • Research Site
  • Jiangxi
    • Nanchang, Jiangxi, China, 330006
      • Recruiting
      • Research Center
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 201620
      • Recruiting
      • Research Center
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Recruiting
      • Research Site
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310000
      • Recruiting
      • Research Center
    • Hangzhou, Zhejiang, China, 310003
      • Recruiting
      • Research Site
• Colombia
  • Barranquilla, Colombia, 080020
    • Recruiting
    • Research Site
  • Cali, Colombia, 760042
    • Recruiting
    • Research Site
  • Puerto Colombia, Colombia, 081007
    • Recruiting
    • Research Site
• Hungary
  • Budapest, Hungary, 1083
    • Recruiting
    • Research Site
  • Budapest, Hungary, 1132
    • Recruiting
    • Research Site
  • Szeged, Hungary, 6725
    • Recruiting
    • Research Site
• Jordan
  • Amman, Jordan, 11821
    • Recruiting
    • Research Center
  • Amman, Jordan, 11190
    • Recruiting
    • Research Site
  • Amman, Jordan, 11942
    • Recruiting
    • Research Site
  • Irbid, Jordan, 21166
    • Recruiting
    • Research Center
  • Irbid, Jordan, 22110
    • Recruiting
    • Research Center
• Mexico
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44670
      • Recruiting
      • Research Site
  • Mexico City
    • Mexico City, Mexico City, Mexico, 06700
      • Recruiting
      • Research Site
• Oman
  • Muscat, Oman, 123
    • Recruiting
    • Research Site
• Saudi Arabia
  • Riyadh, Saudi Arabia, 11211
    • Recruiting
    • Research Site
  • Riyadh, Saudi Arabia, 11426
    • Recruiting
    • Research Site
  • Riyadh, Saudi Arabia, 11472
    • Recruiting
    • Research Site
• Serbia
  • Belgrade, Serbia, 11000
    • Recruiting
    • Research Site
  • Belgrade, Serbia, 11000
    • Recruiting
    • Research Center
  • Pančevo, Serbia, 26000
    • Recruiting
    • Research Site
  • Zaječar, Serbia, 19000
    • Recruiting
    • Research Center
• South Korea
  • Busan, South Korea, 49201
    • Recruiting
    • Research Site
  • Sejong, South Korea, 30099
    • Recruiting
    • Research Site
  • Seoul, South Korea, 06351
    • Recruiting
    • Research Site
  • Seoul, South Korea, 05505
    • Recruiting
    • Research Site
  • Seoul, South Korea, 06591
    • Recruiting
    • Research Site
  • Seoul, South Korea, 02841
    • Recruiting
    • Research Site
  • Gyeonggi-do
    • Seongnam-si, Gyeonggi-do, South Korea, 13620
      • Recruiting
      • Research Site
  • Jeollabuk-do
    • Jeonju, Jeollabuk-do, South Korea, 54907
      • Recruiting
      • Research Site
• Sweden
  • Gothenburg, Sweden, 41345
    • Recruiting
    • Research Center
  • Stockholm, Sweden, 14186
    • Recruiting
    • Research Center
• United Arab Emirates
  • Abu Dhabi, United Arab Emirates, 133500
    • Recruiting
    • Research Site
  • Abu Dhabi, United Arab Emirates, 51900
    • Recruiting
    • Research Site
  • Al Ain City, United Arab Emirates, 15258
    • Recruiting
    • Research Site
• United States
  • California
    • Los Angeles, California, United States, 90027
      • Recruiting
      • Research Site
    • Santa Clarita, California, United States, 91321
      • Recruiting
      • Clinical Research Site 4
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Recruiting
      • Research Site
  • Illinois
    • Springfield, Illinois, United States, 62702
      • Recruiting
      • Clinical Research Site 6
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Recruiting
      • Research Site
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Recruiting
      • Research Site
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • Research Site
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Recruiting
      • Research Site
  • Nebraska
    • North Platte, Nebraska, United States, 69101
      • Recruiting
      • Clinical Research Site 5
  • North Carolina
    • Greensboro, North Carolina, United States, 27401
      • Recruiting
      • Clinical Research Site 3
    • Wilmington, North Carolina, United States, 28412
      • Recruiting
      • Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Recruiting
      • Clinical Research Site 7
    • Pittsburgh, Pennsylvania, United States, 15213
      • Recruiting
      • Research Site
  • Texas
    • Mesquite, Texas, United States, 75149
      • Recruiting
      • Clinical Research Site 1
    • San Antonio, Texas, United States, 78233
      • Recruiting
      • Clinical Research Site 2
  • Washington
    • Seattle, Washington, United States, 98109
      • Recruiting
      • Research Site

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Males, or nonpregnant (who do not plan to become pregnant) nonlactating females
• Established diagnosis of SHTG and prior documented evidence of fasting TG levels of ≥ 880 mg/dL (≥ 10 mmol/L)
• Documented evidence of at least 1 prior AP event not attributed to other etiologies occurring within the last 60 months prior to Screening.
• Fasting low-density lipoprotein cholesterol (LDL-C) ≤ 130 mg/dL (≤ 3.37 mmol/L) at Screening
• Screening hemoglobin A1c (HbA1c) ≤ 9.5%
• Willing to follow diet counseling and maintain a stable low-fat diet
• Must be on standard of care lipid and TG-lowering medications per local guidelines (unless documented as intolerant, or a treatment failure 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.
• Use of any other hepatocyte targeted siRNA or antisense oligonucleotide molecule within 60 days or within 5 half-lives lives before day 1. Whichever is longer.
• AP ≤ 4 weeks prior to Randomization/Day 1
• Body mass index (BMI) > 45 kg/m^2
• Any planned bariatric surgery or similar procedures to induce weight lost starting at consent through End of Study (EOS)
• Planned coronary intervention (e.g. stent placement or heart bypass) during the study
• History of arterial revascularization within 16 weeks of Screening
• History of acute coronary syndrome event within 24 weeks of Screening
• Recent atherosclerotic cardiovascular disease (ASCVD) event within 24 weeks of Screening
• Recent unstable or symptomatic cardiac arrhythmia (including any associated medication changes) within 90 days of Screening. Individuals with stable well-controlled atrial arrhythmia will be allowed to participate in the study
• History of pacemaker or automatic implantable cardioverter defibrillators implant within 30 days before Screening
• New York Heart Association Class III-IV heart failure or last known ejection fraction of < 30%
• Current diagnosis of nephrotic syndrome
• Chronic kidney disease, defined by an estimated glomerular filtration rate (eGFR) < 20 mL/min/1.73 m^2
• Liver disease defined as cirrhosis or Child-Pugh Class B and C, or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5× Upper Limit of Normal (ULN) at Screening

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
Experimental: Plozasiran Injection; Plozasiran by SC injection every 3 months (Q3M) through completion of the randomized period Plozasiran by SC injection Q3M through completion of the OLE period	Drug: Plozasiran; ARO-APOC3 injection; Other Names: ARO-APOC3
Experimental: Placebo; calculated volume to match active treatment by SC injection (randomized period)	Drug: Placebo; sterile normal saline (0.9% NaCl)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Time to First Occurrence of Positively Adjudicated AP Event (Event Occurring More Than 10 Days After First Dose of Study Drug)	Randomization up to end of Double Blind Treatment Period compared to placebo (Approximate Maximum 50 Months)]

Secondary Outcome Measures

Outcome Measure	Time Frame
Percent Change from Baseline in Fasting Serum Triglyceride (TG) Levels	Baseline up to end of Double Blind Treatment Period compared to placebo (Approximate Maximum 50 Months)
Proportion of Participants Who Achieve Average Fasting TG Levels of < 880 mg/dL (10 mmol/L)	From Month 3 up to end of Double Blind Treatment Period compared to placebo (Approximate Maximum 50 Months)
Proportion of Participants Who Achieve Fasting TG Levels of < 500 mg/dL (5.65 mmol/L)	From Month 3 up to end of Double Blind Treatment Period compared to placebo (Approximate Maximum 50 Months)
Change from Baseline in Patient-Reported Productivity and Activity Impairment as Assessed by the Work Productivity and Activity Impairment Questionnaire - Specific Health Problem (WPAI-SHP) Score	Baseline up to end of Double Blind Treatment Period Study compared to placebo (Approximate Maximum 50 Months)
Change from Baseline in Patient-Reported Health Status as Assessed by the EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Score	Baseline up to end of Double Blind Treatment Period compared to placebo (Approximate Maximum 50 Months)
Number of Participants with Treatment-Emergent Adverse Events (TEAEs) compared to placebo	From first dose of study drug up to Study Completion (Approximate Maximum 62 Months)
Rate of Occurrence of Adjudicated Major Cardiovascular Events (MACE)	From first dose of study drug up to Study Completion (Approximate Maximum 62 Months)
Time to First Occurrence of Major Abdominal Pain Event (Event Occurring More Than 10 Days After the First Dose of Study Drug).	Randomization up to end of Double Blind Treatment Period compared to placebo (Approximate Maximum 50 Months)

Collaborators and Investigators

• Sponsor: Arrowhead Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): April 24, 2025
• Primary Completion (Estimated): March 1, 2029
• Study Completion (Estimated): June 1, 2029

Study Registration Dates

• First Submitted: March 12, 2025
• First Submitted That Met QC Criteria: March 12, 2025
• First Posted (Actual): March 18, 2025

Study Record Updates

• Last Update Posted (Actual): May 6, 2026
• Last Update Submitted That Met QC Criteria: May 1, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Nutritional and Metabolic Diseases; Hypertriglyceridemia; Substandard Drugs; Pharmaceutical Preparations; plozasiran
• Other Study ID Numbers: AROAPOC3-3011

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