Study of Plozasiran in Adults With Severe Hypertriglyceridemia at Risk of Acute Pancreatitis

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