Long-Term Safety and Efficacy of Plozasiran in Adults With Hypertriglyceridemia

Inclusion Criteria:

• Adult males, or nonpregnant (who do not plan to become pregnant), nonlactating adultfemales, who are able and willing to provide written informed consent prior to theperformance of any study-specific procedures

• Completed all required study visits per protocol in the parent study

• Female subjects of childbearing potential must agree to use a highly effectivemethod of contraception during the study and for at least 90 days after the End ofStudy (EOS) or the last dose of plozasiran, whichever is later. Male subjects mustagree to use a condom during the study and for at least 90 days after the EOS orlast dose of plozasiran whichever is later. Subjects must not donate sperm or eggsduring the study and for at least 90 days after the EOS or last dose of plozasiran,whichever is later. Female subjects of childbearing potential on hormonalcontraceptives must be stable on medication for >1 menstrual cycle prior to Day 1.

• Subjects must be on standard of care lipid and TG-lowering medications per localguidelines (unless documented as intolerant as determined by the Investigator,including an inability to safely administer or re-administer a specific drug becauseof fear, preference, genetic, clinical, or metabolic considerations, or due to aprevious adverse reaction associated with, attributed to, or caused by specificdrug)

• If the subject has a medical history of clinical atherosclerotic cardiovasculardisease (ASCVD) or elevated 10-year ASCVD risk (eg, ≥7.5% per American HeartAssociation/American College of Cardiology [AHA/ACC] risk calculator for subjects ≥40 years of age or Framingham risk score calculator for subjects under the age of 40), the subject must be on appropriate lipid-lowering therapy as per local standardof care (ie, including moderate-to-high intensity statin, as indicated).

If the subject has diabetes:

1. Subject must be on optimized antidiabetic regimen as defined by the local standards,Investigator, and institutional practices

2. Subject must have no events of diabetic ketoacidosis, diabetic decompensation/hyperosmolar hyperglycemic nonketotic coma, diabetes complications, recurrentinfections, or hospitalization related to poor glycemic control within 24 weeks ofthe Day 1 visit - Willing to follow diet counseling and maintain a stable low-fatdiet

Subjects in the USA and Canada who completed protocol AROAPOC3-2003 meeting all eligibility criteria (with the exception of inclusion criteria #9 which is not applicable to these subjects) who also meet the following additional criteria may enroll in this trial:

• HbA1c ≤10% within 30 days prior to Day 1

• Completed AROAPOC3-2001 prior to entry into AROAPOC3-2003 AND either (c) or (d)below:

• Baseline fasting TG level of ≥500 mg/dL and prior history of acute pancreatitis atthe time of enrollment into AROAPOC3-2001

• Baseline fasting TG level of ≥1000 mg/dL at the time of enrollment intoAROAPOC3-2001

• Subjects who previously met all eligibility requirements for AROAPOC3-3003, orAROAPOC3-3004 and were not permitted to proceed to randomization per Sponsor'sdirection in order to prevent excessive over-enrollment may also be enrolled inthis trial. These subjects must meet all eligibility criteria prior toenrollment (with the exception of inclusion criteria #2 and #8 which are notapplicable to these subjects) and have an HbA1c ≤10% within 30 days of Day 1.

Exclusion Criteria:

• Subject was permanently discontinued from receiving plozasiran in the parent studydue to elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT)or due to HbA1c elevation that did not respond to antidiabetic regimen

• Subject withdrew consent for continued study treatment in the parent study

• Known hypersensitivity to the active substance or to any of the excipients ofplozasiran

• Known hypersensitivity to the active substance or to any of the excipients ofplozasiran

• Any new condition or worsening of existing condition or any other situation that inthe Investigator's judgment, would make the subject unsuitable for enrollment, couldinterfere with the subject participating in or completing the study, would make itdifficult to comply with protocol requirements, or put the subject at an additionalsafety risk

• Unwilling to limit alcohol consumption to within moderate limits for the duration ofthe study.

• Poorly controlled glycemia (ie, HbA1c >10%) based upon the most recent HbA1c levelreported in the parent trial prior to Day 1

• Acute pancreatitis within 4 weeks prior to Day 1

• Use of any hepatocyte-targeted siRNA that targets lipids and/or triglycerides within 365 days before Day 1 (except plozasiran or inclisiran, which are permitted).Administration of inclisiran must be separated from administration of plozasiran byat least 4 weeks throughout the treatment period

• Use of any other hepatocyte targeted siRNA or antisense oligonucleotide moleculewithin 60 days or within 5 half-lives before Day 1 based on plasma PK, whichever islonger.

• Use of an investigational agent (other than plozasiran) or device within 30 days orwithin 5 half-lives, based on plasma PK, whichever is longer, prior to Day 1 (V1) orcurrent participation in an interventional investigational study.

• Recent unstable or symptomatic cardiac arrhythmia (including any associatedmedication changes) within 90 days prior to Day 1. Individuals with stablewell-controlled atrial arrhythmias will be allowed to participate in the study.

• Uncontrolled hypertension (ie, seated systolic blood pressure >160 mmHg and/ordiastolic blood pressure >100 mmHg) at Day 1; subject may be re-evaluated whenhypertension is controlled.

Note: Other inclusion/exclusion criteria may apply per protocol