This is a treatment program for the use of plozasiran in adults (AROAPOC3-EAP-002) and adolescents (AROAPOC3-EAP-003) with familial chylomicronemia syndrome (FCS) as well as in adults (AROAPOC3-EAP-004) with high risk severe hypertriglyceridemia (SHTG).

The program will enroll eligible patients ≥ 15 years of age, with fasting triglycerides (TGs) ≥ 880 mg/dL (≥ 10 mmol/L) that is not adequately controlled with standard lipid-lowering therapy, and with a diagnosis of FCS. Patients will receive 25 mg of plozasiran by subcutaneous (sc) injection on Day 1 and every 3 months for a total of 5 injections. The duration of the program is 15 months.

The program will also enroll eligible patients ≥18 years of age, with fasting TGs > 880 mg/dL (> 9.94 mmol/L), or fasting TGs > 500 mg/dL plus a history of acute pancreatitis, that are not adequately controlled with standard lipid-lowering therapy, and with a diagnosis of high risk SHTG. SHTG patients will receive 25 mg of plozasiran by sc injection on Day 1 and every 3 months for a total of 7 injections. The duration of the program is 21 months.

FCS Inclusion Criteria:

• ≥ 15 years of age
• Fasting TG levels ≥ 880 mg/dL that are not sufficiently controlled on standard lipid-lowering therapy
• Established diagnosis of FCS based on documented history of fasting TG levels in excess of 1000 mg/dL on repeated testing (for at least 3 prior occasions), and at least 1 of the following: a supportive genetic test, documented history of recurrent episodes of acute pancreatitis not caused by alcohol or cholelithiasis, documented history of recurrent hospitalizations for severe abdominal pain without other explainable cause, documented history of childhood pancreatitis, family history of hypertriglyceridemia-induced pancreatitis
• Willing to follow dietary counseling based on local standard of care, consistent with an intake of ≤ 20 g of fat per day
• If on medications for management of type 2 diabetes the dosing regimen must be stable.
• Participants of childbearing potential must agree to use a highly effective form of contraception in addition to a male condom during the program and for at least 90 days after the last dose of plozasiran

SHTG Inclusion Criteria:

• Established diagnosis of high risk SHTG and documented evidence (medical history) of either: fasting triglycerides (TG) ≥ 880 mg/dL OR fasting TG levels of ≥ 500 mg/dL AND history of recurrent episodes of acute pancreatitis not caused by alcohol or cholelithiasis
• Hemoglobin A1c (HbA1c) ≤ 9.0% at Day 1
• Fasting low density lipoprotein cholesterol (LDL-C) ≤130 mg/dL (≤ 3.37 mmol/L) at Day 1
• Willing to follow dietary counseling and maintain stable, low-fat diet Participant must be on standard of care lipid and TG-lowering medications per local guidelines,
• If the participant has a medical history of clinical atherosclerotic cardiovascular disease (ASCVD) or an elevated 10-year ASCVD risk, the participant must be on appropriate lipid-lowering therapy as per local standard of care prior to collection of qualifying TG levels
• Females of childbearing potential must agree to use a highly effective form of contraception and males must agree to use a condom during the program and for at least 90 days after the last dose of plozasiran

FCS Exclusion Criteria:

• Diabetes mellitus with any of the following at Day 1: newly diagnosed within the past 24 weeks, HbA1c ≥ 9.0% within the past 4 weeks, meaningful medical events relating to poor glycemic control, changes in basal insulin regimen of more than =/- 10 units within 12 weeks if insulin-dependent
• Clinical evidence of primary hypothyroidism, primary subclinical hypothyroidism, or secondary hypothyroidism
• History of bleeding diathesis or coagulopathy
• Current diagnosis of nephrotic syndrome
• Eligible to receive any commercially available FDA-approved therapeutic for treatment of FCS unless proven to be ineffective or judged inappropriate by the treating physician
• History of acute coronary syndrome events (adults with FCS only)
• New York Heart Association Class III or IV heart failure or last known ejection fraction of <30% (adults with FCS only)
• History of stroke, transient ischemic attack, or peripheral artery disease within 24 weeks of first dose (adults with FCS only)

SHTG Exclusion Criteria:

• Eligible for approved Redemplo®.
• Untreated or inadequately treated hypothyroidism or hypothyroidism
• Eligible for any current study of plozasiran
• History of acute coronary syndrome events
• New York Heart Association Class IV heart failure or last known ejection fraction of < 30%
• Known clinically significant blood dyscrasia

Note: Additional inclusion/exclusion criteria may apply per protocol