A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx in Participants With Chronic Heart Failure With Reduced Ejection Fraction

Inclusion Criteria:

1. Females must be non-pregnant and non-lactating and of non- childbearing potential.
2. Males must be surgically sterile or, abstinent or, if engaged in sexual relations witha woman of child-bearing potential (WOCBP), she must be willing to use a highlyeffective contraceptive method
3. Screening NT-proBNP ≥ 600 picograms per milliliter (pg/mL) and less than (<) 8500pg/mL
4. Established diagnosis of heart failure (HF) with reduced systolic function for atleast 6 months prior to the screening visit (left ventricular ejection fraction, [LVEF] ≤ 40%
5. New York Heart Association class I-III Participants should receive background standard of care for HFrEF. Therapy should have beenindividually optimized and stable for ≥ 4 weeks before randomization and include:
6. An angiotensin-converting-enzyme inhibitor (ACEi), or angiotensin II receptor blockers (ARBs) or sacubitril/valsartan (mandatory)
7. A beta-blocker (unless contraindicated or not tolerated)
8. A mineralocorticoid receptor antagonist (MRA, unless contraindicated or not tolerated)

Exclusion Criteria:

1. HF due to restrictive cardiomyopathy, active myocarditis, chemotherapy, hypertrophiccardiomyopathy, primary cardiac valve disease, non-compaction cardiomyopathy, ortakotsubo cardiomyopathy.
2. Acute decompensated HF requiring intravenous (IV) diuretics, IV inotropes or IVvasodilators with discharge date within 30 days of screening or acute mechanicalsupport (e.g., intra-aortic balloon pump, endotracheal intubation, mechanicalventilation, or any ventricular assist device) with discharge date within 90 days ofscreening.
3. Symptomatic hypotension or systolic blood pressure (SBP) ≤ 90 millimeters of mercury (mmHg) at screening.
4. Uncontrolled hypertension (HTN) (SBP > 160 mmHg or diastolic blood pressure (BP) > 100mmHg) prior to screening.
5. Heart transplant, and/or Left Ventricular Assist Device (LVAD) prior to screening oranticipated heart transplant or LVAD during the study.
6. Implantation of a cardiac resynchronization therapy device (CRT) within 3 months priorscreening or intent to implant a CRT within 3 months after screening.
7. Acute coronary syndrome, unstable angina, stroke, transient ischemic attack (TIA),coronary revascularization, cardiac device implantation, cardiac valve repair, carotidor other major surgery within 3 months of screening.
8. Coronary, valve or carotid artery disease likely to require surgical or percutaneousintervention within the 3 months after screening.
9. Severe pulmonary disease with any of the following:
10. Requirement of continuous (home) oxygen or
11. Known diagnosis of severe chronic obstructive pulmonary disease (as defined bythe American Thoracic Society/European Respiratory Society) or severe restrictivelung disease, in the opinion of the investigator.
12. Screening laboratory results as follows, or any other clinically significantabnormalities in screening laboratory values that would render a participantunsuitable for inclusion in the opinion of the investigator.
13. Alanine aminotransferase/aspartate aminotransferase (ALT/AST) > 2.0 × upper limitof normal (ULN).
14. Total bilirubin ≥ 1.5 × ULN (participants with total bilirubin ≥ 1.5 × ULN may beallowed on study if indirect bilirubin only is elevated, ALT/AST is not greaterthan the ULN, and known to have Gilbert's disease).
15. Platelets < 100,000/millimeter^3 (mm^3).
16. Urine protein creatinine ratio (UPCR) ≥ 500 milligrams per gram (mg/g).
17. Hemoglobin A1c (HbA1c) > 9.5% or uncontrolled diabetes per investigatorjudgement.
18. Estimated glomerular filtration rate (eGFR) < 30 milliliters/ minute /1.73 m^2 (mL/min/1.73 meter^2) at screening.
19. Abnormal thyroid function tests with clinical significance per investigatorjudgement.
20. Serum potassium > 5.1 millimoles per liter (mmol/L) at screening.
21. Requirement of treatment with both ACEi and ARBs.
22. Previous history of intolerance to ACEi or ARBs or history of hyperkalemia.