Hypertension| IONIS-AGT-LRx

Inclusion Criteria:

• Males or females aged 18-80 inclusive and weighing ≥ 50 kilograms (kg) at the time of informed consent
• Females: must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal
• Males must be abstinent, surgically sterile or if engaged in sexual relations with a woman of childbearing potential (WOCBP), a highly effective contraceptive method must be used
• Body mass index (BMI) ≤ 45.0 kilograms per square meter (kg/m^2)
• At screening, the participant must have been on a stable regimen (per Investigator judgement) of 3 or more antihypertensive medications for at least 1 month prior to screening and will be required to maintain this regimen throughout the study. The combination of antihypertensive medications must be in the following categories: a) angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB), b) beta blocker: c) calcium channel blocker d) non-potassium sparing diuretic, e) alpha-1 blocker f) centrally acting sympatholytic agent or g) direct acting vasodilators (e.g. hydralazine)

Exclusion Criteria:

• Clinically significant abnormalities in screening laboratory results, medical history according to Investigator judgment
• History of secondary hypertension (HTN) including, but not limited to any of the following: renovascular HTN (unilateral or bilateral renal artery stenosis), coarctation of the aorta, primary hyperaldosteronism, Cushing’s disease, pheochromocytoma, polycystic kidney disease, and drug-induced HTN
• The use of the following at time of screening and during the course of the study:
• Other medications for the treatment of HTN (e.g., minoxidil, diazoxide, renin inhibitors)
• Medications that may cause hyperkalemia (e.g., cyclosporine or tacrolimus, pentamidine, trimethoprim-sulfamethoxazole, all heparins)
• Use of oral anticoagulants, unless stable for 4 weeks prior to the first dose of study drug and regular monitoring must be performed per clinical practice during the study unless the participant is receiving vitamin K agonists. If the participant is receiving vitamin K antagonists (e.g., warfarin) international normalized ratio (INR) should be in therapeutic range, as established by the Investigator, for 4 weeks prior to the first dose
• Chronic administration of NSAIDs or COX-2 inhibitors (except aspirin for cardiovascular disease provided the total daily dose does not exceed 325 mg)
• Potassium sparing diuretics (e.g., eplerenone, spironolactone, amiloride, triamterene)
• History of bleeding diathesis, coagulopathy, immune thrombocytopenic purpura (ITP), thrombotic cytopenic purpura (TTP), or any qualitative or quantitative platelet defect
• Unstable/underlying known cardiovascular disease defined as:
• Any history of congestive heart failure (New York Heart Association [NYHA] Class III-IV)
• Any history of previous myocardial infarction, coronary revascularization, unstable or stable angina pectoris ˂ 1 year prior to screening
• 12-lead electrocardiogram (ECG) demonstrating a QT interval (corrected using Fridericia’s formula [QTcF]) ˃ 450 milliseconds (msec) in males and ˃ 470 msec in females at screening, or a history or evidence of long QT syndrome
• Any hemodynamically unstable atrial or ventricular arrhythmias
• Significant uncorrected valvular heart disease
• Any history of stroke or transient ischemic attack < 1 year prior to screening
• A cardiac valve repair, cardiac device implantation, and/or a hospitalization for heart failure within 3 months of screening
• Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1
• Participant works nighttime shifts (e.g., 11 PM to 7 AM)