A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx in Hypertensive Participants With Uncontrolled Blood Pressure

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, maximally tolerated 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) 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 unless on a stable dose at least 1 month prior to the screening visit and no known history of hyperkalemia per Investigator judgement * 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 non-steroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase 2 (COX-2) inhibitors (except aspirin for cardiovascular disease provided the total daily dose does not exceed 325 mg) * 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 * 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 * Participant works nighttime shifts (e.g., 11 PM to 7 AM)