This was a Phase 2, double-blind, randomized, placebo-controlled study of IONIS-AGT-LRx conducted in mild hypertensive participants.

Participants were randomized in a 2:1 ratio to receive a once-weekly subcutaneous treatment and an additional loading dose on Study Day 3 with either IONIS-AGT-LRx or placebo for 6 weeks.

All participants completed a 13-week Post-Treatment Period.

Inclusion Criteria

1. Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal.
2. Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential, the participant or the participant's non-pregnant female partner must be using a highly effective contraceptive method
3. Body Mass Index (BMI) ≤ 35.0 kg/m2
4. Participant must have been diagnosed with essential hypertension for a minimum of 3 months prior to screening
5. At Screening, on a stable regimen of antihypertensive medications for at least 1 month prior to screening
6. Agree to conduct at home Blood Pressure (BP) and Heart Rate (HR) monitoring three times weekly and document the average of the triplicate measurements assessed on a day in the patient diary

Exclusion Criteria

1. Clinically-significant (CS) abnormalities in medical history, screening laboratory results, physical or physical examination that would render a participant unsuitable for inclusion

2. The use of the following at time of screening and during the course of the study:

   1. Other medications for the treatment of hypertension (e.g., clonidine, guanfacine, guanabenz, alpha-methyldopa, hydralazine, minoxidil, diazoxide, renin inhibitors)
   2. Medications that also may cause hyperkalemia (e.g., cyclosporine or tacrolimus, pentamidine, trimethoprim-sulfamethoxazole, all heparins)
   3. Oral or subcutaneous anticoagulants (e.g., warfarin, rivaroxaban, apixaban, heparin, lovenox)
   4. Organic nitrate preparations (e.g., nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, or pentaerythritol)
   5. Sildenafil, tadalafil, vardenafil

3. Unwilling to discontinue antihypertensive mediations during Wash Out (WO) and Treatment Period of study

4. Participant has a history of secondary hypertension

5. Unstable/underlying cardiovascular disease defined as:

   1. Any history of congestive heart failure (NYHA class II-IV)
   2. Any history of previous stroke, transient ischemic attack, unstable or stable angina pectoris, or myocardial infarction prior to screening
   3. a history or evidence of long QT syndrome
   4. Any CS active atrial or ventricular arrhythmias
   5. Any history of coronary bypass or percutaneous coronary intervention