A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx, an Antisense Inhibitor Administered Subcutaneously to Hypertensive Subjects With Controlled Blood Pressure

Subjects will be 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 subjects will complete 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 subject or the subject's non-pregnant female
partner must be using a highly effective contraceptive method

3. Body Mass Index (BMI) ≤ 35.0 kg/m2

4. Subject 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 BP and 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 subject unsuitable for
inclusion, including but not limited to:

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

2. Unwilling to discontinue antihypertensive mediations during WO and Treatment Period of
study

3. Subject has a history of secondary hypertension

4. 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 clinically-significant active atrial or ventricular arrhythmias

5. Any history of coronary bypass or percutaneous coronary intervention