A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx

This study evaluated the effect of ISIS 757456 (IONIS-AGT-LRx) on plasma angiotensinogen (AGT) and systolic blood pressure (SBP) in uncontrolled hypertensive participants who were on two to three antihypertensive medications.

This study was a Phase 2, double-blind, randomized, placebo-controlled study in 26 participants. Participants were randomized in a 2:1 ratio and received a once-weekly subcutaneous (SC) treatment with either IONIS-AGT-LRx or placebo, with an additional loading dose administered on Study Day 3. The treatment lasted for 8 weeks and the post-treatment period lasted for 13 weeks.

Eligibility Criteria:
Inclusion criteria:

* Males or females aged 18-75 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 surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential (WOCBP), the participant or participant's non-pregnant female partner must be using a highly effective contraceptive method
* Body mass index (BMI) ≤ 35.0 kg/square meter (m\^2)
* Participant must have been diagnosed with essential hypertension for a minimum of 3 months prior to screening
* At screening, the participant must have been on a stable regimen of 2 to 3 antihypertensive medications for at least 1 month prior to screening and will be required to maintain this regimen throughout the study, using either an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB), as well as 1 or 2 additional antihypertensive medications in the following categories: beta blocker, acebutolol, atenolol, betaxolol, bisoprolol, carvedilol, labetalol, metoprolol, nadolol, nebivolol, propranolol, pindolol, calcium channel blocker or, non-potassium sparing diuretic

Exclusion Criteria:

* Clinically significant abnormalities in medical history, screening laboratory results, or physical examination that would render the participant unsuitable for inclusion
* History of secondary hypertension (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., clonidine, guanfacine, guanabenz, alpha-methyldopa, hydralazine, minoxidil, diazoxide, renin inhibitors)
* Medications that may cause hyperkalemia (e.g., cyclosporine or tacrolimus, pentamidine, trimethoprim-sulfamethoxazole, all heparins)
* Oral or SC anticoagulants (e.g., warfarin, rivaroxaban, apixaban, heparin, lovenox)
* Organic nitrate preparations (e.g., nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, or pentaerythritol)
* Phosphodiesterase 5 inhibitors (e.g., sildenafil, tadalafil, vardenafil, avanafil)
* Potassium-sparing diuretics (e.g., eplerenone, spironolactone, amiloride, triamterene)

Unstable/underlying cardiovascular disease defined as:

* Any history of congestive heart failure (New York Heart Association \[NYHA\] class II-IV)
* Any history of previous stroke, transient ischemic attack, unstable or stable angina pectoris, or myocardial infarction prior to screening
* 12-lead electrocardiogram (ECG) 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 clinically significant active atrial or ventricular arrhythmias
* Any history of coronary bypass or percutaneous coronary intervention