A Study to Assess the Safety, Tolerability, and Efficacy of Monthly Subcutaneous Administration of ION904 in Participants With Uncontrolled Hypertension

A Double-Blind, Placebo-Controlled, Phase 2 Study to Assess the Safety, Tolerability and Efficacy of Monthly Subcutaneous Administration of ION904 in Patients With Uncontrolled Hypertension

The purpose of this study is to evaluate the effect of ION904 on plasma angiotensinogen (AGT) in participants with uncontrolled hypertension.

This is a Phase 2, multicenter, double-blind, randomized, placebo-controlled study. It will include up to approximately 48 participants with mild to moderate hypertension who have uncontrolled blood pressure (˃ 130 - ≤ 170 millimeters of mercury [mmHg] systolic) and have been on one or more anti-hypertensive medications for at least one month. Following an up to 4-week screening period, eligible participants will receive multiple doses of ION904 during a 13-week treatment period, followed by a 13-week post-treatment follow-up period.

General Inclusion Criteria:

1. Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential (WOCBP), she uses a highly effective contraceptive method. Aged 18 - 75 inclusive and weighing ≥ 50 kilograms (kg) at the time of informed consent
2. Body mass index (BMI) ≤ 45.0 kilograms per square meter (kg/m^2) at screening
3. History of uncontrolled hypertension (HTN) on one or more antihypertensive medications without changes in antihypertensive regimen within 4 weeks of screening and will be required to maintain this regimen throughout the Treatment Period

General Exclusion Criteria:

1. History of secondary 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

2. 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 ˂ 6 months prior to screening
   • Any hemodynamically unstable atrial or ventricular arrhythmias
   • Significant uncorrected valvular heart disease
   • Any history of stroke or transient ischemic attack < 6 months prior to screening

3. A cardiac valve repair, cardiac device implantation, and/or a hospitalization for heart failure within 3 months of screening