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

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

Detailed Description
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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.

Official Title
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A Double-Blind, Placebo-Controlled, Phase 2 Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx, an Antisense Inhibitor Administered Subcutaneously to Hypertensive Subjects With Controlled Blood Pressure

Conditions
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Mild Hypertension

Intervention / Treatment
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* Drug: Placebo
* Drug: ISIS 757456


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria 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, the participant or the participant's non-pregnant female partner must be using a highly effective contraceptive method Body Mass Index (BMI) ≤ 35.0 kg/m2 Participant must have been diagnosed with essential hypertension for a minimum of 3 months prior to screening At Screening, on a stable regimen of antihypertensive medications for at least 1 month prior to screening 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 Clinically-significant (CS) abnormalities in medical history, screening laboratory results, physical or physical examination that would render a participant unsuitable for inclusion The use of the following at time of screening and during the course of the study: Other medications for the treatment of hypertension (e.g., clonidine, guanfacine, guanabenz, alpha-methyldopa, hydralazine, minoxidil, diazoxide, renin inhibitors) Medications that also may cause hyperkalemia (e.g., cyclosporine or tacrolimus, pentamidine, trimethoprim-sulfamethoxazole, all heparins) Oral or subcutaneous anticoagulants (e.g., warfarin, rivaroxaban, apixaban, heparin, lovenox) Organic nitrate preparations (e.g., nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, or pentaerythritol) Sildenafil, tadalafil, vardenafil Unwilling to discontinue antihypertensive mediations during Wash Out (WO) and Treatment Period of study Participant has a history of secondary hypertension Unstable/underlying cardiovascular disease defined as: Any history of congestive heart failure (NYHA class II-IV) Any history of previous stroke, transient ischemic attack, unstable or stable angina pectoris, or myocardial infarction prior to screening a history or evidence of long QT syndrome Any CS active atrial or ventricular arrhythmias Any history of coronary bypass or percutaneous coronary intervention

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 72 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo matching solution injected subcutaneously (SC) once weekly for up to 6 weeks and an additional loading dose on Day 3. | Drug: Placebo<br>* Placebo matching solution administered as SC injection.<br>|
| Experimental: ISIS 757456 80 mg<br>ISIS 757456 80 mg injected SC once weekly for up to 6 weeks and an additional loading dose of 80 mg on Day 3. | Drug: ISIS 757456<br>* Administered as SC injection.<br>* Other names: IONIS-AGT-LRx;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Plasma Angiotensinogen (AGT) at Day 43 (Week 7) Compared to Placebo |  | Baseline, Week 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the In-clinic Systolic Blood Pressure (SBP) at Days 3, 8, 15, 22, 29, and 36 |  | Baseline, Days 3, 8, 15, 22, 29, and 36 | 
| Percent Change From Baseline in Plasma AGT at Days 3, 8, 15, 22, 29 and 36 |  | Baseline, Days 3, 8, 15, 22, 29, and 36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypertension, Hypertensive, AGT, Angiotensinogen, Blood Pressure, High Blood Pressure