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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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 for 8 Weeks to Hypertensive Subjects With Uncontrolled Blood Pressure

Conditions
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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: 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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>Participants received ISIS 757456-matching placebo, subcutaneous (SC) injection, once-weekly for 8 weeks and an additional loading dose on Day 3. | Drug: Placebo<br>* ISIS 757456-matching placebo solution administered as SC injection.<br>|
| Experimental: ISIS 757456<br>Participants received ISIS 757456 80 mg, SC injection, once-weekly for 8 weeks and an additional loading dose on Day 3. | Drug: ISIS 757456<br>* ISIS 757456 administered as SC injection.<br>|

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 57 Compared to Placebo | The baseline for plasma AGT was defined as the average of all values prior to the first dose of study drug. | Baseline up to Day 57 (start of Week 9) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Systolic Blood Pressure (SBP) at Each Scheduled, Post-Baseline Visit |  | Baseline, Days 3, 8, 15, 22, 29, 36, 43, 50, 57, 64, 78, 92, 120, and 141 | 
| Absolute Change From Baseline in Plasma AGT at Each Scheduled, Post-Baseline Visit | The baseline for plasma AGT was defined as the average of all values prior to the first dose of study drug | Baseline, Days 3, 8, 15, 22, 29, 36, 43, 50, 57, 64, 78, 92, 120, and 141 | 
| Percent Change From Baseline in Plasma AGT at Each Scheduled, Post-Baseline Visit | The baseline for plasma AGT was defined as the average of all values prior to the first dose of study drug. | Baseline, Days 3, 8, 15, 22, 29, 36, 43, 50, 64, 78, 92, 120, and 141 | 

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