A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx in Hypertensive Participants With Uncontrolled Blood Pressure

Phase 2

Completed

• Conditions: Hypertension
• Interventions: Drug: Placebo; Drug: IONIS-AGT-LRx

• Registration Number: NCT04714320
• Lead Sponsor: Ionis Pharmaceuticals, Inc.

Brief Summary

The purpose of this study was to evaluate the effect of IONIS-AGT-LRx compared to placebo on seated automated office systolic blood pressure (SBP) from baseline to Study Day 85 in uncontrolled hypertensive participants on ≥ 3 antihypertensive medications and to evaluate the effect of IONIS-AGT-LRx on ambulatory blood pressure, seated automated office SBP, seated automated office diastolic blood pressure (DBP), and plasma angiotensinogen (AGT) at each scheduled visit in uncontrolled hypertensive participants on ≥ 3 antihypertensive medications.

Detailed Description

This was a phase 2, double-blind, randomized, placebo-controlled study in up to 160 participants. Participants were randomized in a 2:1 ratio and received a once-weekly subcutaneous (SC) treatment with either IONIS-AGT-LRx or matching placebo. The length of participation in the study was approximately 31 weeks, which included an up to 6-week screening period, a 12-week treatment period, and a 13-week post-treatment period.

Study Timeline

• Study First Submitted: 2021-01-14
• Study First Submitted QC: 2021-01-14
• Study First Posted: 2021-01-19
• Study Start: 2021-04-28
• Primary Completion: 2022-06-29
• Disposition First Submitted: 2022-09-14
• Study Completion: 2022-10-03
• Results First Submitted: 2024-09-13
• Status Verified: 2025-02
• Results First Submitted QC: 2025-02-14
• Last Update Submitted: 2025-02-14
• Results First Posted: 2025-02-18
• Disposition First Posted: 2025-02-18
• Last Update Posted: 2025-02-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 160

Inclusion Criteria

• Males or females aged 18-80 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 abstinent, surgically sterile or if engaged in sexual relations with a woman of childbearing potential (WOCBP), a highly effective contraceptive method must be used
• Body mass index (BMI) ≤ 45.0 kilograms per square meter (kg/m^2)
• At screening, the participant must have been on a stable, maximally tolerated regimen (per Investigator judgement) of 3 or more antihypertensive medications for at least 1 month prior to screening and will be required to maintain this regimen throughout the study. The combination of antihypertensive medications must be in the following categories: a) angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB), b) beta blocker: c) calcium channel blocker d) diuretic, e) alpha-1 blocker f) centrally acting sympatholytic agent or g) direct acting vasodilators (e.g. hydralazine)

Exclusion Criteria

• Clinically significant abnormalities in screening laboratory results, medical history according to Investigator judgment

• History of secondary hypertension (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

• 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., minoxidil, diazoxide, renin inhibitors)
  • Medications that may cause hyperkalemia unless on a stable dose at least 1 month prior to the screening visit and no known history of hyperkalemia per Investigator judgement
  • Use of oral anticoagulants, unless stable for 4 weeks prior to the first dose of study drug and regular monitoring must be performed per clinical practice during the study unless the participant is receiving vitamin K agonists. If the participant is receiving vitamin K antagonists (e.g., warfarin) international normalized ratio (INR) should be in therapeutic range, as established by the Investigator, for 4 weeks prior to the first dose
  • Chronic administration of non-steroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase 2 (COX-2) inhibitors (except aspirin for cardiovascular disease provided the total daily dose does not exceed 325 mg)

• History of bleeding diathesis, coagulopathy, immune thrombocytopenic purpura (ITP), thrombotic cytopenic purpura (TTP), or any qualitative or quantitative platelet defect

• 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 ˂ 1 year prior to screening
  • Any hemodynamically unstable atrial or ventricular arrhythmias
  • Significant uncorrected valvular heart disease
  • Any history of stroke or transient ischemic attack < 1 year prior to screening

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

• Participant works nighttime shifts (e.g., 11 PM to 7 AM)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Pooled Placebo	Placebo	Participants received ISIS 757456 matching placebo subcutaneously once weekly for 12 weeks.
IONIS-AGT-LRx 80 mg	IONIS-AGT-LRx	Participants received ISIS 757456 80 milligrams (mg), subcutaneous (SC) injection, once weekly for 12 weeks.
IONIS-AGT-LRx 120 mg	IONIS-AGT-LRx	Participants received ISIS 757456 120 mg, SC injection, once weekly for 12 weeks.

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Seated Automated Office SBP to Day 85	Baseline to Day 85

Secondary Outcome Measures

Name	Time	Method
Absolute Concentration of Plasma AGT at Each Scheduled, Post-Baseline Visit	Days 15, 29, 43, 57, 71, 85, 92, 106, 120, 148, and 169
Change From Baseline in Plasma AGT to Each Scheduled, Post-Baseline Visit	Baseline, Days 15, 29, 43, 57, 71, 85, 92, 106, 120, 148, and 169
Percent Change From Baseline in Plasma AGT at Each Scheduled, Post-Baseline Visit	Baseline, Days 15, 29, 43, 57, 71, 85, 92, 106, 120, 148, and 169
Percentage of Participants Who Achieved Seated Automated SBP ≤ 130 mmHg, DBP ≤ 80 mmHg, and Both at Each Scheduled Post-Baseline Visit	Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 92, 106, 120, 148, and 169
Change From Baseline to Study Day 85 in 24-hour Mean SBP and Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring (ABPM)	Baseline, Day 85
Percentage of Participants Who Achieved Seated Automated Office SBP ≤ 140 mmHg, DBP ≤ 90 mmHg, and Both at Each Scheduled Post-Baseline Visit	Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 92, 106, 120, 148, and 169
Change From Baseline in Seated Automated Office SBP to Each Scheduled, Post-Baseline Visit	Baseline, Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 92, 106, 120, 148, and 169
Change From Baseline in Seated Automated Office DBP to Each Scheduled, Post-Baseline Visit	Baseline, Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 92, 106, 120, 148, and 169

Trial Locations

Locations (50)

Pinnacle Research Group; 🇺🇸 Anniston, Alabama, United States

Central Research Associates, Inc.; 🇺🇸 Birmingham, Alabama, United States

Achieve Clinical Research, LLC; 🇺🇸 Birmingham, Alabama, United States

Cahaba Research, Inc.; 🇺🇸 Pelham, Alabama, United States

Syed Research Consultants LLC; 🇺🇸 Sheffield, Alabama, United States

Cardiology and Medicine Clinic; 🇺🇸 Little Rock, Arkansas, United States

Advanced Research Center; 🇺🇸 Anaheim, California, United States

National Research Institute - Huntington Park; 🇺🇸 Huntington Park, California, United States

RESPIRE Research; 🇺🇸 La Mesa, California, United States

Clinical Trials Research; 🇺🇸 Lincoln, California, United States

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