Zilebesiran for High Blood Pressure

(ZENITH Trial)

Recruiting at 28 trial locations

Overseen By Clinical Trial Information Line

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Alnylam Pharmaceuticals

Must be taking: Diuretics

Disqualifiers: Secondary hypertension, Orthostatic hypotension, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Event-driven until the targeted number of clinical outcome events are reached

11000 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called zilebesiran to determine if it can better prevent serious heart problems, such as heart attacks, strokes, or heart failure, compared to a placebo. Participants will receive either zilebesiran or a placebo in addition to their regular blood pressure medication every six months. The trial targets individuals with cardiovascular disease or those at high risk who are already taking at least two types of blood pressure medication, including a diuretic, which helps the body eliminate excess salt and water. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants an opportunity to contribute to potentially groundbreaking treatment advancements.

Do I have to stop taking my current medications for the trial?

The trial does not specify if you need to stop taking your current medications. However, it requires that you are on stable therapy with at least two blood pressure medications, including a specific type of diuretic.

Is there any evidence suggesting that zilebesiran is likely to be safe for humans?

Research has shown that zilebesiran is generally safe for people. In earlier studies, patients who took a single dose of 200 mg or more experienced some reduction in blood pressure without major side effects. A review of these studies confirmed that zilebesiran consistently lowered blood pressure both during activity and in a doctor's office. These results suggest the treatment does not cause significant harmful effects. The current trial is in a late stage, indicating sufficient evidence from earlier studies to support testing zilebesiran in more people. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike most treatments for high blood pressure, which typically involve daily oral medications like ACE inhibitors, beta-blockers, or calcium channel blockers, Zilebesiran offers a unique approach by being administered subcutaneously just once every six months. This is exciting because it targets the angiotensinogen pathway, potentially providing a more sustained and consistent blood pressure control compared to the fluctuating levels seen with daily pills. The extended dosing schedule could greatly improve patient adherence, making it easier for people to stick to their treatment regimen and potentially leading to better long-term outcomes.

What evidence suggests that zilebesiran might be an effective treatment for high blood pressure?

Research has shown that zilebesiran, which participants in this trial may receive, can effectively lower blood pressure. In earlier studies, a single 300 mg dose of zilebesiran reduced office systolic blood pressure by 5 mmHg compared to a placebo after three months. Other studies have found that doses of at least 200 mg lowered systolic blood pressure by more than 10 mmHg and diastolic blood pressure by more than 5 mmHg. These consistent reductions suggest that zilebesiran could be a promising treatment for managing high blood pressure and reducing the risk of heart-related issues. ^{1 2 3 4 5}

Who Is on the Research Team?

Medical Director

Principal Investigator

Alnylam Pharmaceuticals Inc

Are You a Good Fit for This Trial?

This trial is for individuals with high blood pressure that's not well-controlled, who also have heart disease or a high risk of cardiovascular issues. Specific eligibility details are not provided, but typically participants must meet certain health criteria to join.

Inclusion Criteria

I am 18 or older with cardiovascular disease.

I am 55 or older and at high risk for cardiovascular disease.

I have heart or blood vessel disease, or I'm at high risk for it.

Exclusion Criteria

Has alanine aminotransferase (ALT) or aspartate aminotransferase >3×upper limit of normal (ULN)

Has total serum bilirubin >1.5×ULN

Has international normalized ratio (INR) >1.5

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 300 mg zilebesiran or placebo subcutaneously every 6 months as add-on therapy to their standard of care antihypertensive medications

Event-driven until the targeted number of clinical outcome events are reached

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Zilebesiran

Trial Overview The study is testing Zilebesiran against a placebo to see if it lowers the chance of serious heart events like death from heart problems, nonfatal heart attacks, strokes, or heart failure. It's an ongoing study until enough cases happen to make conclusions.

How Is the Trial Designed?

Group I: Zilebesiran 300 mg Experimental Treatment 1 Intervention

Participants will be administered 300 mg zilebesiran subcutaneously (SC) once every 6 months as add-on therapy to their standard of care antihypertensive medications.

Group II: Placebo Placebo Group 1 Intervention

Participants will be administered placebo SC once every 6 months as add-on therapy to their standard of care antihypertensive medications.

Who Is Running the Clinical Trial?

Alnylam Pharmaceuticals

Lead Sponsor

Trials

81

Recruited

16,100+

Dr. Yvonne Greenstreet

Alnylam Pharmaceuticals

Chief Executive Officer since 2021

MD from the University of Leeds, MBA from INSEAD

Dr. Pushkal Garg

Alnylam Pharmaceuticals

Chief Medical Officer since 2016

MD from Columbia University

Hoffmann-La Roche

Industry Sponsor

Trials

2,482

Recruited

1,107,000+

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Avastin, Herceptin, Rituxan, Accu-Chek

Dr. Levi Garraway

Hoffmann-La Roche

Chief Medical Officer since 2019

MD from the University of Basel

Dr. Thomas Schinecker

Hoffmann-La Roche

Chief Executive Officer since 2023

PhD in Molecular Biology from New York University

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12530167/

Efficacy and Safety of Zilebesiran for the Management of ... This meta-analysis confirms that Zilebesiran is consistently associated with significant reductions in both ambulatory and office blood pressure ...

2. roche.com roche.com/media/releases/med-cor-2025-08-30

Roche and Alnylam advance zilebesiran into global phase ... No incremental SBP reductions were observed with zilebesiran 600 mg at months three or six. Post-hoc analyses suggest that a greater blood ...

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa2208391

Zilebesiran, an RNA Interference Therapeutic Agent for ... Single doses of zilebesiran (≥200 mg) were associated with decreases in systolic blood pressure (>10 mm Hg) and diastolic blood pressure (>5 mm ...

4. investors.alnylam.com investors.alnylam.com/press-release?id=29246

Alnylam to Advance Zilebesiran into Global Phase 3 ... Results of KARDIA-3 showed a single 300 mg dose of zilebesiran resulted in clinically meaningful, placebo-adjusted reductions of office systolic ...

5. escardio.org escardio.org/The-ESC/Press-Office/Press-releases/KARDIA-3-trial-examines-blood-pressure-lowering-effects-of-zilebesiran-in-hypertensive-patients-at-high-cardiovascular-risk

KARDIA-3 trial examines blood-pressure lowering effects ... A single dose of zilebesiran 300 mg led to a 5-mmHg reduction in office systolic BP at Month 3 compared with placebo, a difference that did not ...