ZENITH: Zilebesiran in Patients with Hypertension Not Adequately Controlled and With Either Established Cardiovascular Disease or High Risk for Cardiovascular Disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Alnylam Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

9 Feb 2026 → ongoing

Decision date (initial)

2026-02-07

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Alnylam Pharmaceuticals, Inc.

External identifiers

EU CT number

2025-522960-34-00

ClinicalTrials.gov

NCT07181109

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety, Pharmacodynamic

01. To evaluate whether zilebesiran compared to placebo reduces the risk of CV death, nonfatal MI, nonfatal stroke, or HF event (hospitalization for HF or urgent HF visit)

Secondary objectives 3

1. 01. To evaluate whether zilebesiran compared to placebo reduces mean seated office SBP
2. 02. To evaluate whether zilebesiran compared to placebo reduces the risk of nonfatal CV events and CV mortality
3. 03. To evaluate whether zilebesiran compared to placebo reduces the risk of all-cause mortality

Conditions and MedDRA coding

Established cardiovascular disease

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-003218-PIP01-22

Plan to share IPD

Yes

IPD plan description

Phase 2 - 4 trials: Access to ananymised individual participant data that support these results is made available 12 months after study completion and not less than 12 months after the product and indication have been approved in the US and/or the EU. Access to the data may be declined where there is likelihood a patient could be identified or other feasibility issue, where htere is a potential conflict of interest, a planned business activities or an actual or potential competitive risk. Data will be provided contingent upon the approval of a reserach proposal and the execution of a data sharing agreement. Timeframes for data access may vary and can take up to 6 months or more. Requests for access to data can be submitted via the website www.vivli.org. Questions can also be directed to [email protected]

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. 01. Age at the time of initial informed consent as follows: a. 18 years or older for patients with established CVD b. 55 years or older for patients with high risk for CVD.
2. 02. Established CVD or high risk for CVD: a. Established CVD defined as 1 or more of the following: Coronary artery disease, Cerebrovascular disease, Peripheral arterial disease OR b. High risk for CVD, defined by the presence of 2 or more of the following CV risk factors: i. Age ≥70 years at the time of initial informed consent ii. eGFR <60 mL/min/1.73m2 during screening iii. Urine albumin:creatinine ratio >300 mg/g during screening iv. Current smoker v. Atrial fibrillation on medical therapy (eg, anticoagulation or rate control) vi. Documented history of CAC with most recent CAC score >100 Agatston Units vii. NT-proBNP >125 pg/mL (15 pmol/L) during screening viii. Presence of 1 or both of the following (multiple events are counted as 1 total CV risk factor): • Type 1 or 2 diabetes mellitus • BMI ≥30 kg/m2 or ≥27 kg/m2 if the patient is of East Asian, Southeast Asian, or South Asian descent (eg, Chinese, Japanese, Korean, Indian, Pakistani, Thai)
3. 03. Treated hypertension on stable therapy with a thiazide, thiazide-like, or loop diuretic and at least 1 other standard of care antihypertensive medication from the classes below. Fixed-dose combination medications will be considered as multiple medications based on their individual components. Stable therapy is defined as having no change in the prescription of antihypertensive medications or dosing regimens within 30 days prior to screening and during the Screening period. Antihypertensive medications must be prescribed consistent with guideline recommendations and/or local standards. If clinically appropriate, per Investigator discretion, patients not receiving a diuretic at the time of the Prescreening visit may have a thiazide or thiazide-like diuretic added before screening; patients must maintain this new antihypertensive regimen for at least 30 days prior to screening and during the Screening period to establish stability and should intend to continue this medication through the study period. a. ACE inhibitor or ARB b. CCB c. Beta blocker d. MRA e. Vasodilator (eg, hydralazine, minoxidil, alpha blocker) f. Centrally acting antihypertensive medication (eg, clonidine)
4. 04. Seated automated mean office SBP ≥145 mmHg and <180 mmHg during the Screening period and ≥140 mmHg and <180 mmHg on Day 1 (before randomization) with measurements taken at least 7 days apart.
5. 05. Patient is able to understand and is willing and able to comply with the study requirements and to provide written informed consent.

Exclusion criteria 24

1. 01. Known history of secondary hypertension (including, but not limited to, due to known history of renovascular hypertension, primary aldosteronism, pheochromocytoma, Cushing syndrome, or aortic coarctation). Hypertension secondary to CKD is not a criterion for exclusion.
2. 02. Symptomatic orthostatic hypotension, defined as a fall of ≥20 mmHg SBP or ≥10 mmHg diastolic blood pressure (DBP) within approximately 1 to 3 minutes of standing up from a seated position by office blood pressure that is accompanied by symptoms (eg, dizziness, weakness, lightheadedness, or syncope) during screening.
3. 03. Has any of the following laboratory parameter assessments at screening: a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3×upper limit of normal (ULN). b. Total serum bilirubin >1.5×ULN. Patients with elevated total bilirubin that is secondary to documented Gilbert’s syndrome are eligible if the total bilirubin is <2×ULN. c. International normalized ratio (INR) >1.5 (patients on warfarin with an elevated INR will be allowed). d. Serum potassium >4.8 mEq/L (most recent value prior to randomization will be used for eligibility). e. eGFR <30 mL/min/1.73m2 (calculation will be based on the CKD Epidemiology Collaboration [CKD-EPI] equation)
4. 04. Has known active human immunodeficiency virus (HIV) infection. Patients on antiretroviral therapy who are clinically stable and compliant with treatment for 6 months before screening per Investigator judgement are eligible for inclusion if they meet all of the inclusion criteria and none of the exclusion criteria.
5. 05. Received an investigational agent within the last 30 days or 5 half-lives, whichever is longer, before the first dose of study drug. Any agent that has received health agency authorization (including for emergency use) by local or regional regulatory authorities is not considered investigational.
6. 06. Currently taking both an ARB and an ACE inhibitor (either as single medications or part of combination medications such as ACE inhibitor/diuretic combinations or ARNIs that include an ARB).
7. 07. Use of a potassium binder for the treatment of hyperkalemia within 3 months before screening and during the Screening period.
8. 08. Currently taking, taken within 6 months before screening and during the Screening period, or anticipated to receive any therapeutic agent that targets AGT (approved or investigational) during the study Note: Patients who were in other zilebesiran clinical studies are eligible if it is known that they did not receive zilebesiran and they have completed their participation in the study.
9. 09. Current or prior known history of severe intolerance to an ARB or ACE inhibitor other than cough (eg, angioedema, recurrent hyperkalemia, recurrent acute kidney injury), per Investigator judgement.
10. 10. Hemoglobin A1c (HbA1c) >10% within 60 days before screening or during the Screening period.
11. 11. Known weight loss >10% in the 3 months before screening. Patients receiving drugs that have the potential to cause significant weight loss (eg, glucagon-like peptide-1 agonists) should be on a stable dose for at least 3 months before screening.
12. 12. Hospitalization for HF within 60 days before screening or during the Screening period.
13. 13. History of clinically significant CV event (eg, MI, stroke, revascularization procedure) within 60 days before screening or during the Screening period.
14. 14. Known history of left ventricular ejection fraction <40% on most recent echocardiogram or equivalent imaging.
15. 15. Severe aortic stenosis.
16. 16. Has undergone major organ transplantation or is anticipated to undergo transplantation during the study.
17. 17. Known medical history or evidence of liver cirrhosis.
18. 18. Medical history that might limit the individual’s ability participate for the duration of the study (eg, severe respiratory disease; NYHA Class IV heart failure; cancer or evidence of spread within approximately the last 5 years, other than non-melanoma skin cancer).
19. 19. For whatever reason, the Investigator believes the patient is not likely to be able to follow the protocol (eg, intolerance to SC injections or any excipient of the study drug) or the risk is likely greater than benefit from a persistent inhibitor of the RAS (eg, a patient with bilateral renal artery stenosis who developed renal failure following treatment with a RAS inhibitor).
20. 20. Is not willing to comply with the contraceptive requirements during the study, as described in Section 5.10.1 of the Protocol.
21. 21. Female patient is pregnant, planning a pregnancy, or breast-feeding.
22. 22. Known history of alcohol use disorder or other substance abuse, within the last 12 months before screening, in the opinion of the Investigator
23. 23. Blood pressure cannot be accurately assessed (eg, due to cuff size limitations).
24. 24. Placed in an institution on the basis of an official or court order.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 01. Time to first occurrence of a composite endpoint of CV death, nonfatal MI, nonfatal stroke, or HF event (hospitalization for HF or urgent HF visit).

Secondary endpoints 5

1. 01. Change from baseline in mean seated office SBP at Month 6
2. 02. Time to first occurrence of a composite endpoint of CV death, nonfatal MI, or nonfatal stroke
3. 03. Composite endpoint of CV death and total (first and subsequent) HF events (hospitalization for HF or urgent HF visit)
4. 04. Time to first occurrence of composite endpoint of CV death, nonfatal MI, nonfatal stroke, or coronary revascularization
5. 05. Time to all-cause death

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Alnylam Pharmaceuticals Inc.

Sponsor organisation

Alnylam Pharmaceuticals Inc.

Address

300 3rd Street

City

Cambridge

Postcode

02142-1103

Country

United States

Scientific contact point

Organisation

Alnylam Pharmaceuticals Inc.

Contact name

Alnylam Clinical Trial Information Line

Public contact point

Organisation

Alnylam Pharmaceuticals Inc.

Contact name

Alnylam Clinical Trial Information Line

Third parties 11

Locations

17 EU/EEA countries · 494 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 247 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

19 submissions — initial application plus substantial / non-substantial modifications