ZENITH: A Phase 3 Global, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Zilebesiran in Addition to Standard of Care in Reducing Major Adverse Cardiovascular Events in Adult Patients with Hypertension Not Adequately Controlled and With Either Established Cardiovascular Disease or High Risk for Cardiovascular Disease

The primary objective of this study is to evaluate whether zilebesiran compared to placebo reduces the risk of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or heart failure event (hospitalization for heart failure or urgent heart failure visit) in adult patients with hypertension not adequately controlled and with either established cardiovascular disease or high risk for cardiovascular disease. This composite endpoint represents major adverse cardiovascular events that constitute significant morbidity and mortality burden in the hypertensive population with established or high-risk cardiovascular disease.

The secondary objectives are:

• To evaluate whether zilebesiran compared to placebo reduces mean seated office systolic blood pressure

• To evaluate whether zilebesiran compared to placebo reduces the risk of nonfatal cardiovascular events and cardiovascular mortality

• To evaluate whether zilebesiran compared to placebo reduces the risk of all-cause mortality

The clinical trial enrolled a total of **7,056 participants** with established **cardiovascular disease**, **hypertension**, or high cardiovascular risk. The study population included both **male and female subjects** aged 18 years or older for those with established cardiovascular disease, and 55 years or older for individuals at high risk for cardiovascular disease. Participants were required to have treated hypertension managed with stable antihypertensive therapy, including a **thiazide**, thiazide-like, or **loop diuretic** in combination with at least one additional standard antihypertensive medication such as an **ACE inhibitor**, **ARB**, **calcium channel blocker**, **beta blocker**, **mineralocorticoid receptor antagonist**, vasodilator, or centrally acting agent. Eligible participants demonstrated seated automated mean office **systolic blood pressure** between 145 mmHg and 180 mmHg during screening, and between 140 mmHg and 180 mmHg on the day of randomization. The trial population was selected based on the presence of established cardiovascular conditions including **coronary artery disease**, **cerebrovascular disease**, or **peripheral arterial disease**, or alternatively, the presence of two or more cardiovascular risk factors such as advanced age, reduced **eGFR**, elevated urine albumin-to-creatinine ratio, current smoking status, **atrial fibrillation** on medical therapy, elevated coronary artery calcium score, elevated **NT-proBNP** levels, **diabetes mellitus**, or elevated **body mass index**. Participants were required to maintain stable antihypertensive medication regimens for at least 30 days prior to and during the screening period.

This is a Phase 3, global, randomized, double-blind, placebo-controlled clinical trial evaluating the efficacy and safety of **zilebesiran** in addition to standard of care in adult patients with **hypertension** not adequately controlled and with either established **cardiovascular disease** or high risk for cardiovascular disease. The trial aims to assess whether zilebesiran reduces the risk of major adverse cardiovascular events. **Zilebesiran** is a GalNAc-conjugated **siRNA** targeting liver-expressed mRNA for AGT, administered as a **solution for injection** via **subcutaneous use**. The investigational medicinal product is supplied in a prefilled syringe with a needle safety device. The comparator is **placebo**, consisting of 0.9% (w/v) sodium chloride with 5 mM phosphate buffered solution.

The **primary endpoint** is the time to first occurrence of a composite endpoint of cardiovascular death, nonfatal **myocardial infarction**, nonfatal **stroke**, or heart failure event (hospitalization for heart failure or urgent heart failure visit). **Secondary endpoints** include change from baseline in mean seated office systolic blood pressure at Month 6, time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, composite endpoint of cardiovascular death and total heart failure events, time to first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or **coronary revascularization**, and time to all-cause death.

Eligible participants include adults aged 18 years or older with established cardiovascular disease or 55 years or older with high cardiovascular risk. Established cardiovascular disease is defined as having one or more of the following: coronary artery disease, cerebrovascular disease, or peripheral arterial disease. High cardiovascular risk is defined by the presence of two or more specified cardiovascular risk factors, including advanced age, reduced **eGFR**, elevated urine albumin:creatinine ratio, current smoking status, **atrial fibrillation** on medical therapy, documented history of coronary artery calcium score greater than 100 Agatston Units, elevated NT-proBNP, **type 1 or 2 diabetes mellitus**, or elevated body mass index. Participants must have treated hypertension on stable therapy with a thiazide, thiazide-like, or loop **diuretic** and at least one other standard of care antihypertensive medication from specified classes, including **ACE inhibitor** or **ARB**, **calcium channel blocker**, **beta blocker**, **mineralocorticoid receptor antagonist**, vasodilator, or centrally acting antihypertensive medication. Stable therapy is defined as no change in antihypertensive medications or dosing regimens within 30 days prior to screening and during the screening period. Participants must have seated automated mean office systolic blood pressure between 145 mmHg and 180 mmHg during the screening period and between 140 mmHg and 180 mmHg on Day 1 before randomization, with measurements taken at least 7 days apart.

The maximum daily dose of zilebesiran is 300 mg, with a maximum total dose of 3000 mg administered over a maximum treatment period of 60 months. The estimated recruitment start date is April 30, 2026, and the estimated end date is October 9, 2030. Participant involvement begins with the screening visit, during which eligibility criteria are assessed, including blood pressure measurements, laboratory evaluations, and confirmation of stable antihypertensive therapy. Following successful screening, eligible participants are randomized on Day 1 to receive either zilebesiran or placebo. Follow-up visits occur at scheduled intervals throughout the treatment period to monitor efficacy and safety outcomes, including blood pressure measurements, assessment of cardiovascular events, and evaluation of adverse events. The end-of-study visit is conducted to complete final assessments and document participant status. Participants may be discontinued from the study early due to withdrawal of consent, loss to follow-up, adverse events requiring discontinuation, protocol violations, or investigator discretion based on safety concerns.

**Zilebesiran** (also known as **ALN-AGT01**) is a **GalNAc-conjugated siRNA** targeting liver-expressed **mRNA** for **AGT**. The active substance is zilebesiran, classified as a **nucleic acid** derivative. The investigational medicinal product is formulated as a **solution for injection** and is administered via the **subcutaneous route**. The drug product is supplied as a 1.5 mL fill in a 2.25 mL single-use glass **prefilled syringe** with a **needle safety device** inclusive of the needle guard and plunger rod. The maximum daily dose is **300 mg**, with a maximum total dose of **3000 mg** over a maximum treatment period of **60 weeks**. Zilebesiran is manufactured by Alnylam Pharmaceuticals Inc.

The **placebo** comparator consists of **0.9% (w/v) sodium chloride** with **5 mM phosphate buffered solution**. This formulation serves as the control treatment in the double-blind study design. The placebo is administered to match the experimental treatment regimen to maintain blinding throughout the trial. Both the experimental medication and placebo are administered in addition to **standard of care** therapy for **hypertension** management in participants with established **cardiovascular disease** or high risk for cardiovascular disease.

The primary efficacy endpoint will be assessed as the time to first occurrence of a composite endpoint consisting of **cardiovascular death**, nonfatal **myocardial infarction**, nonfatal **stroke**, or **heart failure** event, defined as hospitalization for heart failure or urgent heart failure visit. Secondary efficacy endpoints will include the change from baseline in mean seated office **systolic blood pressure** at Month 6, time to first occurrence of a composite endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, a composite endpoint of cardiovascular death and total (first and subsequent) heart failure events (hospitalization for heart failure or urgent heart failure visit), time to first occurrence of composite endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization, and time to all-cause death. Seated automated mean office systolic blood pressure measurements will be obtained during the Screening period and on Day 1 before randomization, with measurements taken at least 7 days apart, and at Month 6 to evaluate blood pressure control.