What Is Zilebesiran?
Zilebesiran is an investigational medication currently being studied for the treatment of high blood pressure, also known as hypertension, and conditions associated with high cardiovascular risk. The medication is administered by subcutaneous (SC) injection, meaning it is given under the skin. While the specific mechanism of action is not detailed in the available trial descriptions, its development focuses on managing blood pressure and reducing cardiovascular risk factors.
Clinical trials for Zilebesiran began in 2021, with the latest trial projected to conclude in 2025. There are a total of 4 trials, involving 12,074 participants, sponsored by Alnylam Pharmaceuticals. These studies are exploring Zilebesiran's potential as a new therapeutic option for patients with various forms of hypertension and those at elevated risk for heart-related conditions.
Uses and Conditions Under Study
Zilebesiran is currently under investigation for several conditions related to blood pressure and heart health. The primary focus of the clinical trials is on hypertension, commonly known as high blood pressure. Hypertension is a widespread condition where the long-term force of the blood against your artery walls is high enough that it may eventually cause health problems, such as heart disease. Zilebesiran is being studied to determine if it can effectively lower and manage blood pressure levels.
The drug is also being explored for its potential role in managing conditions associated with high cardiovascular risk and high risk cardiovascular disease. These categories encompass individuals who have a greater chance of developing heart attacks, strokes, or other serious heart-related issues. By targeting blood pressure, Zilebesiran aims to mitigate these risks. A total of 3 trials are specifically looking at hypertension, while 2 trials address high cardiovascular risk, and 1 trial focuses on high risk cardiovascular disease. One trial also specifically investigates mild to moderate hypertension.
Across all these studies, the goal is to assess Zilebesiran's effectiveness and safety profile in improving outcomes for patients facing these significant health challenges.
Dosing
Zilebesiran is administered as a subcutaneous (SC) injection, meaning it is injected under the skin. The specific dosage forms studied in clinical trials indicate that it is given as an injection, rather than an oral tablet or solution.
In the ongoing clinical investigations, various dosing regimens have been explored:
- Zilebesiran 300 mg: This specific strength has been studied as a standalone treatment.
- Zilebesiran (Add-on to Indapamide): Zilebesiran has been investigated for use in combination with Indapamide, an oral diuretic often used to treat high blood pressure.
- Zilebesiran (Add-on to Amlodipine): Another regimen involves Zilebesiran being added to Amlodipine, a calcium channel blocker commonly prescribed for hypertension.
- Zilebesiran (Add-on to Olmesartan): Studies also include Zilebesiran as an add-on therapy to Olmesartan, an angiotensin receptor blocker used to treat high blood pressure.
The exact frequency of administration (e.g., daily, weekly) is not detailed in the provided data. These different approaches aim to determine the most effective ways to use Zilebesiran, either alone or in combination with existing blood pressure medications, to achieve optimal therapeutic benefits.
Side Effects
In a clinical trial involving 1,785 patients, Zilebesiran was compared to a placebo to identify common side effects. The most frequently reported side effect that occurred more often with Zilebesiran than with placebo was dizziness.
- Dizziness was experienced by 2.3% of patients taking Zilebesiran, compared to 1.1% on placebo.
- Hyperkalaemia (high potassium levels) occurred in 1.8% of patients on Zilebesiran, versus 1.4% on placebo.
- Injection site reactions were reported by 1.4% of patients receiving Zilebesiran, compared to 0.6% on placebo.
- Hypertension (high blood pressure) was observed in 3.0% of patients on Zilebesiran, which was less frequent than the 7.6% seen in patients on placebo.
- Headache occurred in 1.8% of patients taking Zilebesiran, compared to 2.3% on placebo.
- Urinary tract infection was reported by 0.4% of patients on Zilebesiran, versus 0.8% on placebo.
Clinical Trial Results
The efficacy of Zilebesiran as an add-on therapy for patients with hypertension not adequately controlled by standard medications was evaluated in the KARDIA-2 study (NCT05103332). This study assessed Zilebesiran when added to three different classes of antihypertensive medications: amlodipine, indapamide, and olmesartan. Blood pressure changes were measured using both 24-hour ambulatory blood pressure monitoring (ABPM) and office blood pressure readings. A reduction in blood pressure is considered an improvement.
Add-on to Amlodipine
When Zilebesiran was added to amlodipine, patients experienced significant reductions in blood pressure:
- At Month 3, 24-hour mean systolic blood pressure (SBP) decreased by 10.5 mmHg with Zilebesiran, compared to a 0.7 mmHg decrease with placebo. Diastolic blood pressure (DBP) decreased by 6.6 mmHg with Zilebesiran, versus 0.8 mmHg with placebo.
- At Month 6, 24-hour mean SBP decreased by 9.7 mmHg with Zilebesiran, compared to 1.8 mmHg with placebo. DBP decreased by 6.2 mmHg with Zilebesiran, versus 1.1 mmHg with placebo.
- A greater proportion of patients on Zilebesiran achieved a 24-hour mean SBP below 130 mmHg and/or a reduction of 20 mmHg or more (39.8%) compared to placebo (13.7%) at Month 6.
- Zilebesiran also led to a significant reduction in serum angiotensinogen (AGT) levels, a key marker of its mechanism of action, decreasing by approximately 96%, while placebo saw an increase of about 10%.
Add-on to Indapamide
When Zilebesiran was added to indapamide, even larger blood pressure reductions were observed:
- At Month 3, 24-hour mean SBP decreased by 15.7 mmHg with Zilebesiran, compared to 3.7 mmHg with placebo. DBP decreased by 9.1 mmHg with Zilebesiran, versus 1.3 mmHg with placebo.
- At Month 6, 24-hour mean SBP decreased by 15.6 mmHg with Zilebesiran, compared to 4.6 mmHg with placebo. DBP decreased by 8.5 mmHg with Zilebesiran, versus 2.3 mmHg with placebo.
- A substantial 64.2% of patients on Zilebesiran achieved a 24-hour mean SBP below 130 mmHg and/or a reduction of 20 mmHg or more, compared to 14.0% on placebo at Month 6.
- Serum AGT levels were reduced by approximately 93% with Zilebesiran, while placebo showed an increase of about 4%.
Add-on to Olmesartan
When Zilebesiran was added to olmesartan, an angiotensin receptor blocker (ARB), blood pressure reductions were also seen, though the additional effect was less pronounced compared to the other add-on groups:
- At Month 3, 24-hour mean SBP decreased by 7.7 mmHg with Zilebesiran, compared to 3.2 mmHg with placebo. DBP decreased by 3.4 mmHg with Zilebesiran, versus 1.4 mmHg with placebo.
- At Month 6, 24-hour mean SBP decreased by 7.6 mmHg with Zilebesiran, compared to 5.8 mmHg with placebo. DBP decreased by 3.5 mmHg with Zilebesiran, versus 3.1 mmHg with placebo.
- At Month 6, 25.9% of patients on Zilebesiran achieved a 24-hour mean SBP below 130 mmHg and/or a reduction of 20 mmHg or more, compared to 17.2% on placebo.
- Serum AGT levels were reduced by approximately 91% with Zilebesiran, while placebo showed an increase of about 5%.
Currently Recruiting Trials
Zilebesiran is an investigational medication being studied for its potential to manage hypertension and reduce cardiovascular risks. Clinical trials are essential to understand how new treatments work, and patients who participate play a vital role in advancing medical knowledge.
One significant trial currently seeking participants is sponsored by Alnylam Pharmaceuticals. This Phase 3 study, known as NCT07181109, is investigating Zilebesiran in patients whose hypertension is not adequately controlled, and who also have either established cardiovascular disease or a high risk for developing it. The primary goal of this large-scale study is to determine if Zilebesiran, compared to a placebo, can reduce the occurrence of major cardiovascular events. These events include cardiovascular death, nonfatal myocardial infarction (heart attack), nonfatal stroke, or heart failure events. The trial is designed to continue until a specific number of these events have occurred, providing robust data on the drug's effectiveness.
This important study aims to enroll approximately 11,000 participants. Individuals aged 18 years and older, of any gender, who meet the criteria for uncontrolled hypertension and high cardiovascular risk may be eligible to participate. It is not open to healthy volunteers or children. By joining this trial, participants contribute directly to research that could potentially offer a new treatment option for managing high blood pressure and its associated cardiovascular complications.
Where to Participate
The clinical trial for Zilebesiran, NCT07181109, is designed to be widely accessible, with study sites across numerous locations. This broad reach helps ensure diverse participation and facilitates the collection of comprehensive data. The study is currently active in 35 states across the United States, encompassing 185 cities and a total of 1 site. This extensive network allows many individuals to consider participating closer to home.
Top cities with participating sites include:
- Houston, Texas (8 sites)
- Miami, Florida (5 sites)
- San Antonio, Texas (4 sites)
- Little Rock, Arkansas (3 sites)
- Kansas City, Missouri (3 sites)
- Bountiful, Utah (2 sites)
- Austin, Texas (2 sites)
- Suffolk, Virginia (2 sites)
- Las Vegas, Nevada (2 sites)
- Phoenix, Arizona (2 sites)
To be eligible for this study, participants must be between 18 and 18 years of age. The trial is open to all genders, but it is not seeking healthy volunteers and does not include children.
Development Timeline
The journey of Zilebesiran began with its first clinical trial initiated on November 2, 2021, marking the start of its formal investigation. Since then, the development program has steadily progressed, with the latest trial projected to conclude on September 18, 2025. All four clinical trials for Zilebesiran have been sponsored by Alnylam Pharmaceuticals, demonstrating a consistent commitment to exploring its therapeutic potential.
Initially, the research into Zilebesiran explored its use for conditions such as IBS-C (irritable bowel syndrome with constipation) and hyperphosphatemia. However, the development pipeline has since expanded, with a strategic focus on cardiovascular health. The program now primarily targets High Risk Cardiovascular Disease and Mild to Moderate Hypertension, reflecting an evolution in understanding the drug's most promising applications.
Across its development, Zilebesiran has advanced through various phases of clinical research. The program includes one Phase 1/Phase 2 study, two Phase 2 studies, and one pivotal Phase 3 study, which is currently recruiting. In total, these 4 trials have aimed to enroll approximately 12,074 participants, gathering crucial data on safety and efficacy as the drug moves closer to potential approval.