A novel approach to blood pressure control
For decades, managing hypertension has relied on a daily regimen of oral medications. However, challenges with treatment adherence mean many patients struggle to achieve and maintain optimal blood pressure levels. A new investigational drug called zilebesiran represents a paradigm shift in treatment, offering a long-acting, injectable solution that targets the root cause of high blood pressure. Developed by Alnylam Pharmaceuticals and Roche, zilebesiran is an RNA interference (RNAi) therapeutic that works upstream in the body’s blood pressure regulation system.
How zilebesiran works: Targeting the source
Zilebesiran operates through a sophisticated mechanism known as RNA interference. Instead of blocking the effects of a protein, like traditional drugs, it prevents the protein from being made in the first place.
- Targeting angiotensinogen (AGT): Zilebesiran targets the gene responsible for creating angiotensinogen (AGT) in the liver. AGT is the starting point of the renin-angiotensin-aldosterone system (RAAS), the body’s primary blood pressure control pathway.
- Using siRNA technology: The drug utilizes a small interfering RNA (siRNA) molecule, which is delivered specifically to liver cells using a special delivery mechanism.
- Silencing the gene: Inside the liver cells, the siRNA binds to the AGT messenger RNA (mRNA), triggering its degradation. This effectively “silences” the gene, preventing the production of AGT.
- Reducing angiotensin II: With AGT production inhibited, the entire RAAS cascade is suppressed. This leads to a reduction in the vasoconstrictor angiotensin II, causing blood vessels to relax and blood pressure to fall.
This upstream mechanism provides a broad and consistent blockade of the RAAS, differing from traditional therapies that target later stages of the cascade.
Results from the KARDIA clinical trials
Clinical trials have demonstrated zilebesiran's potential to provide durable and significant blood pressure reductions. The KARDIA program includes several key studies evaluating the drug's efficacy and safety.
- KARDIA-1 (Phase 2): In this study on patients with mild-to-moderate hypertension, a single injection of zilebesiran led to significant and sustained reductions in 24-hour ambulatory systolic blood pressure for up to six months. Doses of 300mg and 600mg given every six months, or 300mg every three months, showed a placebo-adjusted blood pressure reduction of 15 mmHg or more at three months.
- KARDIA-2 (Phase 2): This trial evaluated zilebesiran as an add-on therapy for patients with uncontrolled hypertension despite taking standard oral medications. It confirmed that adding zilebesiran to existing regimens, including diuretics and calcium channel blockers, resulted in significantly greater blood pressure drops compared to placebo. The benefits were sustained over six months.
- KARDIA-3 (Phase 2): Focusing on high-risk patients with uncontrolled hypertension and existing cardiovascular risk, this study also showed clinically meaningful blood pressure reductions with zilebesiran added to standard care. Based on these and prior results, zilebesiran was advanced into Phase 3 trials in late 2025.
Zilebesiran vs. traditional oral medications
| Feature | Zilebesiran (RNAi Injection) | Traditional Oral Medications (e.g., ACE Inhibitors, ARBs) |
|---|---|---|
| Mechanism of Action | Inhibits the production of angiotensinogen (AGT), the upstream precursor in the RAAS. | Block the action of downstream effectors in the RAAS, such as angiotensin-converting enzyme or angiotensin II receptors. |
| Dosing Frequency | Infrequent dosing, potentially once every three or six months. | Daily, requiring consistent adherence. |
| Patient Adherence | Significantly improved, as fewer doses are required. | Often compromised, contributing to suboptimal blood pressure control. |
| Tonic Blood Pressure Control | Provides sustained, consistent control throughout the 24-hour period, for months at a time. | Effects wear off within hours, requiring consistent daily intake. |
| Adverse Events | Mostly mild injection-site reactions; low rates of renal or electrolyte issues in early trials. | Can include dry cough (ACE inhibitors), angioedema, and electrolyte abnormalities (e.g., hyperkalemia). |
| Development Status | Investigational, currently in Phase 3 trials. | Well-established and widely used, with many available formulations. |
Potential benefits and risks
Potential Benefits:
- Improved Adherence: Infrequent dosing could be a game-changer for patients who struggle to remember daily pills, leading to more consistent blood pressure control.
- Sustained Control: The long duration of action ensures a stable, 24-hour blood pressure reduction, which can help mitigate the risks associated with blood pressure variability.
- Effective for Resistant Hypertension: Zilebesiran shows promise as an add-on therapy for patients with resistant hypertension, offering a new avenue for control.
Potential Risks and Considerations:
- Investigational Status: Zilebesiran has not yet received regulatory approval from agencies like the FDA. Its long-term safety and efficacy are still being studied.
- Side Effects: While generally well-tolerated in trials, the most common side effects are localized injection-site reactions.
- Cost: As a cutting-edge RNAi therapeutic, the eventual cost of zilebesiran could be a factor in its accessibility once approved.
- Reversibility: In cases of adverse events, reversing the long-lasting effect of zilebesiran would be challenging compared to stopping a daily oral pill.
Conclusion
Zilebesiran represents a significant leap forward in hypertension treatment. Its novel mechanism, which targets the source of high blood pressure, and its potential for long-lasting efficacy with infrequent dosing, could dramatically improve patient adherence and outcomes. While still under investigation, the promising results from the KARDIA clinical program suggest that this RNAi therapeutic could become an important new option for managing high blood pressure, especially for patients who have struggled with conventional oral treatments. The progression into a Phase 3 cardiovascular outcomes trial marks a crucial step toward its potential availability, offering new hope for millions of people worldwide.
Looking ahead: The future of injectable hypertension therapy
As research continues, zilebesiran's place in the broader landscape of cardiovascular medicine will become clearer. Ongoing studies will further evaluate its role in high-risk populations and its potential impact on reducing cardiovascular events like heart attacks and strokes. With its unique approach to tackling hypertension, zilebesiran highlights the exciting potential of gene-silencing therapies to transform chronic disease management.
Visit the American Heart Association for more information on managing hypertension.
