A new drug administered by injection just a few times per year could revolutionize treatment for the tens of millions of Americans living with high blood pressure.
Results from an early stage clinical trial suggest the medication, called Zilebesiran, can lower blood pressure for months at a time after a single dose.
High Blood Pressure Remains a Leading Health Concern
High blood pressure, or hypertension, continues to impact public health in the United States and globally. According to the American Heart Association’s 2023 report, around 46.7% of American adults have hypertension.
This equates to well over 100 million people with elevated blood pressure levels that put them at increased risk of heart attacks, strokes, and other cardiovascular complications if left untreated.
The condition is typically managed using medications like ACE inhibitors or calcium channel blockers. But these must be taken once or twice per day long-term, which can be burdensome for patients. Finding ways to reduce the treatment burden of high blood pressure could lead to better health outcomes.
How Zilebesiran Works to Lower Blood Pressure
Zilebesiran is an emerging drug that takes a novel approach to lowering blood pressure. It belongs to a class of medications called RNA interference (RNAi) agents. RNAi drugs work by reducing levels of target proteins in the body that contribute to disease progression.
In the case of Zilebesiran, the drug blocks production of angiotensinogen (AGT), a hormone made in the liver that helps regulate blood pressure. Previous research has shown that inhibiting AGT can lower blood pressure for extended periods of time.
Zilebesiran is designed to be administered via subcutaneous injection, similar to insulin for diabetes, every few months. This infrequent dosing schedule could relieve much of the daily medication burden of standard blood pressure drugs.
Early Clinical Trial Shows Promise
The safety and effectiveness of Zilebesiran have now been investigated in an early stage phase 2 clinical trial. The results were announced at the American Heart Association’s Scientific Sessions 2022 conference and simultaneously published in the journal Circulation.
The trial enrolled 377 adults with mild to moderate hypertension. Their average blood pressure levels ranged from 135 to 160 mmHg systolic pressure, despite already taking standard oral blood pressure medications.
Participants were randomly assigned to receive injections of Zilebesiran at doses of 150 mg, 300 mg, or 600 mg either every 3 or 6 months. A control group received placebo injections on the same schedules.
All doses of Zilebesiran led to significant reductions in 24-hour average systolic blood pressure compared to placebo after 3 and 6 months of treatment. The 300 mg dose every 3 months lowered systolic blood pressure by 16.7 mmHg at 3 months and 15.2 mmHg at 6 months.
Patients on Zilebesiran were also more likely to achieve systolic pressure reductions of at least 20 mmHg, which for many brought levels below the 130 mmHg threshold for mild hypertension. Zilebesiran provided consistent blood pressure control throughout day and night, whereas oral medications lose effectiveness overnight.
Few safety issues occurred during the trial. Mild injection site reactions were the most common side effect. Only 4 patients out of 377 had reactions leading to drug discontinuation.
If confirmed in larger studies, these results suggest Zilebesiran could effectively replace daily oral medication for many hypertension patients. The long-lasting blood pressure reductions after each dose would relieve much of the treatment burden.
Lead researcher Dr. George Bakris commented, “Our study demonstrates that either quarterly or biannual doses of Zilebesiran can effectively and safely lower blood pressure in patients with uncontrolled hypertension.
It is well known that reductions in systolic blood pressure of greater than or equal to 5 mmHg are linked to a reduction in cardiovascular risk.”
Next Steps for Zilebesiran Development
Zilebesiran will now progress to phase 3 clinical trials, which involve larger numbers of patients followed for longer periods of time. These late stage trials are designed to more definitively confirm the efficacy, safety, and optimal dosing regimen of the drug.
Researchers will also investigate whether Zilebesiran can actually improve cardiovascular outcomes, reducing the occurrence of events like heart attacks and strokes. Preventing these complications of hypertension is the ultimate goal of blood pressure treatment.
If successful in phase 3, Zilebesiran manufacturer Ionis Pharmaceuticals plans to file for regulatory approval from the FDA and other agencies around 2026. This would allow the drug to be prescribed for hypertension and provide an easier treatment option for millions of patients.
Expert Commentary on Potential Impact
Medical experts not involved in the research are optimistic about Zilebesiran’s potential to change hypertension management. Dr. Suzanne Oparil, a cardiologist and hypertension specialist at the University of Alabama at Birmingham, offered the following perspective:
“This novel approach of RNA interference to block production of angiotensinogen could revolutionize the way we treat high blood pressure. The infrequent subcutaneous injection dosing regimen showed remarkable abilities to lower blood pressure for months at a time after a single dose in this trial.”
“If these results hold up, Zilebesiran could drastically reduce the medication burden and inconvenience that many patients struggle with currently. Better adherence to blood pressure therapy should then lower risks of heart disease, stroke, and kidney failure.”
“There is still need for further research on long-term safety and definitive cardiovascular outcome benefits. But I believe this drug may become part of first-line treatment if proven successful in larger phase 3 studies.”
Broader Implications for Hypertension Care
Beyond just Zilebesiran, the trial highlights the potential for RNA interference drugs to improve treatment of various chronic diseases that currently rely on daily medication. Similar agents targeting other molecular drivers of high blood pressure are also under development.
The research also emphasizes the need for continued innovation in a condition as common as hypertension. Although dozens of blood pressure medications exist, adherence remains suboptimal.
By reducing dosing frequency, next-generation therapies like Zilebesiran could significantly move the needle on cardiovascular health outcomes worldwide.