New RNA injection to lower blood pressure
Key Takeaways
Zilebesiran, an RNA-interfering agent delivered as a subcutaneous injection, was found to significantly decrease systolic blood pressure in adults with mild to moderate hypertension.
Zilebesiran targets hepatic angiotensinogen synthesis, reducing the availability of the most upstream precursor of the renin-angiotensin-aldosterone system.
The most common drug-related adverse effects were injection-site reactions and mild hyperkalemia. Longer-term studies are needed to assess whether blood pressure reduction will be sustained.
Hypertension (HTN) remains the leading cause of disability-adjusted life-years worldwide, and is the leading risk factor for noncommunicable disease burden and premature mortality. Well known to cardiologists among these noncommunicable diseases are atherosclerosis and coronary artery disease (CAD), heart failure (HF), and stroke.
Adherence to treatment for HTN has been a major obstacle to achieving blood pressure (BP) control and reducing burden of disease. Now, a novel therapeutic option has shown promise in addressing the issue of adherence.
The KARDIA-1 study
Results from the KARDIA-1 RCT highlighted the potential of an RNA interfering agent, zilebesiran, to treat mild to moderate HTN.[] In this phase 2 trial, subcutaneous doses of zilebesiran (150 mg, 300 mg, or 600 mg every 6 months; or 300 mg every 3 months) significantly decreased systolic BP (SBP) at both 3 and 6 months, compared with placebo.
Zilebesiran targets hepatic angiotensinogen synthesis through RNA interference, thereby reducing the availability of angiotensinogen, which is the most upstream precursor of the renin-angiotensin-aldosterone system.
The KARDIA-1 study was a placebo-controlled trial that specifically enrolled adults with a daytime mean SBP of 135 mm to 160 mm Hg. At month 3, participants receiving zilebesiran demonstrated a drop in 24-hour mean ambulatory SBP of 7.3 mm Hg with zilebesiran 150 mg (6-month dosing interval); a drop of 10 mm Hg with zilebesiran 300 mg (every 3 and 6 months, combined); and a drop of 8.9 mm Hg with zilebesiran 600 mg (6-month dosing interval). This compared with a reduction of 6.8 mm Hg on placebo.
The most common non-serious drug-related adverse effects, occurring in 16.9% of zilebesiran-treated participants, were injection-site reactions and mild hyperkalemia.
One limitation of the study was that follow-up was only 6 months, meaning that participants received only one or two doses of treatment with zilebesiran.
Thus, it remains to be seen whether or not the SBP reductions induced by zilebesiran would be sustained for a longer period of time, or whether the safety profile might change over time.
In his JAMA editorial on the trial, Dr. Ernesto Schiffrin commented, “The data from the trial represent a rigorous study that supports further investigation of zilebesiran as a therapeutic approach to treatment of patients with hypertension. If sustained BP reduction is confirmed with few adverse effects, zilebesiran administration every 6 months could represent a significant advance in hypertension therapeutics because it could potentially overcome lack of adherence to treatment, which remains to be demonstrated.”[]
RNA-interfering agents in cardiology
Zilebesiran is just the latest in the pipeline of RNA-interfering agents being investigated for cardiovascular therapeutic uses. The broader class of RNA therapeutics has particular significance for the field of cardiology, because these agents could potentially reach previously “undruggable” pathways in CVD.[]
The allure of therapeutic agents that can be delivered as infrequently as twice a year, with the attendant implications for improved adherence, enhances the promise of agents like zilebesiran.
However, as with all long-acting agents, the flip side of the coin is that the duration of their effect can become problematic if significant adverse effects are encountered. This makes longer-term studies even more important.
What this means for you
To cardiologists, the development of zilebesiran and other RNA-interfering agents presents a promising new therapeutic approach for managing hypertension, a leading risk factor for CVD. Poor adherence to antihypertensive treatment has been a major obstacle in achieving blood pressure control, and therefore agents like zilebesiran—with its relatively infrequent dosing—could possibly improve adherence. However, longer-term studies are needed to fully understand the efficacy and safety of these novel agents, and it will be worth watching for the results of ongoing phase 3 trials.