Zilebesiran — the first siRNA-based drug in hypertensiology: why is it needed, and will it change the treatment approach of hypertension?

Abstract

Arterial hypertension is the most common cardiovascular risk factor in the world. The prevalence of hypertension has doubled over the last 30 years. Despite the availability of many antihypertensive drugs, including angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs), the level of uncontrolled blood pressure (BP) in hypertensive patients remains very high, which contributes to the lack of optimization of cardiovascular risk. Antihypertensive treatment had cardioprotective effects [each reduction in systolic BP by 5 mm Hg reduced the risk of cardiovascular events in both primary and secondary cardiovascular disease (CVD) prevention by 9% and 11%, respectively]. The reasons for the lack of BP control are lack of adherence and persistence in treatment, as well as therapeutic inertia. Therefore, new therapeutic options are being sought to improve BP control. Zilebesiran, the first drug based on small interference RNA (siRNA) technology for the treatment of hypertension, is currently being tested in randomized clinical trials (KARDIA-2; KARDIA-3). The results of the phase 1 study showed that zilebesiran in a single dose allowed for a sustained reduction in systolic BP by 22 mm Hg and diastolic BP by 10 mm Hg for as long as 6 months. This effect is related to this drug’s unique mechanism of action — silencing of the angiotensinogen (AGT) gene in the liver. Zilebesiran reduces serum AGT levels by > 90%. In clinical trials, this drug had a satisfactory safety profile and was well tolerated by patients. The use of drugs that need to be taken less frequently contributed to a significant improvement in compliance with medical recommendations in patients with lipid disorders. Therefore, it is expected that using zilebesiran only twice a year would improve compliance with medical recommendations (adherence and persistence) and contribute to improved BP control in patients with hypertension. This article summarizes information on the mechanism of action, effectiveness, and safety of zilebesiran and presents the most important arguments indicating the need to introduce this drug into clinical practice.