Zilebesiran is a single-dose subcutaneously administered RNA interference drug that specifically inhibits the production of angiotensinogen (AGT) in the liver, the primary precursor of all angiotensin peptides.

The trial's purpose was to compare zilebesiran versus a placebo in patients with uncontrolled hypertension.

The study was a phase 2, double-blind, placebo-controlled study involving 672 patients. Patients who had uncontrolled hypertension were randomly assigned to receive either zilebesiran or a placebo. Prior to this, following the discontinuation of their previous antihypertensive drugs, participants were randomly assigned to receive one of three once-daily medications: indapamide, amlodipine, or olmesartan. Following a minimum duration of four weeks, all patients underwent 24-hour blood pressure monitoring. Participants who regularly adhered to their medication regimen and maintained an average 24-hour systolic blood pressure (SBP) ranging from 130 mm Hg to 160 mm Hg were randomly assigned to receive a single injection of either zilebesiran 600 mg or a placebo. Subsequently, patients were monitored for an additional duration of six months. At three months, the inclusion of additional antihypertensive medications was allowed in order to reach the blood pressure targets specified by the guidelines.

Main Results: The main result of the study was a decrease in 24-hour mean ambulatory systolic blood pressure of -12.1 mm Hg in the indapamide group for zilebesiran compared to placebo (p < 0.001), -9.7 mm Hg in the amlodipine group for zilebesiran compared to placebo (p < 0.001), and -4.0 mm Hg in the olmesartan group for zilebesiran compared to placebo (p = 0.036). The blood pressure difference was maintained for 6 months in the indapamide and amlodipine groups. Additional outcomes: The indapamide group experienced a decrease of 18.5 mm Hg in office systolic blood pressure after three months compared to the placebo group (p < 0.001). Similarly, the amlodipine group had a decrease of 10.2 mm Hg (p < 0.001), and the olmesartan group had a decrease of 7.0 mm Hg (p < 0.001) compared to the placebo group. These reductions in office SBP remained statistically significant up to month six. No safety concerns were observed for potassium elevations, kidney damage, or low blood pressure (SBP) between the zilebesiran group and the placebo group remained statistically significant up to month six for both groups. No safety concerns were observed for potassium elevations, kidney damage and low BP.

Zilebesiran treatment significantly reduced BP at three months after each background treatment, and in many cases for six months after treatment with additional medications.

Although there are many treatment options for hypertension, the number of patients requiring multiple drugs for blood pressure regulation is quite high. Zilebesiran treatment, which can be used as a single subcutaneous dose, is promising in terms of rational drug use. In this phase 2 study, zilebesiran showed good blood pressure reduction, especially in the amlodipine and indapamide groups. The upcoming KARDIA-3 study will further evaluate the efficacy and safety of zilebesiran in patients with hypertension uncontrolled by two to four BP medications, particularly in those with high cardiovascular risk or advanced chronic kidney disease.