A single SC dose of Zilebesiran reduced systolic blood pressure in uncontrolled hypertension: KARDIA-2

By Christina Lalani on

Key Points: 

    • Zilebesiran is a subcutaneous injectable that targets hepatic angiotensinogen (AGT) synthesis by RNA interference.
    • The KARDIA-1 trial showed that subcutaneous zilebesiran is associated with sustained reduction in systolic blood pressure. 
    • In KARDIA-2, patients with mild to moderate uncontrolled hypertension were randomized to receive one subcutaneous injection of zilebesiran 600 mg versus placebo in addition to one standard-of-care anti-hypertensive therapy.
    • The investigators found a statistically significant reduction in average ambulatory systolic blood pressure with the addition of zilebesiran at 3 months and 6 months compared to placebo.
    • The most commonly seen adverse events with the use of zilebesiran were hypotension, hyperkalemia and decrease in renal function, all of which were typically transient issues.

The KARDIA-2 trial is the largest trial thus far to evaluate the safety and efficacy of zilebesiran, a small-interfering RNA (siRNA) that acts by inhibiting the renin-angiotensin-aldosterone system. Zilebesiran acts by targeting the hepatic synthesis of angiotensinogen, which is the precursor of all angiotensin peptides. In the previously published phase 1 trial, patients with hypertension were randomly assigned to receive a single incremental subcutaneous dose of zilebesiran (10, 25, 50, 100, 200, 400 or 800) versus placebo. The trial found dose-dependent decreases in blood pressure that were sustained for up to 24 weeks in patients who had received a ≥ 200 mg of zilebesiran. 

In the KARDIA-2 trial, the investigators aim to evaluate zilebesiran in combination with standard-of-care anti-hypertensives. To be enrolled, patients had to have mild-moderate hypertension that was either untreated or treated with 1-2 anti-hypertensives. During the run-in period, patients were randomized to treatment with olmesartan, amlodipine, or indapamide as a baseline anti-hypertensive. After at least 4 weeks on therapy, patients with an average SBP of 130-160 mmHg on 24-hour ambulatory blood pressure monitoring were randomized to placebo versus zilebesiran 600 mg. The primary efficacy endpoint was change from baseline mean blood pressure on 24-hour ambulatory blood pressure monitoring and the primary safety endpoint was the frequency of adverse events.

The authors found a statistically significant reduction in 24-hour mean ambulatory systolic blood pressure at 3 months in patients who received zilebesiran, regardless of which of the three standard-of-care anti-hypertensives a patient was taking during the roll-in period. There were no adverse events leading to death or trial discontinuation. The most notable adverse events were hypotension, hyperkalemia, and changes in renal function, all of which were often transient and resolved without intervention. 

This study demonstrates the potential value of addon treatment of a novel si-RNA, zilebesiran, to aid with blood pressure control in patients with uncontrolled hypertension. Given the challenge of medication adherence that comes with the need to take multiple anti-hypertensives on a daily basis, the possible benefit of zilebesiran as far as six months after administration is a particularly exciting development in the world of hypertension treatment. Future studies will be necessary to further evaluate the adverse events seen with zilebesiran and optimize patient selection. The KARDIA-3 study has been initiated and will evaluate the use of zilebesiran in patients with cardiovascular risk or advanced chronic kidney disease and uncontrolled blood pressure.