Angiotensinogen RNAi therapeutic lowers SBP up to 6 months in patients with hypertension

AHA 2023 In the phase 2 KARDIA-1 trial, a single dose of the RNA interference therapeutic zilebesiran led to reductions in 24-h ambulatory systolic BP at month 3 in patients with hypertension, and these effects were sustained over 6 months.

Presented at the ESC congress 2023 by: George Bakris, MD - Chicago, IL, USA

Introduction and methods

Zilebesiran is a RNA interference therapeutic that inhibits the synthesis of hepatic angiotensinogen. In a phase 1 study with zilebesiran , a single dose of zilebesiran lowered serum angiotensinogen levels in a dose-dependent manner in patients with hypertension over a 24 week period. The aim of the phase 2 KARDIA-1 study was to investigate the efficacy and safety of different doses of zilebesiran in patients with mild-to-moderate hypertension.

KARDIA-1 was a randomized, double-blind, placebo-controlled, multi-center, dose-ranging study of zilebesiran in adults with mild-to-moderate hypertension. A total of 384 patients with daytime systolic BP (SBP) ≥135-160 mmHg as measured by ambulatory blood pressure monitoring were enrolled. After a washout period of previous anti-hypertensive medications, patients were randomized in a 1:1:1:1:1 ratio to subcutaneous administration of zilebesiran (150 mg, 300 mg or 600 mg once every six months [Q6M]; 300 mg once every three months [Q3M]) or placebo Q3M.

The primary endpoint was change in mean 24-h ambulatory SBP from baseline to month 3.

Main results

Efficacy outcomes

• Sustained reductions in serum angiotensinogen were observed in all zilebesiran treatment groups through 6 months.
• All doses of zilebesiran reduced mean 24-h ambulatory SBP from baseline to month 3 compared with placebo (difference of -14.1 mmHg; 95%CI: -19.2 to -9.0, with 150 mg Q6M; -16.7 mmHg; 95%CI: -21.2 to -12.3, with 300 mg Q3M and Q6M; and -15.7 mmHg; 95%CI: -20.8 to -10.6, with 600 mg Q6M).
• Zilebesiran reduced mean 24-h ambulatory SBP from baseline to month 6 compared with placebo (difference of -11.1 mmHg [95%CI: -15.8 to -6.4], -14.5 mmHg [95%CI: -19.1 to -9.9], -14.1 mmHg [95%CI: -18.9 to -9.4], and -14.2 mmHg [95%CI: -18.9 to -9.5], with 150 mg Q6M, 300 mg Q6M, 300 mg Q3M, and 600 mg Q6M, respectively).
• All doses of zilebesiran reduced office SBP compared with placebo from baseline to month 3 (difference of -9.6 mmHg [95%CI: -13.8 to -5.3], -12.0 mmHg [95%CI: -15.7 to -8.3], and -9.1 mmHg [95%CI: -13.4 to -4.8], with 150 mg Q6M, 300 mg Q3M and Q6M, and 600 mg Q6M, respectively).
• All doses of zilebesiran reduced office SBP compared with placebo from baseline to month 6 (difference of -7.5 mmHg [95%CI: -12.4 to -2.7], -10.5 mmHg [95%CI: -15.3 to -5.7], -12.1 mmHg [95%CI: -17.2 to -7.1], and -10.2 mmHg [95%CI: -15.1 to -5.3], with 150 mg Q6M, 300 mg Q3M, 300 mg Q6M, and 600 mg Q6M, respectively).

Safety outcomes

• At least 1 study drug related adverse event leading to discontinuation of study medication was reported in 1 patient in each of the zilebesiran treatment groups, whereas this outcome was not reported in the placebo group.
• Zilebesiran was generally well tolerated. There were no clinically relevant changes in renal or hepatic function. There were reports of hypotension, but these were mild or moderate and transient.

Conclusion

The phase 2 KARDIA-1 study showed that a single dose of zilebesiran lowers 24-h mean SBP compared with placebo in patients with hypertension at month 3, and these effects were sustained over 6 months. The safety profile of zilebesiran was encouraging, with low rates of serious or severe adverse events. The effect of zilebesiran on top of standard of care in patients with hypertension is currently being evaluated in the phase 2 KARDIA-2 study.

- Our reporting is based on the information provided at the AHA Scientific Session 2023 –

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