KARDIA-2: Zilebesiran Reduces Blood Pressure in Addition to Standard of Care


In new topline results from the KARDIA-2 trial, zilebesiran added to standard-of-care antihypertensive treatments showed significant reductions in systolic blood pressure.

Blood pressure monitoring | Image Credit: Fotolia

Credit: Fotolia

Topline results from the phase 2 KARDIA-2 study show zilebesiran led to clinically, statistically significant reductions in 24-hour mean systolic blood pressure (SBP) at 3 months when added to standard-of-care antihypertensive treatments.1

Announced by Alnylam Pharmaceuticals, Inc. on March 5, 2024, the investigational RNAi therapeutic, targeting liver-expressed angiotensinogen (AGT) in development for the treatment of hypertension, exhibited a strong safety and tolerability profile among nearly 700 patients in KARDIA-2.

“We are thrilled that a single dose of zilebesiran achieved clinically significant, additional reductions in systolic blood pressure when administered to patients who are not adequately controlled with commonly prescribed antihypertensives,” said Simon Fox, PhD, vice president and program lead for zilebesiran at Alnylam.1

Zilebesiran is an investigational therapeutic in development for the treatment of hypertension in high unmet-need populations. AGT is the most upstream precursor in the Renin-Angiotensin-Aldosterone System (RAAS), a cascade with a demonstrated role in blood pressure (BP) regulation.2 Zilebesiran inhibits the synthesis of AGT in the liver, leading to durable reductions in AGT protein and ultimately, the vasoconstrictor angiotensin II.1

The randomized, double-blind, placebo-controlled, multicenter phase 2 KARDIA-2 study evaluated the efficacy and safety of zilebesiran added to standard-of-care antihypertensives in adults with mild-to-moderate hypertension. Overall, the global study enrolled 672 adults with hypertension.

Individuals who met all inclusion criteria in a screening period were randomized into three cohorts to receive open-label treatment with olmesartan, amlodipine, or indapamide as a protocol-specified background antihypertensive medication during a run-in period of ≥4 weeks. After the run-in period, eligible patients were randomized 1:1 to receive 600 mg zilebesiran or placebo alongside protocol-specified background antihypertensive medications for 6 months.

The study’s primary endpoint was the change from baseline in mean SBP at month 3, assessed by 24-hour ambulatory blood pressure monitoring (ABPM). Further end points included the change in 24-hour mean SBP after 6 months measured by ABPM, change in office SBP at months 3 and 6, and change in diastolic blood pressure (DBP) measured by ABPM and office blood pressure at months 3 and 6.

“These KARDIA-2 results, showing durable additional levels of blood pressure reduction on top of what is achieved by standard of care first-line antihypertensives with an encouraging safety profile, reinforce our confidence in zilebesiran’s differentiated profile,” Fox added.

Zilebesiran is being co-developed and co-commercialized by Alnylam and Roche.3 Alnylam has announced plans to share the full KARDIA-2 trial data in a late-breaking session at the 2024 American College of Cardiology (ACC) Annual Scientific Session in Atlanta, Georgia.1

The companies also announced the initiation of the global, phase 2 KARDIA-3 study, designed to evaluate the efficacy and safety of zilebesiran as an add-on therapy for adults with high cardiovascular risk and uncontrolled hypertension despite standard-of-care antihypertensive treatment.

In KARDIA-3, those with an estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.72m2 will be enrolled in cohort A and those with eGFR 30 to <45 mL/min/1.73m2 will be enrolled in cohort B. All patients who match inclusion criteria after screening will be randomized to receive zilebesiran (300 or 600 mg) or placebo in cohort A, or zilebesiran (150, 300, or 600 mg) or placebo in cohort B, for a 6-month, double-blind treatment period.

The primary study endpoint will be the change from baseline at month 3 in mean seated office SBP. Other endpoints will include the change from baseline at month 3 in 24-hour mean SBP assessed by ABPM, change from baseline at month 6 in mean seated office SBP, and 24-hour SBP assessed by ABPM. Safety will be assessed during a 6-month follow-up period following the treatment period.


  1. Alnylam reports positive kardia-2 topline study results demonstrating clinically significant blood pressure re. Investor Relations | Alnylam Pharmaceuticals, Inc. March 5, 2024. Accessed March 5, 2024. https://investors.alnylam.com/press-release?id=28036.
  2. Rahimi Z, Moradi M, Nasri H. A systematic review of the role of renin angiotensin aldosterone system genes in diabetes mellitus, diabetic retinopathy and diabetic neuropathy. J Res Med Sci. 2014 Nov;19(11):1090-8. PMID: 25657757; PMCID: PMC4310085.
  3. Alnylam announces partnership with Roche to co-develop and co-commercialize zilebesiran, an investigational RN. Investor Relations | Alnylam Pharmaceuticals, Inc. July 24, 2023. Accessed March 5, 2024. https://investors.alnylam.com/press-release?id=27611.
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