Key Points:
- Many patients do not achieve BP goals in hypertension (HTN) due to adherence issues, so zilebesiran, a twice-yearly dosed RNA-i antihypertensive, may demonstrate benefit in these patients
- The KARDIA-3 trial was a phase 2, randomized, double-blind, placebo-controlled trial testing subcutaneous zilebesiran (300 or 600 mg) added to 2-4 background antihypertensives in adults with CVD or high CV risk
- The study was negative for its primary endpoint: at 3 months, office SBP was lower vs placebo by -5.0 mmHg with 300 mg and -3.3 mmHg with 600 mg (not significant after multiplicity adjustment).
- However, the trial was notable for signals of benefit, including larger ambulatory and nighttime BP reductions and a sizable effect in patients on diuretics with baseline SBP ≥140 mmHg (-9.2 mmHg at 3 months)
Despite broad availability of oral agents, many patients do not achieve sustained blood-pressure (BP) control, partly due to adherence barriers. Zilebesiran, an RNA-interference therapy that suppresses hepatic angiotensinogen (upstream in the RAAS), offers twice-yearly dosing and previously showed add-on efficacy in KARDIA-2. KARDIA-3 was designed to evaluate zilebesiran on top of multiple antihypertensives in a higher-risk population.
KARDIA-3 was a double-blind, placebo-controlled, randomized trial conducted across five countries in adults with established cardiovascular disease (CVD) or high CV risk (e.g., 10-year ASCVD risk >15% or eGFR 30–59 mL/min/1.73 m²) and uncontrolled hypertension (office SBP 140-170 mmHg; 24-hr SBP 130-170 mmHg) while taking 2-4 antihypertensives (including a CCB or a diuretic). The primary analysis set included patients with eGFR ≥45; those with eGFR 30 to <45 will be reported separately. Participants were randomized 1:1:1 to single-dose zilebesiran 300 mg, 600 mg, or placebo; background therapy was held stable through 3 months unless clinically necessary. The primary endpoint was change from baseline in mean office SBP at 3 months.
Among 270 analyzed patients (median age 67, 45% women), baseline office BP averaged 144/80 mmHg while on 2-4 agents. At 3 months, placebo-adjusted office SBP change was -5.0 mmHg (95% CI, -9.9 to -0.2) with 300 mg and -3.3 mmHg (95% CI, -8.2 to 1.6) with 600 mg; neither reached statistical significance after multiplicity correction. At 6 months, placebo-adjusted office SBP changes were -3.9 and -3.6 mmHg, respectively. Notably, 24-hour ambulatory SBP at 6 months favored zilebesiran by -5.5 (300 mg) and -7.4 mmHg (600 mg), with larger nighttime reductions (-6.6 and -8.2 mmHg). A post-hoc subgroup on diuretics with baseline SBP ≥140 mmHg showed a larger office SBP reduction at 3 months (-9.2 mmHg). Adverse events (AEs), including hyperkalemia, kidney dysfunction, and hypotension, were mostly mild/moderate and transient; serious AEs were similar to placebo (~4%).
KARDIA-3 did not meet its multiplicity-adjusted primary endpoint, limiting enthusiasm for broad add-on use. However, consistent ambulatory and nighttime BP reductions and the diuretic-treated subgroup signal suggest a biologically plausible effect (aligned with RAAS suppression and prior KARDIA-2 data) that may translate to outcome benefits in selected patients or combinations. Reflecting this “totality of evidence,” the sponsors announced a global phase 3 cardiovascular outcomes trial (dose, population, and design informed by KARDIA-3). Trial presenter Neha Pagidipati, MD, emphasized that while the 3-month primary outcome was not statistically significant, “the trial met its objective of informing the design of future trials,” and that the phase 2 program collectively supports proceeding to a phase 3 outcomes study in uncontrolled hypertension.
