ESC Congress 2026 Abstract · Oct 26, 2026

Dose-response and efficacy ceiling of zilebesiran: a bayesian non-linear spline meta-analysis of phase 1 and KARDIA phase 2 trials

By Keswani K, Bakhsh A, Elshabrawi MN et al.

Background: Hypertension remains the leading modifiable driver of global cardiovascular mortality. Zilebesiran, an investigational small-interfering RNA (siRNA) therapeutic, silences hepatic angiotensinogen (AGT) synthesis—the most upstream precursor in the renin–angiotensin–aldosterone system—offering sustained blood-pressure (BP) lowering via semiannual subcutaneous dosing. Following the foundational NEJM Phase 1 study, the KARDIA Phase 2 program [1] evaluated monotherapy, add-on, and high-risk cohorts. However, the global dose–response relationship across these diverse clinical contexts has not been quantitatively synthesized. Purpose: To characterize the dose-dependent antihypertensive effect of zilebesiran and identify the optimal dosing plateau using all available randomized evidence. Methods: A dose–response meta-analysis was performed using a one-stage random-effects framework with restricted cubic splines (RCS). We incorporated data from 5 randomized trials (N = 1,491) across Phase 1, KARDIA-1, KARDIA-2, and KARDIA-3 trials [1,2]. Change from baseline in systolic BP (SBP) was modeled as a function of dose (10–800 mg). Office and 24-hour ambulatory BP were analyzed separately. Nonlinearity was evaluated via Wald χ2 tests; Bayesian hierarchical spline models assessed the posterior probability of efficacy across the dose range. Results: Zilebesiran demonstrated a significant nonlinear dose–response for both office (χ2 = 9.23, p = 0.009) and ambulatory (χ2 = 26.16, p < 0.001) SBP. Bayesian posterior mean reductions were −7.6 mmHg (95% CrI: −8.7 to −6.6) for office and −6.9 mmHg (95% CrI: −10.6 to −3.6) for ambulatory SBP, with posterior simulations identifying a potential for SBP reductions exceeding 20 mmHg in optimized clinical subgroups. The dose-response curve exhibited a steep initial slope, with efficacy saturation observed between 300 mg and 600 mg. Doses above 600 mg (up to 800 mg) provided negligible incremental BP lowering, indicating a clear ceiling effect for AGT suppression. Conclusion: Integrating Phase 1 and KARDIA Phase 2 data, zilebesiran demonstrates durable, dose-proportional BP reduction that plateaus at 300–600 mg. These findings consolidate zilebesiran as a first-in-class long-acting RNAi antihypertensive and support the selection of 300 mg as the optimal therapeutic dose for future cardiovascular outcome trials.dose-response for ambulatory BPdose-response for office BP

doi.org/10.1093/eurheartj/ehag785.3062 Open access Interventions