ESC Congress 2026 Abstract · Oct 26, 2026

Potent and sustained blood pressure reduction with a novel small interfering RNA targeting hepatic angiotensinogen: results from a first-in-human, randomised, phase 1 study

By Yang M, Su W, Li P et al.

Background: Hypertension control remains suboptimal globally due to poor adherence and significant blood pressure variability. Targeted inhibition of hepatic angiotensinogen (AGT) via RNA interference represents a promising strategy for achieving stable, long-term haemodynamic control with low-frequency dosing. Purpose: This study aimed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of a novel N-acetylgalactosamine-conjugated small interfering RNA targeting AGT in healthy volunteers and participants with mild hypertension. Methods: This was a single-centre, randomised, double-blind, placebo-controlled, single ascending dose trial. Fifty participants were enrolled and assigned to receive either a single subcutaneous injection of the investigated agent (25, 75, 150, 300, or 600 mg) or a placebo in a 4:1 ratio. The primary endpoints were safety and tolerability. Secondary and exploratory outcomes included changes in serum AGT levels and 24-hour ambulatory blood pressure monitoring (ABPM) throughout a 24-week follow-up period. Results: The investigated agent demonstrated a favourable safety profile; the most frequent treatment-related adverse events were mild, transient injection-site reactions. No serious adverse events, dose-limiting toxicities, or symptomatic hypotension were reported. Treatment induced profound, dose-dependent, and sustained reductions in serum AGT. In cohorts receiving ≥ 150 mg, mean AGT inhibition exceeded 90% at week 12 and was maintained above 80% at week 24. This pharmacodynamic effect translated into clinically meaningful blood pressure reductions. The 150 mg dose provided maximal haemodynamic efficacy, with a mean 24-hour systolic blood pressure reduction of 19.00 mmHg at week 12. ABPM profiles confirmed sustained blood pressure control throughout the full 24-hour dosing interval, preserving physiological circadian rhythms at both week 12 and week 24. Conclusion(s): The novel agent was well tolerated and achieved potent, sustained inhibition of serum AGT and clinically significant reductions in blood pressure for up to 24 weeks. These findings provide a robust therapeutic platform for the further development of this siRNA as a twice-yearly or quarterly treatment for hypertension.

doi.org/10.1093/eurheartj/ehag785.4074Open accessInterventions