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

Abstract 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.