N -Acetylgalactosamine–Conjugated Small Interfering RNA Targeting Hepatic Angiotensinogen in Hypertension

Importance: Angiotensinogen (AGT) is the precursor of angiotensin peptides and a key determinant of renin-angiotensin-aldosterone system activity. ART101 is an investigational N-acetylgalactosamine-conjugated small interfering RNA (GalNAc-siRNA) designed to durably suppress hepatic AGT synthesis. Objective: To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of the AGT-targeting GalNAc-siRNA in healthy volunteers and to provide an initial exploratory assessment of blood pressure effects in patients with hypertension. Design, Setting, and Participants: This phase I study was conducted from January 2025 to April 2026 with 24-week follow-up. Part A was a double-blind, placebo-controlled, single ascending-dose trial; part B was an open-label, single-dose study. The study took place at Beijing Friendship Hospital, Capital Medical University, Beijing, China. Part A enrolled 40 healthy adults randomized 6:2 to receive the GalNAc-siRNA (25-600 mg) or placebo; 39 completed the study. Part B enrolled 8 patients with hypertension receiving the GalNAc-siRNA, 600 mg; all completed the study. Interventions: A single subcutaneous injection of the AGT-targeting GalNAc-siRNA (25, 75, 150, 300, or 600 mg) or placebo in part A; a single open-label subcutaneous injection of GalNAc-siRNA, 600 mg, in part B. Main Outcomes and Measures: The primary outcome was safety and tolerability; secondary outcomes included pharmacokinetics, pharmacodynamics, exploratory blood pressure assessments, and renin-angiotensin-aldosterone system biomarkers. Results: Among 40 healthy volunteers (27 [67.5%] male; mean [SD] age, 40.4 [7.8] years) and 8 patients (6 [75.0%] male; mean [SD] age, 47.3 [10.3] years) with hypertension, the AGT-targeting GalNAc-siRNA was well tolerated. In part A, treatment-emergent adverse events (TEAEs) occurred in 23 of 30 active-treatment participants (76.7%) vs 7 of 10 placebo recipients (70.0%); in part B, 6 of 8 patients (75.0%) had TEAEs. No serious adverse events, injection site reactions, or hyperkalemia were observed; all TEAEs were mild to moderate. Plasma exposure (maximum plasma concentration [Cmax] and area under the plasma concentration-time curve [AUC]) increased with dose over the wide dose range from 25 mg to 600 mg. Mean maximum serum AGT reductions of 93% (at 600 mg) in healthy volunteers and 90% (at 600 mg) in patients with hypertension were observed. At 24 weeks after a single 600-mg dose, the placebo-corrected 24-hour ambulatory systolic blood pressure decreased by 12.9 mm Hg in healthy participants. Conclusion and Relevance: In this phase I study, no serious treatment-related safety signals were identified. Sustained, dose-dependent AGT reductions and exploratory blood pressure lowering were observed. These findings support further investigation of the AGT-targeting GalNAc-siRNA as a potential long-acting therapeutic for hypertension. Trial Registration: China Drug Clinical Registry Identifiers: CTR20250041 (part A) and CTR20253973 (part B).