N -Acetylgalactosamine–Conjugated Small Interfering RNA Targeting Hepatic Angiotensinogen in Hypertension
Jianxiong Zhang, Jingxuan Wu, Que Liu, Lingdong Kong, Xia Li, Qiannan Gao, Hang Yin, Jiangshuo Li, Alan Shi, Lingdi Zhang, Aidong Shen, Xuehai Liang, Yanfeng Wang, Ruihua DongImportance
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: