N-Acetylgalactosamine-Conjugated Small Interfering RNA Targeting Hepatic Angiotensinogen in Hypertension: A Phase I Clinical Trial With Randomized Part A and Open-Label Part B.
4 affiliations
- 1Research Ward, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
- 2Beijing Key Laboratory of Early Clinical Evaluation of Nucleic Acid Products and Cell Therapy, Beijing, China.
- 3Arnatar Therapeutics Inc, San Diego, California.
- 4Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Abstract
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).
Related
- BPR‐30901649, An Angiotensinogen‐Targeting Small Interfering RNA, Achieves Ultra‐Durable Target Silencing and Sustained Blood Pressure Reduction Through 20 Weeks in Hypertensive Non‐Human Primates
- Comparative Efficacy of Treatments for Resistant or Uncontrolled Hypertension : A Network Meta-Analysis of Randomized Trials
- Oral Potassium Supplementation Lowers Clinic Blood Pressure in Untreated Primary Hypertension—Systematic Review and Meta‐Analysis of Randomized Trials
- mHealth-based lifestyle intervention for hypertension in community-dwelling adults: a cluster-randomized controlled trial with exploratory multi-omics analyses
- Lower circulating angiotensinogen levels across ACLD stages are associated with hepatic dysfunction and mortality
BibTeX
@article{zhang2026nacetylgalactosamineconjugated,
title = {{N-Acetylgalactosamine-Conjugated Small Interfering RNA Targeting Hepatic Angiotensinogen in Hypertension: A Phase I Clinical Trial With Randomized Part A and Open-Label Part B.}},
author = {Jianxiong Zhang and Jingxuan Wu and Que Liu and Lingdong Kong and Xia Li and Qiannan Gao and Hang Yin and Jiangshuo Li and Alan Shi and Lingdi Zhang and Aidong Shen and Xuehai Liang and Yanfeng Wang and Ruihua Dong},
journal = {JAMA cardiology},
year = {2026},
month = oct,
doi = {10.1001/jamacardio.2026.4936},
url = {https://europepmc.org/article/MED/42961436},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - N-Acetylgalactosamine-Conjugated Small Interfering RNA Targeting Hepatic Angiotensinogen in Hypertension: A Phase I Clinical Trial With Randomized Part A and Open-Label Part B.
AU - Jianxiong Zhang
AU - Jingxuan Wu
AU - Que Liu
AU - Lingdong Kong
AU - Xia Li
AU - Qiannan Gao
AU - Hang Yin
AU - Jiangshuo Li
AU - Alan Shi
AU - Lingdi Zhang
AU - Aidong Shen
AU - Xuehai Liang
AU - Yanfeng Wang
AU - Ruihua Dong
PY - 2026
DA - 2026/10/30
JO - JAMA cardiology
DO - 10.1001/jamacardio.2026.4936
UR - https://europepmc.org/article/MED/42961436
AB - 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).
SN - 2380-6583
SN - 2380-6591
ER -