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
Authors' conclusion
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.
Study context
- Population
- Healthy adults (part A) and patients with hypertension (part B)Part A: 40 healthy adults randomized 6:2, 39 completed, Part B: 8 patients with hypertension, all completed · Part A healthy adults 40 · Part B patients with hypertension 8
- Participants
- 30 / 10 / 8
- Comparison
- Angiotensinogen (AGT)-targeting GalNAc-siRNA (25-600 mg) vs placebo in healthy adults; single-dose open-label GalNAc-siRNA, 600 mg, in patients with hypertension
- GalNAc-siRNA (part A)n = 30
- Placebo (part A)n = 10
- GalNAc-siRNA, 600 mg (part B)n = 8
- Outcome
- Safety and tolerability: treatment-emergent adverse events (TEAEs)
Methodological detailsPart A: double-blind, placebo-controlled, single ascending-dose trial, Part B: open-label, single-dose study, Beijing Friendship Hospital, Capital Medical University, Beijing, China, 24-week follow-up
- Part A: double-blind, placebo-controlled, single ascending-dose trial
- Part B: open-label, single-dose study
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
- 24-week follow-up
Main finding
As reported in the abstract
Secondary outcomes
Plasma exposure (Cmax and AUC)
- Increased with dose over the wide dose range from 25 mg to 600 mg
Mean maximum serum AGT reduction
- Healthy volunteers (at 600 mg)
- 93%
- Patients with hypertension (at 600 mg)
- 90%
Placebo-corrected 24-hour ambulatory systolic blood pressure decrease (exploratory), healthy participants, single 600-mg dose · 24 weeks
- Decrease
- 12.9 mm Hg
- Exploratory
Original publication
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. JAMA Cardiol. Published 30 October 2026. doi:10.
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