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

BACKGROUND: Hypertension affects over 1.3 billion adults worldwide, and poor adherence to daily oral therapy contributes to inadequate blood pressure (BP) control. We characterized BPR-30901649, a liver-targeted small interfering RNA (siRNA) against angiotensinogen (AGT), hypothesizing that its optimized design would confer greater potency and durability than an advanced clinical-stage AGT siRNA benchmark. METHODS: screening in HepG2 cells and human AGT (hAGT) transgenic mice. Off-target risk was assessed by RNA sequencing in primary human hepatocytes. Pharmacodynamics were evaluated in hAGT mice after single and repeat subcutaneous (SC) dosing, and in hypertensive cynomolgus monkeys given a single SC dose of 1.5 or 3.0 mg/kg, with serum AGT and systolic BP (SBP) monitored for 20 weeks. Investigational New Drug (IND)-enabling toxicology was conducted in rats and nonhuman primates (NHPs). RESULTS: RNA sequencing indicated low off-target risk. In hAGT mice, BPR-30901649 produced significantly deeper serum AGT knockdown than the benchmark. In hypertensive NHPs, a single SC injection produced rapid, dose-dependent, and sustained AGT suppression; at week 20, SBP remained reduced by 14.2% (20.3 mm Hg) and 17.3% (25.3 mm Hg) in the low- and high-dose groups, respectively. In repeat-dose toxicology, the no-observed-adverse-effect level was 100 mg/kg in NHPs. CONCLUSIONS: BPR-30901649 surpassed an advanced clinical-stage AGT siRNA benchmark in vivo and showed a wide preclinical safety margin, supporting its clinical development as a potential twice-yearly therapy for hypertension.