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 BPR‐30901649 was selected through in vitro and in vivo 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.