Abstract 4362610: Safety, Pharmacokinetics, and Pharmacodynamics of SGB-3908, A siRNA Targeting AGT in Healthy and Mildly Hypertensive Subjects

Introduction: SGB-3908 (IBI 3016) is a GalNAc-conjugated siRNA targeting hepatic angiotensinogen (AGT), a critical upstream component of the RAAS, for hypertension. SGB-3908 utilizes SanegeneBio’s proprietary Ligand and Enhancer Assisted Delivery (LEAD™) Platform to enhance intrinsic potency, durability and target specificity. Methods: This is a randomized, double-blind, placebo-controlled single-dose escalation study in healthy and mildly hypertensive subjects, evaluating the safety, pharmacokinetics, and pharmacodynamics of SGB-3908 following subcutaneous administration. Results: Forty participants were enrolled into five cohorts (6:2 active: placebo). All participants were Chinese, with a median (range) age of 38 (24–54) years, 37.5% female, mean BMI of 25.2 kg/m 2 , and baseline 24-hour ambulatory blood pressure mean of 123/75 mmHg. SGB-3908 demonstrated a favorable safety and tolerability, with no dose-limiting toxicities, SAE, or discontinuations due to AEs. There were no episodes of hypotension. Most AEs were mild to moderate and reversible. Treatment-related AEs occurring in ≥5% of SGB-3908 participants included injection site reaction and mild increases in C-reactive protein. The observed plasma PK profile aligns with siRNA kinetics, with C max occurring at 6–8 hours and levels falling below the detection limit by 48 hours post-dose. After a single dose, AGT levels dropped below 80% of baseline within 2 weeks and then reached maximum mean reductions of 91.7%, 91.4%, 94.7%, 96.2%, and 97.5% for Doses 1-5 at approximately 4 weeks. At 3 months, sustained reductions were 91.2%, 90.0%, 93.8%, 96.2%, and 96.6% for Doses 1-5, respectively. For Doses 1-3, reductions of 85.9%, 84.0%, and 90.8% persisted at 6 months (study ongoing)(Figure 1). At 3 months, the 24-hour mean ambulatory daytime SBP/DBP changes from baseline were −8.8/-9.7, −2.1/0.8, −7.1/-5.5, −11.0/-12.5, and −16.7/-14.7 mmHg for Dose 1–5, respectively, compared to −3.2/-5.7 mmHg with placebo. Nighttime SBP/DBP changes were −9.4/-3.3, −7.1/-4.9, −15.1/-10.7, −11.6/-6.7, and −16.0/-12.9 mmHg for Doses 1–5, respectively, versus −5.0/-2.6 mmHg with placebo (Figure 2). Conclusion: SGB-3908 demonstrated a favorable safety profile, sustained AGT reduction, and preliminary BP reduction in healthy and mildly hypertensive subjects. These findings support further investigation for hypertension and other indications where RAAS inhibitors are effective, with potential advantages in dosing frequency and adherence.