A single subcutaneous dose of BW-00112 (150-600 mg) was well tolerated and reduced ANGPTL3 levels by 76-89%, triglycerides by 62-76%, and LDL-C by 31-34% at 12 weeks.
RCT
Double-blind
Randomized
Yes
Does a single subcutaneous dose of BW-00112 improve lipid profiles and demonstrate safety in healthy subjects with elevated LDL-C and triglycerides?
A single subcutaneous dose of the ANGPTL3 siRNA BW-00112 was well tolerated and produced substantial, prolonged reductions in ANGPTL3, triglycerides, and LDL-C in healthy subjects with elevated lipids.
Abstract Background/Introduction Dyslipidemia is a significant risk factor for cardiovascular disease (CVD), and a residual risk of CVD remains despite the current standard of care. While combination therapies are often employed, some patients experience safety concerns and adverse side effects. Angiopoietin-like protein 3 (ANGPTL3) has emerged as a promising therapeutic target for the treatment of dyslipidemia. Genome-wide association studies have identified ANGPTL3 as a critical regulator of blood lipid levels in humans. It modulates lipid and lipoprotein metabolism by inhibiting lipoprotein lipase (LPL) and endothelial lipase (EL). BW-00112 is a fully synthetic, chemically optimized, double-stranded ANGPTL3 siRNA conjugated with N-acetylgalactosamine (GalNAc) for targeted delivery. This innovative approach shows great potential in addressing unmet needs in the management of dyslipidemia. Purpose The primary objective of this study was to assess the safety and tolerability of a single dose of BW-00112 in Chinese healthy subjects with 100 mg/dL ≤ LDL-C 190 mg/dL and 100 mg/dL≤ TG 500 mg/dL up to 12 weeks. The secondary objectives of this study were to characterize pharmacokinetics (PK) profile and evaluate the pharmacodynamics (PD) effect (ANGPTL3, TG, LDL-C, non-HDL-C) of a single dose of BW-00112 up to 12 weeks. Methods This was a phase 1, randomized, double-blind, placebo-controlled, single dose study to evaluate the safety, tolerability, PK, and PD of subcutaneous doses of BW-00112 in Chinese healthy subjects with elevated LDL-C who were not receiving lipid-lowering therapy. Results BW-00112 was well tolerated with subcutaneous administration as a single dose ranging from 150 mg to 600 mg in Chinese healthy subjects. There were no serious adverse events, and no death or study discontinuations due to treatment-emergent adverse events (TEAEs). Most of the TEAEs were mild in severity. Adverse events of special interest, including injection site reactions and abnormalities in liver function, did not raise safety concerns. Exposure (AUC0-last and Cmax) increased in a dose-dependent manner within the linear range of 150 mg to 600 mg. However, the increase was slightly more than dose proportional. BW-00112 at doses of 150 mg to 600 mg resulted in substantial reductions in ANGPTL3 levels (mean -76% to -89%) 12 weeks after dosing. BW-00112 at doses of 150 mg to 600 mg also led to reductions in triglyceride (mean -62% to -76%), LDL-C (mean -31% to -34%), ApoB (mean -26% to -31%), Non-HDL-C (mean -32% to -36%), and remnant-C (mean -38% to -41%). Conclusion BW-00112 was generally well tolerated when administered subcutaneously as a single dose ranging from 150 mg to 600 mg. Substantial PD effects were observed with single subcutaneous doses of BW-00112 ranging from 150 mg to 600 mg, including reductions in ANGPTL3, triglycerides, LDL-C, ApoB, non-HDL-C, and remnant-C. No big difference was observed on safety, PK, and PD in Australian and Chinese healthy subjects.Reductions in serum ANGPTL3 and lipids
Qian et al. (2025) conducted an RCT in Elevated LDL-C and triglycerides. BW-00112 vs. Placebo was evaluated on Safety and tolerability. A single subcutaneous dose of BW-00112 (150-600 mg) was well tolerated and reduced ANGPTL3 levels by 76-89%, triglycerides by 62-76%, and LDL-C by 31-34% at 12 weeks.