Inhibition of liver ApoC3 by GalNAc-conjugated siRNA RBD5044: first-in-human trial to evaluate the safety, pharmacokinetics (PK), and pharmacodynamic (PD) effects on atherogenic lipid profiles in heal

Abstract Background Reduction of ApoC3 has the potential to significantly reduce triglyceride-rich lipoprotein particle load, including the highly atherogenic remnant cholesterol particles, thereby reducing residual CV-risk related to dyslipidemia and remnant cholesterol burden. Purpose To investigate the GalNAc-conjugated siRNA RBD5044 first-in-human safety, PK and PD effects on ApoC3 and atherogenic lipid profile by specifically targeting and suppressing ApoC3 protein synthesis in the liver. Methods A randomized, double-blind, placebo-controlled phase I trial with single- and multiple ascending doses (S/MAD) in healthy participants (N=72) with TG levels > 80 mg/dL. Cohorts of eight were randomized 3:1 to receive escalating doses of RBD5044 (SAD: 5, 20, 60, 90, 120 and 150 mg; MAD: 60, 90 and 150 mg – 2 doses 4 weeks apart) or placebo administered subcutaneously (SC). Results Following SC dosing, RBD5044 was rapidly absorbed with median time to reach maximum plasma concentrations ranging from 2-6 hours. Plasma concentrations thereafter declined rapidly with a mean half-life ranging between 3.3 - 6.7 hours, consistent with rapid GalNAc-mediated uptake of the siRNA into the liver (Figure 1). There was a dose dependent and sustained (>6 months) suppression of ApoC3 levels (Figure 1) at higher doses, accompanied by robust reductions in plasma triglycerides and atherogenic lipid particles (LDL, ApoB, calculated remnant Cholesterol[1] & VLDL[2]) in combination with increased HDL (Figure 2). RBD5044 was well tolerated, with few mild (grade 1) injection site reactions. No alerting liver or other dose-dependent safety lab signals, including fasting glucose or HbA1c levels, or changes in vital signs were observed. Conclusion(s) RBD5044 demonstrated favorable safety, predictable PK, and durable PD effects on the lipid profile. These results support the further development of RBD5044, maintaining a robust ApoC3 and lipid lowering effect with a once every 3 months or less frequent SC dosing regimen. RBD5044 provides potential for enhanced compliance and lipid control and for combination development with siRNAs targeting other lipid-lowering pathways to most effectively eliminate residual lipid-risk. Target population dose-range for efficacy and safety is being investigated in the ongoing phase II study in EU.Figure 1 Figure 2