First-in-human study to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of RBD4059, a GalNAc-siRNA drug targeting coagulation factor XI (FXI), in healthy subjects

Abstract Background Patients at risk of thrombosis/thromboembolism, require effective and safe anti-coagulation with high compliance. Inhibiting FXI has emerged as a promising strategy with potential for lower bleeding risk compared to currently approved anti-coagulants. Here we report on the safety, PK and PD effects of the GalNAc-conjugated siRNA RBD4059, specifically targeting and repressing FXI protein synthesis in the liver. Purpose Investigate safety, PK, and PD of first-in-human dosing of RBD4059 in healthy subjects. Methods A randomized, single-blind, placebo-controlled, single ascending dose (SAD) phase I study in healthy subjects (NCT05653037), in cohorts of eight randomized 3:1 to receive escalating doses of RBD4059 (50, 150, and 400 mg) or placebo administered subcutaneously. Results As of January 25, 2024, 24 subjects (with follow-up to week 24) with demographics and baseline clinical characteristics shown in Table 1 were enrolled. RBD4059 was well tolerated (Table 2), all related AEs were grade 1. There was no evidence of any clinically relevant bleeding events. Plasma exposure of RBD4059 tended to increase in proportion to the dose. Maximum concentration in plasma (Cmax) was reached in 2 to 4 h and then declined in line with one-compartment kinetics. The mean plasma half-life (t1/2) ranged from 3.2 to 7.0 h. RBD4059 treatment resulted in dose dependent and sustained reductions in FXI activity and FXI antigen (Figure 1A, B, D). Observed mean maximum percentage change from baseline in FXI activity from the 50 mg, 150 mg, and 400 mg SAD cohorts were 67.5%, 81.0%, and 85.8%, respectively, recovering with a maintained effect observed on D141 (50mg: 50.6% inhibition; 150mg: 68.2% inhibition). The reduction in FXI antigen showed a very similar pattern as the reduction in FXI activity, and reductions were accompanied by a concomitant increase in APTT. (Figure 1C, D). PKPD modelling supports that RBD4059 may be dosed every 3 months or less frequent with a >90% FXI reduction throughout the dosing interval, and will be tested in the upcoming phase 2 study. Conclusion(s) RBD4059 demonstrated favorable safety, predictable PK, and pronounced durable PD effect in the dose range of 50 mg - 400 mg. This first-in-human SAD study supports the further development of RBD4059 as an anticoagulant that can maintain a high level of PD effect with a once every 3 month or less frequent dosing regimen, with potential for enhanced compliance in chronic anti-coagulant therapy.Table 1 & Table 2Figure 1.Panels A-D