RNA interference therapy targeting coagulation factor XI - a first-in-human trial of RBD4059

Inhibiting coagulation Factor XI (FXI) activity has emerged as a promising strategy to prevent intravascular thrombosis. Here, we describe the first-in-human trial with an N-acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA), RBD4059, targeting FXI. In this Phase 1 single ascending-dose study (NCT05653037), healthy volunteers were randomized to receive active drug or placebo (6+2), administered subcutaneously, in four consecutive dose cohorts from 50 mg to 600 mg. The primary endpoint was safety and tolerability up to Day 169 post dose. Secondary endpoints included pharmacokinetic and pharmacodynamic (PD) parameters. Single ascending doses of RBD4059 were well tolerated and no apparent safety concerns were identified. RBD4059 was associated with a dose-dependent and durable suppression of FXI activity up to greater than 90%. Modeling of the available PD data supports clinical dosing schemes of 3-6 months to achieve a robust antithrombotic effect. Altogether, these observations support the further clinical development of RBD4059 to provide an siRNA-based therapeutic option targeting FXI for patients inadequately treated with or contraindicated for thrombosis prophylaxis.