RNA interference therapy targeting coagulation factor XI: a first-in-human trial of RBD4059 (vortosiran)

Area of Science:

• Pharmacology
• Thrombosis Research
• RNA Interference Therapeutics

Background:

• Intravascular thrombosis is a significant clinical challenge.
• Inhibiting coagulation Factor XI (FXI) is a promising antithrombotic strategy.
• RNA interference (RNAi) offers a targeted therapeutic approach.

Purpose of the Study:

• To evaluate the safety and tolerability of the first-in-human administration of RBD4059, an N-acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) targeting FXI.
• To assess the pharmacokinetic and pharmacodynamic effects of single ascending doses of RBD4059 in healthy volunteers.

Main Methods:

• Phase 1, single ascending-dose, randomized, placebo-controlled study (NCT05653037).
• Healthy volunteers received subcutaneous doses of RBD4059 (50 mg to 600 mg) or placebo.
• Safety, tolerability, pharmacokinetic, and pharmacodynamic parameters were monitored up to 169 days post-dose.

Main Results:

• Single ascending doses of RBD4059 were well tolerated with no identified safety concerns.
• RBD4059 demonstrated dose-dependent and durable suppression of FXI activity, exceeding 90%.
• Pharmacodynamic modeling suggests 3-6 month dosing intervals for sustained antithrombotic effect.

Conclusions:

• RBD4059 is safe and effectively suppresses FXI activity.
• These findings support the further clinical development of RBD4059 as an siRNA-based therapy for thrombosis prevention.
• RBD4059 may offer a new therapeutic option for patients with thrombosis risk.