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RNA interference therapy targeting coagulation factor XI: a first-in-human trial of RBD4059 (vortosiran)
Anders Gabrielsen1, Sebastian Ueckert1, Catarina Nilsson1
1Ribocure Pharmaceuticals AB, Gothenburg, Sweden.
Abstract:
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-conjugated small interfering RNA (siRNA), RBD4059, targeting FXI. In this phase 1 single ascending dose study (NCT05653037), healthy volunteers were randomized to receive either active drug or placebo (6 + 2), administered subcutaneously, in 4 consecutive dose cohorts ranging from 50 mg to 600 mg. The primary end point was safety and tolerability up to day 169 after dose. Secondary end points 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 >90%. Modeling of the available PD data supports clinical dosing schemes of 3 to 6 months to achieve a robust antithrombotic effect. Altogether, these observations support further clinical development of RBD4059 to provide an siRNA-based therapeutic option targeting FXI for patients inadequately treated with or contraindicated for current available thrombosis prophylaxis. This trial was registered at www.clinicaltrials.gov as #NCT05653037.
Insights
A novel RNA interference therapy, RBD4059, targeting Factor XI (FXI) shows excellent safety and achieves significant, lasting FXI activity reduction in its first human trial. This supports its potential for preventing thrombosis.
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.
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