Factor XI antisense oligonucleotide for prevention of venous thrombosis

Abstract

Background: Experimental data indicate that reducing factor XI levels attenuates thrombosis without causing bleeding, but the role of factor XI in the prevention of postoperative venous thrombosis in humans is unknown. FXI-ASO (ISIS 416858) is a second-generation antisense oligonucleotide that specifically reduces factor XI levels. We compared the efficacy and safety of FXI-ASO with those of enoxaparin in patients undergoing total knee arthroplasty.

Methods: In this open-label, parallel-group study, we randomly assigned 300 patients who were undergoing elective primary unilateral total knee arthroplasty to receive one of two doses of FXI-ASO (200 mg or 300 mg) or 40 mg of enoxaparin once daily. The primary efficacy outcome was the incidence of venous thromboembolism (assessed by mandatory bilateral venography or report of symptomatic events). The principal safety outcome was major or clinically relevant nonmajor bleeding.

Results: Around the time of surgery, the mean (±SE) factor XI levels were 0.38±0.01 units per milliliter in the 200-mg FXI-ASO group, 0.20±0.01 units per milliliter in the 300-mg FXI-ASO group, and 0.93±0.02 units per milliliter in the enoxaparin group. The primary efficacy outcome occurred in 36 of 134 patients (27%) who received the 200-mg dose of FXI-ASO and in 3 of 71 patients (4%) who received the 300-mg dose of FXI-ASO, as compared with 21 of 69 patients (30%) who received enoxaparin. The 200-mg regimen was noninferior, and the 300-mg regimen was superior, to enoxaparin (P<0.001). Bleeding occurred in 3%, 3%, and 8% of the patients in the three study groups, respectively.

Conclusions: This study showed that factor XI contributes to postoperative venous thromboembolism; reducing factor XI levels in patients undergoing elective primary unilateral total knee arthroplasty was an effective method for its prevention and appeared to be safe with respect to the risk of bleeding. (Funded by Isis Pharmaceuticals; FXI-ASO TKA ClinicalTrials.gov number, NCT01713361.).

Figure 1. Effect of FXI-ASO on the Coagulation System

FXI-ASO (ISIS 416858) is a factor XI (FXI)–targeted second-generation antisense oligonucleotide. Tissue damage after surgery exposes tissue factor and results in the release of DNA, RNA, and inorganic polyphosphate from damaged cells and from activated platelets and neutrophils. Tissue factor binds factor VIIa and initiates the extrinsic pathway of coagulation, whereas DNA, RNA, and polyphosphate activate factor XII and initiate the intrinsic pathway of coagulation. Factor XI–targeted antisense oligonucleotide attenuates the intrinsic pathway by binding to factor XI messenger RNA (mRNA) in the liver, which results in ribonuclease H1 (RNase H1)–mediated degradation of FXI messenger RNA, thereby preventing protein synthesis and reducing circulating FXI levels.

Figure 2. Enrollment, Randomization, and Populations for Analysis

The initial protocol (Panel A) called for random assignment of patients to one of three dose regimens of FXI-ASO (100 mg, 200 mg, or 300 mg) or enoxaparin. After 14 patients had undergone randomization, the steering committee amended the protocol (Panel B) to discontinue the 100-mg dose regimen. Random assignment to the 300-mg FXI-ASO cohort was discontinued when the target sample of 70 patients was recruited in that group. Enrollment was continued in the 200-mg cohort until the study ended.

Figure 3. Activated Partial-Thromboplastin Time (aPTT) Ratios and Factor XI Levels before and after Surgery on Day 36, According to Treatment Group

All patients were followed until plasma factor XI levels were 0.3 units per milliliter or more.