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.)

Antisense inhibition of apolipoprotein (a) to lower plasma lipoprotein (a) levels in humans

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“…1 ). These drugs also have an improved therapeutic index due to reduced pro-infl ammatory properties (22)(23)(24)(25)(26).…”

FXIa and platelet polyphosphate as therapeutic targets during human blood clotting on collagen/tissue factor surfaces under flow

“…[24][25][26] Recently, a phase 2 trial demonstrated that FXI-antisense oligonucleotide (FXI-ASO) reduced FXI levels and decreased the incidence of deep vein thrombosis (DVT) after knee arthroplasty without increasing bleeding, thus providing evidence that FXIa can contribute to thrombosis in humans. 27 However, postoperative bleeding in knee arthroplasty is relatively uncommon, and the rate of bleeding with FXI-ASO was not significantly lower than that seen with enoxaparin. 28,29 The FXI-ASO trial demonstrated a role for FXIa in DVT but did not resolve the role of either platelet polyP or FXIIa in postarthroplasty DVT because FXIa can inactivate tissue factor pathway inhibitor, 30 and FXI can be feedback-activated by thrombin.…”

RNA Therapeutics in Oncology: Advances, Challenges, and Future Directions

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