Factor XI Antisense Oligonucleotide for Prevention of Venous Thrombosis

Abstract

BACKGROUND: Patients undergoing total knee arthroplasty are at risk for postoperative venous thromboembolism (VTE). The pathogenesis of postoperative VTE is incompletely understood, but tissue factor exposed at the surgical site is thought to be the major driver through the extrinsic pathway of coagulation. Experimental data indicate that reducing factor XI (FXI), a key component of the intrinsic pathway, attenuates thrombosis without causing bleeding, but the role of FXI in postoperative VTE in humans is unknown. There is evidence that patients with congenital FXI deficiency are at a reduced risk of VTE. FXI levels can be lowered with ISIS 416858 (FXI-ASO), an antisense oligonucleotide that specifically reduces human FXI mRNA expression in the liver. To determine whether lowering FXI levels prevents VTE without increasing the risk of bleeding, we compared several doses of FXI-ASO with enoxaparin on the rates of postoperative VTE and bleeding in patients undergoing total knee arthroplasty. METHODS: We randomized 300 patients to one of two FXI-ASO regimens (200 or 300 mg) or to 40 mg enoxaparin once daily in an open-label, parallel group study. FXI-ASO was administered as 9 subcutaneous injections starting 36 days before surgery with the last dose given 3 days postoperatively. Enoxaparin was to be continued for at least 8 days postoperatively. The primary efficacy outcome was the incidence of VTE detected by mandatory bilateral venography (performed on days 8 to 12 postoperatively) or symptomatic events. The principal safety outcome was major and clinically relevant nonmajor bleeding. All outcomes were adjudicated by a committee blinded to treatment allocation. RESULTS: FXI-ASO prolonged the activated partial thromboplastin time in a dose-dependent manner, but had no effect on the prothrombin time. Around the time of surgery, mean FXI activities were 0.38 ± 0.01, 0.20 ± 0.01 and 0.93 ± 0.02 units/ml in patients given the 200 and 300 mg FXI-ASO regimens and enoxaparin, respectively. In contrast, levels of FXII, FIX and FVIII, other components of the intrinsic pathway, were unaffected by FXI-ASO. The primary efficacy outcome occurred in 36 of 134 (26.9%) and 3 of 71 (4.2%) patients given the 200 and 300 mg FXI-ASO regimens, respectively, compared with 21 of 69 (30.4%) patients in the enoxaparin group. The 200 mg regimen was non-inferior, while the 300 mg regimen was superior to enoxaparin (P<0.001). Bleeding occurred in 2.8%, 2.6% and 8.3% of patients in the 200 mg, 300 mg, and enoxaparin groups, respectively. Preoperative and postoperative hemoglobin values and transfusion requirements were similar in the three treatment groups. CONCLUSIONS: This study is the first to show that FXI contributes to postoperative VTE and that lowering FXI levels is very effective for its prevention and appears to be safe. Additional studies are needed to confirm the safety of FXI-ASO, although the fact that patients receiving this therapy safely underwent major orthopedic surgery is reassuring. Our findings support the concept that thrombosis and hemostasis can be dissociated with strategies that target FXI. The profile of FXI-ASO renders it an appealing option for treatment of patients with a wide range of chronic thrombotic conditions. Disclosures Buller: Isis Pharmaceuticals Daiichi-Sankyo Bayer Health-Care Pfizer Bristol-Myers-Squibb: Consultancy, Honoraria. Bethune:Isis Pharmaceuticals: Employment. Bhanot:Isis Pharmaceuticals: Employment. Gailani:Aronora: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Dyax: Consultancy, Research Funding; Instrument Laboratory: Consultancy, Research Funding; Isis: Consultancy; Merck: Consultancy; Novartis: Consultancy. Monia:Isis Pharmaceuticals, Inc.: Employment. Raskob:Bayer Healthcare: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; ISIS Pharmaceuticals: Consultancy, Honoraria. Segers:Isis Pharmaceuticals Daiichi-Sankyo Bayer Health-Care Pfizer Bristol-Myers-Squibb: Medical Director ofAcademic Research Organization which received services fees for the scientific coordination of clinical studies Other. Weitz:Pfizer, Inc.: Consultancy, Honoraria.

Prospective study of circulating factor XI and incident venous thromboembolism: The Longitudinal Investigation of Thromboembolism Etiology (LITE)

“…In whites, an association of a F11 genetic variant with VTE suggests a causal relation, but we did not observe this genetic relation in African‐Americans. Clinical trial evidence that inhibition of factor XI can prevent VTE further supports its role in VTE etiology .…”

“…Another study reported that patients with severe factor XI deficiency have reduced incidence of VTE . Moreover, a clinical trial showed that inhibition of factor XI prevents postsurgical VTEs .…”

Monocytes as immune targets in arterial hypertension

“…Interestingly, the TF‐mediated thrombin activity appears to be propagated by an amplification loop via the coagulation factor FXI in hypertension. That pathway was proposed earlier in coagulation research (Gailani and Broze Jr, ) and can be exploited therapeutically to perform safe thromboprophylaxis (Buller et al ., ). Blocking FXI synthesis prevented localized thrombin generation in platelets and lowered pro‐inflammatory platelet‐monocyte complexes, the vascular accumulation of myeloid cells, ROS formation in the vessel wall and ultimately dampened the blood pressure increase in models of hypertension (Kossmann et al ., ).…”

F11 rs2289252T and rs2036914C Polymorphisms Increase the Activity of Factor XI in Post‐trauma Patients with Fractures Despite Thromboprophylaxis

“…Data from FXI‐deficient animal models indicate that FXI deficiency results in a relatively mild bleeding disorder. A recent study demonstrated that FXI contributes to postoperative thrombosis and that reducing FXI concentrations in patients undergoing total knee arthroplasty helped to prevent DVT and appeared to be safe, doing so without increasing bleeding. These findings support the concept that inhibition of FXI may serve as a safe, specific, novel therapeutic approach to thrombosis treatment and prevention.…”