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Factor XI(a) inhibitors for thrombosis: an updated patent review (2016-present).

ABSTRACT: Introduction: Anticoagulation without bleeding is an ideal goal in treating thrombosis, however, this goal has not been achieved. All current anticoagulants are associated with significant bleeding which limits their safe use. Genetic and pharmacological findings indicate that factor XIa is a key player in thrombosis, yet it is a relatively marginal one in hemostasis. Thus, factor XIa and its zymogen offer a unique opportunity to develop anticoagulants with low bleeding risk.Areas covered: A survey of patent literature has retrieved more than 50 patents on the discovery of novel therapeutics targeting factor XI(a) since 2016. Small molecules, monoclonal antibodies, oligonucleotides, and polypeptides have been developed to inhibit factor XI(a). Many inhibitors are in early development and few have been evaluated in clinical trials.Expert opinion: Factor XI(a) is being actively pursued as a drug target for the development of effective and safer anticoagulants. Although many patents claiming factor XI(a) inhibitors were filed prior to 2016, recent literature reveals a moderately declining trend. Nevertheless, more agents have entered different levels of clinical trials. These agents exploit diverse mechanistic strategies for inhibition. Although further development is warranted, reaching one or more of these agents to the clinic will transform the anticoagulation therapy.

SUBMITTER: Al-Horani RA

PROVIDER: S-EPMC7515655 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Factor XI(a) inhibitors for thrombosis: an updated patent review (2016-present).

Al-Horani Rami A RA

Expert opinion on therapeutic patents 20191219 1

<b>Introduction</b>: Anticoagulation without bleeding is an ideal goal in treating thrombosis, however, this goal has not been achieved. All current anticoagulants are associated with significant bleeding which limits their safe use. Genetic and pharmacological findings indicate that factor XIa is a key player in thrombosis, yet it is a relatively marginal one in hemostasis. Thus, factor XIa and its zymogen offer a unique opportunity to develop anticoagulants with low bleeding risk.<b>Areas cove ...[more]

PMID: 31847619

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Project description:BackgroundExperimental 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.MethodsIn 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.ResultsAround 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.ConclusionsThis 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.).

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Factor XI(a) inhibitors for thrombosis: an updated patent review (2016-present).

Publications

Factor XI(a) inhibitors for thrombosis: an updated patent review (2016-present).

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