Factor IX(a) inhibitors: an updated patent review (2003-present)

Afosah, Daniel K.; Ofori, Edward; Mottamal, Madhusoodanan; Al‐Horani, Rami A.

doi:10.1080/13543776.2022.2026926

Cited by 8 publications

(6 citation statements)

References 113 publications

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“…The recent emergence of factor XI inhibitors potentially strengthens the approach we have suggested because these novel agents seem to carry a very low risk of bleeding and targeted to patients at higher risk of stroke may further tip the benefit-to-risk balance in a favorable direction. [36][37][38][39] Although questions remain regarding the relative roles of thrombosis and thromboembolism in HFpEF versus HFrEF, in patients with AF, anticoagulant therapy is equally effective in individuals with HFrEF and HFpEF. 32 Clearly, this hypothetical strategy of stroke risk-stratification and targeted anticoagulation needs to be tested in a prospective randomized controlled trial.…”

Section: Discussionmentioning

confidence: 99%

Predicting Stroke in Heart Failure and Preserved Ejection Fraction Without Atrial Fibrillation

Kondo

Jering

Jhund

et al. 2023

Circ: Heart Failure

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Background: The rate of stroke in patients with heart failure (HF) and preserved ejection fraction but without atrial fibrillation (AF), is uncertain as is whether it is possible to reliably predict the risk of stroke in these patients. Methods: We validated a previously developed simple risk model for stroke among patients enrolled in the I-Preserve trial (Irbesartan in Heart Failure With Preserved Systolic Function) and PARAGON-HF trial (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction). The risk model consisted of 3 variables: history of previous stroke, insulin-treated diabetes, and plasma N-terminal pro-B-type natriuretic peptide level. Results: Of the 8924 patients included in the pooled trial dataset, 5126 patients did not have AF at baseline. Among patients without AF, 190 (3.7%) experienced a stroke over a median follow-up of 3.6 years (rate 10.5 per 1000 patient-years). The risk for stroke increased with increasing risk score: second tertile hazard ratio, 1.78 (95% CI, 1.17–2.71); third tertile hazard ratio, 3.03 (95% CI, 2.06–4.47), with the first tertile as reference. For patients in the third tertile, the occurrence rate of stroke was 17.7 per 1000 patient-years, similar to that in patients with AF not receiving anticoagulation (20.7 per 1000 patient-years), and those with AF who were receiving anticoagulation (14.5 per 1000 patient-years). Model discrimination was good with a C index of 0.81 (0.68–0.91) and a simple score could be created from the model. Conclusions: A simple risk model can detect a subset of HF and preserved ejection fraction patients without AF who have a higher risk for stroke. The balance of risk-to-benefit in these individuals may justify the use of prophylactic anticoagulation, but this hypothesis needs to be prospectively evaluated. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT00095238 and NCT01920711.

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Section: Discussionmentioning

confidence: 99%

Predicting Stroke in Heart Failure and Preserved Ejection Fraction Without Atrial Fibrillation

Kondo

Jering

Jhund

et al. 2023

Circ: Heart Failure

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“…However, coagulation factors in the intrinsic pathway, such as FXI, appear to be key players in thrombosis but have a minimal role in bleeding, and thus, intrinsic coagulation factors are suggested to be suitable targets for effective and relatively safer anticoagulant drugs. 94 Many research groups work on FXI(a), as evidenced by a large number of patents, 95,96 and several have already moved on to different stages of clinical trials. For example, the AXIOMATIC-TKA and ANT-005 TKA trials showed superior DVT prevention by FXIa-inhibitor milvexian and anti-FXI antibody abelacimab in patients undergoing total-knee arthroplasty compared with enoxaparin.…”

Section: New Antithrombotic Drugsmentioning

confidence: 99%

“…Many research groups work on FXI(a), as evidenced by a large number of patents, 95 , 96 and several have already moved on to different stages of clinical trials. For example, the AXIOMATIC-TKA and ANT-005 TKA trials showed superior DVT prevention by FXIa-inhibitor milvexian and anti-FXI antibody abelacimab in patients undergoing total-knee arthroplasty compared with enoxaparin.…”

Section: Where Do We Stand?mentioning

confidence: 99%

Pathophysiological Changes in the Hemostatic System and Antithrombotic Management in Kidney Transplant Recipients

et al. 2023

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Nowadays, the main cause for early graft loss is renal graft thrombosis because kidney transplant outcomes have improved drastically owing to advances in immunological techniques and immunosuppression. However, data regarding the efficacy of antithrombotic therapy in the prevention of renal graft thrombosis are scarce. Adequate antithrombotic management requires a good understanding of the pathophysiological changes in the hemostatic system in patients with end-stage kidney disease (ESKD). Specifically, ESKD and dialysis disrupt the fine balance between pro- and anticoagulation in the body, and further changes in the hemostatic system occur during kidney transplantation. Consequently, kidney transplant recipients paradoxically are at risk for both thrombosis and bleeding. This overview focuses on the pathophysiological changes in hemostasis in ESKD and kidney transplantation and provides a comprehensive summary of the current evidence for antithrombotic management in (adult) kidney transplant recipients.

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“…The possible reason is that the FIXa/FVIIIa complex could be activated by the FVIIa/TF complex to further activate FX, which is a crucial process for the physiological hemostasis. Encouragingly, some evidence suggests that FIX inhibition has a lower bleeding risk than FX or thrombin inhibition. , FXIII is the coagulation factor that functions in the final step of the coagulation pathway, and its deficiency in humans results in spontaneous or delayed life-threatening bleeding . Because FXIII has no effect on thrombin activation and fibrin formation, partial inhibition against it may reduce the bleeding risk. , Overall, PKal, FXIIa, and FXIa in the intrinsic pathway are the most promising targets for anticoagulant discovery with minimal or no bleeding (Figure B).…”

Section: Coagulationmentioning

confidence: 99%

“…Encouragingly, some evidence suggests that FIX inhibition has a lower bleeding risk than FX or thrombin inhibition. 44,45 FXIII is the coagulation factor that functions in the final step of the coagulation pathway, and its deficiency in humans results in spontaneous or delayed lifethreatening bleeding. 46 Because FXIII has no effect on thrombin activation and fibrin formation, partial inhibition against it may reduce the bleeding risk.…”

Section: Coagulationmentioning

confidence: 99%

Factor XIa Inhibitors in Anticoagulation Therapy: Recent Advances and Perspectives

et al. 2023

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Factor XIa (FXIa) in the intrinsic pathway of the coagulation process has been proven to be an effective and safe target for anticoagulant discovery with limited or no bleeding. Numerous small-molecule FXIa inhibitors (SMFIs) with various scaffolds have been identified in the early stages of drug discovery. They have served as the foundation for the recent discovery of additional promising SMFIs with improved potency, selectivity, and pharmacokinetic profiles, some of which have entered clinical trials for the treatment of thrombosis. After reviewing the coagulation process and structure of FXIa, this perspective discusses the rational or structure-based design, discovery, structure−activity relationships, and development of SMFIs disclosed in recent years. Strategies for identifying more selective and druggable SMFIs are provided, paving the way for the design and discovery of more useful SMFIs for anticoagulation therapy.

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Factor IX(a) inhibitors: an updated patent review (2003-present)

Cited by 8 publications

References 113 publications

Predicting Stroke in Heart Failure and Preserved Ejection Fraction Without Atrial Fibrillation

Predicting Stroke in Heart Failure and Preserved Ejection Fraction Without Atrial Fibrillation

Pathophysiological Changes in the Hemostatic System and Antithrombotic Management in Kidney Transplant Recipients

Factor XIa Inhibitors in Anticoagulation Therapy: Recent Advances and Perspectives

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