Inhibition of Tissue Factor Pathway Inhibitor (TFPI) as a Treatment for Haemophilia: Rationale with Focus on Concizumab

Chowdary, Pratima

doi:10.1007/s40265-018-0922-6

Cited by 44 publications

(40 citation statements)

References 63 publications

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“…A phase 1 study (concizumab) showed no serious adverse events or antidrug antibodies. Currently, dosing is restricted to once‐daily administration because of inter‐patient variability in thrombin generation, elevated D‐dimer and prothrombin F 1+2 levels, and non‐linear pharmacokinetics . This study showed a tendency towards decreased bleeding, although no statistically significant efficacy data have been reported .…”

Section: Beyond Traditional Bypassing Agentsmentioning

confidence: 76%

“…Currently, dosing is restricted to once‐daily administration because of inter‐patient variability in thrombin generation, elevated D‐dimer and prothrombin F 1+2 levels, and non‐linear pharmacokinetics . This study showed a tendency towards decreased bleeding, although no statistically significant efficacy data have been reported . TFPI inhibitors are unlikely to be useful to treat an ongoing bleeding event as no hemostatic effect was observed in a hemophilic rabbit bleeding model when dosed after induction of a bleed ; it is currently unknown whether safety issues may exist when hemostatic agents are co‐administered during a breakthrough bleeding event.…”

Section: Beyond Traditional Bypassing Agentsmentioning

confidence: 82%

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The future of bypassing agents for hemophilia with inhibitors in the era of novel agents

Shapiro

Mitchell²,

Nasr³

2018

Journal of Thrombosis and Haemostasis

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Summary Bypassing agents are presently the standard of care for the treatment of bleeding episodes in patients with hemophilia and high‐titer inhibitors and are also used for bleed prevention. Only two bypassing agents are available to patients, and these products trace their lineage to the 1970s (activated prothrombin complex concentrates) and the 1980s (recombinant factor VIIa). Given the limited repertoire of available products, clinicians have relied on experience, empirical observation, registry data and individualized care to improve clinical outcomes on a case‐by‐case basis. Research over the past two decades has culminated in a greatly improved understanding of human coagulation; resulting from this, new products have been developed that offer treatment options and mechanisms of actions that differ from current bypassing agents. The most advanced in clinical development is emicizumab, a bispecific antibody that mimics the function of FVIIIa in the intrinsic Xase complex and is indicated for once‐weekly or every‐other‐week prophylactic dosing in inhibitor patients. Other non‐traditional products in clinical development include fitusiran and antibodies directed against tissue factor pathway inhibitor. As non‐factor‐based therapies become more widely utilized over time, the use of bypassing agents may be expected to decrease; however, bypassing agents will remain essential for the foreseeable future. As such, clinical development of bypassing agents continues, with some products (e.g. eptacog beta) under regulatory review. In this review we examine the optimal use of bypassing agents and their mechanism of action. We also discuss newer products and how these might theoretically be administered in conjunction with traditional bypassing agents.

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Section: Beyond Traditional Bypassing Agentsmentioning

confidence: 76%

Section: Beyond Traditional Bypassing Agentsmentioning

confidence: 82%

The future of bypassing agents for hemophilia with inhibitors in the era of novel agents

Shapiro

Mitchell²,

Nasr³

2018

Journal of Thrombosis and Haemostasis

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“…TFPI inhibition is of interest as a novel approach to treating haemophilia A and B. Concizumab is a monoclonal humanized antibody to TFPI that binds it and blocks the ability to inhibit factor Xa with efficacy in patients with haemophilia A and B with inhibitors . A previous study with concizumab in spiked haemophilia A and B patients and administration in healthy volunteers demonstrated near normalization of ETP/peak thrombin generation and increased ETP/peak thrombin generation in the respective groups .…”

Section: Discussionmentioning

confidence: 99%

Investigation of patients with unclassified bleeding disorder and abnormal thrombin generation for physiological coagulation inhibitors reveals multiple abnormalities and a subset of patients with increased tissue factor pathway inhibitor activity

MacDonald

White

Langdown

et al. 2020

Int J Lab Hematology

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Introduction:We have routinely used thrombin generation to investigate patients with unclassified bleeding disorder (UBD). Aims: To investigate haemostatic abnormalities in patients with UBD that had abnormal thrombin generation on at least one occasion.Methods: Investigation of 13 known UBD patients with thrombin generation and detailed haemostatic testing was undertaken including TFPI assays but also thrombomodulin and fibrinogen-γ.Results: 12 females and 1 male were included. No patient had a platelet function disorder or coagulation factor deficiency that explained the bleeding phenotype, though 2 patients had factor deficiencies; a factor X of 0.41 IU/mL and a factor XI of 0.51 IU/ mL. ThromboGenomics revealed variants for these factors but no other abnormalities. Patients were included who previously had either prolonged lag time or decreased endogenous thrombin potential (ETP) via high dose tissue factor (5 pmol/L) or low dose tissue factor (1.5 pmol/L) with corn trypsin inhibitor (CTI). Tissue factor pathway inhibitor (TFPI) activity was significantly increased (P < .001; increased in 8 patients) compared with controls and abnormalities in soluble thrombomodulin (2 patients), fibrinogen-γ (1 patient) and tPA (4 patients for each) were seen. Total and free TFPI levels were not increased. Mixing studies of patient plasma with 50:50 normal plasma for thrombin generation via low dose tissue factor failed to correct the ETP consistent with ongoing inhibition. Addition of an anti-TFPI antibody partially corrected thrombin generation to normal levels. TFPI sequencing was unremarkable.Conclusion: TFPI activity may be increased in a subset of UBD patients. Further research studies are warranted in UBD patients for coagulation inhibitor abnormalities. | 247MacDONaLD et aL.

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“…They all exhibit target-mediated drug disposition (TMDD, whereby pharmacokinetics are affected by the drug's high binding affinity). [62][63][64][65] The key implication is the necessity for more frequent infusions than could be otherwise expected from an antibody, given their long half-lives. Consequently, the ongoing phase 2/3 trials administer anti-TFPI antibodies as often as once daily.…”

Section: Emicizumab: Fviiia In Disguise Of An Antibodymentioning

confidence: 99%

A Molecular Revolution in the Treatment of Hemophilia

et al. 2020

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For decades, the monogenetic bleeding disorders hemophilia A and B (coagulation factor VIII and IX deficiency) have been treated with systemic protein replacement therapy. Now, diverse molecular medicines, ranging from antibody to gene to RNA therapy, are transforming treatment. Traditional replacement therapy requires twice to thrice weekly intravenous infusions of factor. While extended half-life products may reduce the frequency of injections, patients continue to face lifelong burden of the therapy, suboptimal protection from bleeding and joint damage, and potential development of neutralizing anti-drug antibodies (inhibitors) that require less efficacious bypassing agents and further reduce quality of life. Novel non-replacement and gene therapies aim to address these remaining issues. A recently approved factor VIII-mimetic antibody accomplishes hemostatic correction in patients both with and without inhibitors. Antibodies against Tissue Factor Pathway Inhibitor (TFPI) and antithrombin-specific siRNA target natural anticoagulant pathways to rebalance hemostasis. Adeno-associated viral (AAV) gene therapy provides lasting clotting factor replacement and can also be used to induce immune tolerance. Multiple gene editing techniques are under clinical or preclinical investigation. Here, we provide a comprehensive overview of these approaches, explain how they differ from standard therapies, and predict how the hemophilia treatment landscape will be reshaped.

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Inhibition of Tissue Factor Pathway Inhibitor (TFPI) as a Treatment for Haemophilia: Rationale with Focus on Concizumab

Cited by 44 publications

References 63 publications

The future of bypassing agents for hemophilia with inhibitors in the era of novel agents

The future of bypassing agents for hemophilia with inhibitors in the era of novel agents

Investigation of patients with unclassified bleeding disorder and abnormal thrombin generation for physiological coagulation inhibitors reveals multiple abnormalities and a subset of patients with increased tissue factor pathway inhibitor activity

A Molecular Revolution in the Treatment of Hemophilia

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