Administration of recombinant FVIIa (rFVIIa) to concizumab‐dosed monkeys is safe, and concizumab does not affect the potency of rFVIIa in hemophilic rabbits

Lauritzen, Brian; Olling, Janne; Abel, Kristin; Augustsson, Cecilia; Balling, Kristoffer W.; Bjelke, Mads; Hegelund, Anne Charlotte; Hilden, Ida

doi:10.1111/jth.14380

Cited by 8 publications

(7 citation statements)

References 21 publications

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“…The combination of concizumab and rFVIIa was previously evaluated in vivo in a bleeding model in rabbits with antibody‐induced hemophilia and in a safety study in cynomolgus monkeys. 20 No signs of additive or synergistic effects of rFVIIa and concizumab were observed in the rabbit model, possibly because the maximal effect was already achieved by individual treatment with concizumab or rFVIIa. Consistent with the clinical phase 1 and 2 data, 7 , 21 , 22 treatment with concizumab resulted in increased thrombin‐antithrombin (TAT) and D‐dimer levels in monkeys, indicating activation of coagulation and fibrinolytic pathways.…”

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

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Thrombin generation potential in the presence of concizumab and rFVIIa, APCC, rFVIII, or rFIX: In vitro and ex vivo analyses

Kjalke

Kjelgaard‐Hansen

Andersen

et al. 2021

Journal of Thrombosis and Haemostasis

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Background The anti‐tissue factor plasma inhibitor monoclonal antibody concizumab is under clinical investigation for subcutaneous prophylaxis of hemophilia A/B (HA/HB) with or without inhibitors. Breakthrough bleeds while on concizumab prophylaxis may be treated with bypassing agents (recombinant activated factor VIIa [rFVIIa] and activated prothrombin complex concentrate [APCC]), or with factor VIII (FVIII) or factor IX (FIX). Objectives To evaluate the effect of combining concizumab with rFVIIa, APCC, rFVIII, and rFIX on thrombin generation (TG) potential. Methods Pooled HA plasma was spiked in vitro with concizumab alone or together with rFVIIa, APCC, or rFVIII. rFVIIa, APCC, and rFVIII were added ex vivo to plasma from HA patients receiving concizumab prophylaxis. Pooled HB plasma was spiked with concizumab alone or together with rFIX. TG potential was measured after initiation with tissue factor. Results Concizumab increased thrombin peak in a concentration‐dependent manner. Adding rFVIIa, APCC, rFVIII, or rFIX caused a further increase in thrombin peak. The effects of concizumab and rFVIIa, APCC, rFVIII, or rFIX were mainly additive, with no or up to maximally ~25% extra effect caused by drug‐‐drug interaction. No strong synergistic effects were observed upon combining concizumab with rFVIIa, APCC, rFVIII, or rFIX. The thrombin peak obtained with 0.5 IU/ml rFVIII or rFIX in the presence of concizumab was on occasion slightly higher, but mostly comparable to the thrombin peak with 1 IU/ml rFVIII or rFIX in the absence of concizumab. Conclusion rFVIIa, APCC, rFVIII, and rFIX enhanced plasma TG potential in the presence of concizumab. Dose levels of concomitant use should be adjusted accordingly to balance potential safety concerns while maintaining the necessary hemostatic effect. Please see the video in the Supplementary Material for an animated summary of the data presented.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Thrombin generation potential in the presence of concizumab and rFVIIa, APCC, rFVIII, or rFIX: In vitro and ex vivo analyses

Kjalke

Kjelgaard‐Hansen

Andersen

et al. 2021

Journal of Thrombosis and Haemostasis

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“…Another report always published by Lauritzen et al 14 explored the efficacy and the safety of concizumab and rFVIIa when simultaneously administered. Three different studies were described.…”

Section: Resultsmentioning

confidence: 99%

Concizumab as a Subcutaneous Prophylactic Treatment Option for Patients with Hemophilia A or B: A Review of the Evidence and Patient’s Perspectives

Pasca¹

2022

JBM

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Concizumab is a monoclonal, humanized IgG4 antibody specific for the Kunitz-2 domain of Tissue Factor Pathway Inhibitor (TFPI). Preclinical studies in vitro or on animal models and in vivo have demonstrated the ability of concizumab to restore thrombin generation, promoting the establishment of a procoagulant action; all these results were subsequently confirmed in the studies of EXPLORER program. Concizumab may represent a new opportunity for the treatment of persons with hemophilia, so there is much anticipation for the results of the ongoing trials still. This review retraces all the studies on concizumab published to date, with a brief discussion about the patient’ perspectives.

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“…While concizumab and rFVIIa showed synergistic effect on thrombin generation in vitro, no such effect emerged in hemophilic rabbits or cynomolguses. 69 The authors propose that rFVIIa at pharmacological doses activates FX independent from TF on the surface of activated platelets in the propagation phase of coagulation, while TFPI only acts in the initiation phase. 70 However, upon activation, platelets release their intracellular pool of TFPI, part of which remains on the platelet surface and may be blocked by anti-TFPI antibodies (Fig.…”

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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Administration of recombinant FVIIa (rFVIIa) to concizumab‐dosed monkeys is safe, and concizumab does not affect the potency of rFVIIa in hemophilic rabbits

Cited by 8 publications

References 21 publications

Thrombin generation potential in the presence of concizumab and rFVIIa, APCC, rFVIII, or rFIX: In vitro and ex vivo analyses

Thrombin generation potential in the presence of concizumab and rFVIIa, APCC, rFVIII, or rFIX: In vitro and ex vivo analyses

Concizumab as a Subcutaneous Prophylactic Treatment Option for Patients with Hemophilia A or B: A Review of the Evidence and Patient’s Perspectives

A Molecular Revolution in the Treatment of Hemophilia

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