Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results

Shapiro, Amy D.; Angchaisuksiri, Pantep; Astermark, Jan; Benson, Gary; Castaman, Giancarlo; Chowdary, Pratima; Eichler, Hermann; Jiménez‐Yuste, Víctor; Kavaklı, Kaan; Matsushita, Tadashi; Poulsen, Lone Hvitfeldt; Wheeler, Allison P.; Young, Guy; Zupančić-Šalek, Silva; Oldenburg, Johannes

doi:10.1182/blood.2019001542

Cited by 118 publications

(129 citation statements)

References 24 publications

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“…9 In the phase 2 trials, increasing concizumab exposure was associated with lower free TFPI and normalized thrombin generation potential, consistent with phase 1 data. Importantly, this result indicates that the initiation phase of coagulation is still active at this time point.…”

Section: Concizumab Promotes Haemostasis Via a Tissue Factor-factorsupporting

confidence: 75%

Concizumab promotes haemostasis via a tissue factor‐factor VIIa–dependent mechanism supporting prophylactic treatment of haemophilia: Results from a rabbit haemophilia bleeding model

Lauritzen

Hilden

2019

Haemophilia

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In recent years, the development of novel therapeutic agents for haemophilia has focused on molecules allowing subcutaneous and/ or less frequent administration compared with intravenous factor replacement therapies in order to improve adherence and compliance and, ultimately, long-term outcomes. Concizumab (Novo Nordisk A/S) is a novel agent currently in phase 2 clinical development as a subcutaneous treatment for the prevention of bleeding episodes, including long-term prophylaxis, in patients with haemophilia A and haemophilia B with and without inhibitors.Concizumab is a high-affinity, humanized, monoclonal IgG 4 antibody against the Kunitz 2 domain of tissue factor (TF) pathway inhibitor (TFPI). 1 TFPI downregulates the initiation phase of coagulation by inhibiting the TF/activated factor VII (FVIIa)/activated factor X (FXa) complex. 1 In addition, TFPI binds activated factor V (FVa), thereby inhibiting the assembly of the prothrombinase complex. 2 Thus, inhibition of TFPI with concizumab extends FX activation within the initiation phase of coagulation and protects the prothrombinase complex at the platelet surface. Therefore, thrombin generation is facilitated, compensating for inadequate tenase complex-mediated generation of FXa under haemophilic conditions. 3,4 Concizumab exhibits cross-reactivity with rabbit TFPI and reduced bleeding dose-dependently in haemophilic rabbits after intravenous or subcutaneous administration prior to and up to 5 minutes after bleeding initiation. 1 Recombinant activated coagulation factor VII (rFVIIa, NovoSeven ® ; Novo Nordisk A/S) is a bypassing agent used in haemophilia A and haemophilia B patients with inhibitors against factor VIII (FVIII) and factor IX (FIX), respectively. 5 Accumulating data suggest that rFVIIa primarily acts through a TF-independent mechanism. 6,7In the present study, the effect of concizumab and rFVIIa on blood loss in a cuticle bleeding model in haemophilic rabbits was compared when the compounds were administered at different time points after bleeding induction. We aimed to elucidate the differences in mechanism of action of rFVIIa and concizumab in the coagulation phases. These data provide an unexpected insight into the duration of the coagulation initiation phase in vivo.Three independent cuticle bleeding studies were performed in unfasted, female New Zealand White rabbits (NZW Crl:KBL; Charles River Laboratories) after approval by the Danish Animal ExperimentsInspectorate at the Ministry of Environment and Food of Denmark.Following anaesthetization, the vena jugularis of the rabbits was catheterized for administration of the test compounds. After stabilization, initial blood sampling took place and rabbits were made transiently haemophilic by intravenous infusion of 2000 rabbit Bethesda units/kg of a monoclonal anti-human FVIII antibody cross-reactive to rabbit FVIII (FVIII4F30). After 35 minutes in study 1, and 15 minutes in studies 2/3, one forepaw was placed in a beaker containing 37°C saline for 10 minutes. At 45 minutes in study 1, and 2...

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Section: Concizumab Promotes Haemostasis Via a Tissue Factor-factorsupporting

confidence: 75%

Concizumab promotes haemostasis via a tissue factor‐factor VIIa–dependent mechanism supporting prophylactic treatment of haemophilia: Results from a rabbit haemophilia bleeding model

Lauritzen

Hilden

2019

Haemophilia

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“…The findings of the early EXPLORER trials have been concisely summarized by the same authors [11]. More recently, the results of a Phase 2 study were published [17]. In this trial concizumab was administered by daily subcutaneous injections.…”

Section: Current Progress and Future Direction In The Treatment For Hmentioning

confidence: 97%

Current progress and future direction in the treatment for hemophilia

Shima

2019

Int J Hematol

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“…Применяется у пациентов с гемофилией А и В и ингибиторной формой. Результаты исследования фазы II подтвердили значительное снижение частоты кровотечений на 80-90% при сравнении с терапией эптакогом альфа по требованию [32]. На фазе III клинических исследований возникло 3 случая тромбоза, в связи с чем исследование приостановлено до выяснения обстоятельств.…”

Section: таблицаunclassified

Modern approaches in hemophilia therapy

Флоринский

Zharkov

2020

Voprosy gematologii/onkologii i immunopatologii v pediatrii

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For 60 years the “gold standard” of hemophilia treatment has been the use of concentrates factors. In recent years, there has been a rapid development of therapeutics. Several extended half-life concentrates have been introduced into clinical practice, as well as a non – factorial type of therapy-a bispecific antibody mimicking activated factor VIII. Encouraging results in clinical trials show the use of antibodies to tissue factor pathway inhibitor, small interfering RNA to antithrombin and gene therapy. The advantages of new treatment methods are a reduction in the frequency of intravenous injections and improved adherence to therapy, especially in patients with inhibitors. Long-term safety and effectiveness require further study.

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Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results

Cited by 118 publications

References 24 publications

Concizumab promotes haemostasis via a tissue factor‐factor VIIa–dependent mechanism supporting prophylactic treatment of haemophilia: Results from a rabbit haemophilia bleeding model

Concizumab promotes haemostasis via a tissue factor‐factor VIIa–dependent mechanism supporting prophylactic treatment of haemophilia: Results from a rabbit haemophilia bleeding model

Current progress and future direction in the treatment for hemophilia

Modern approaches in hemophilia therapy

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