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

Abstract

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...

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

“…Lauritzen & Hilden in their letter to editor, recently published, 13 described three independent studies performed on hemophilic rabbits. These studies confirmed previous data: escalating doses of concizumab administered within five minutes from cuticle bleeding induction are equally effective to reduce the ongoing bleeds, but concizumab resulted less effective than rFVIIa if administered 15–30 minutes after bleeding induction.…”