Trough levels were maintained above 5% after 7 days when rIX-FP was administered at 25 IU/kg and after 14 days when given at 50 IU kg−1, suggesting that schedules involving weekly dosing or dosing every 2 weeks are feasible [23]. Native FVIII in the circulation is a heterodimer composed of the heavy and light chain held together by a labile metal-ion bridge, which makes the FVIII molecule relatively unstable. CSL Behring has designed a B-domain deleted rFVIII with a covalent bond
between the heavy and the light chain of FVIII, circulating as a single-chain FVIII molecule buy Metformin [22]. A further modification in the rFVIII results in a significantly increased binding to von Willebrand factor (VWF). Free FVIII has only a half-life of 1 h compared to about 12 h when 95% of FVIII Sirolimus is bound to VWF. Therefore, an increased proportion of VWF bound FVIII translates into an extension of
the FVIII half-life, which for the rFVIII-SC is about 1.5-fold [24]. Although clinical studies phase 1–3 have been started, so far only preclinical data are published. In all animal species systemic availability, mean residence time and terminal half life were increased between 1.6- and 2-fold [25]. Chugai (Chugai Pharmaceutical Co., Ltd., Tokyo, Japan) generated a novel bispecific antibody against FIXa and FX, ACE910, which mimics the cofactor function of FVIII to exert in vivo haemostatic activity [26, 27], and started a phase I clinical study on healthy and haemophilic Japanese individuals in 2012. As ACE910 possesses a different antigenicity from FVIII, it can MCE improve the intrinsic pathway coagulation even in the presence of an inhibitor. Therefore, ACE910 will be used for haemophilia A patients without but also with inhibitors. ACE910 can be administered as subcutaneous infusion and long-acting over 1–2 weeks can be expected. Preclinical studies and ex vivo studies on patient samples suggest that the haemostatic potency of a single bolus of ACE910 1 or 3 mg kg−1 could exert haemostatic effect for haemophilia A patients regardless of the presence of inhibitor [28].
Tissue factor mediates thrombin generation by binding VIIa to the subendothelial cell membrane promoting activation of FX in an FVIII independent manner. This FXa generation is limited by a feedback mechanism controlled by the TFPI. Novo Nordisk has developed a monoclonal antibody (mAb 2012) that is blocking the interaction between FXa and TFPI [29]. In a clinical phase I study in healthy subjects mAb 2021 was found to be safe after i.v. and s.c. administration. A mAb 2021 concentration-dependent effect was observed on plasma TFPI functionality and levels [30]. The clinical study has been set on hold due to late preclinical observation that was obtained while the clinical study was started. The preclinical data are currently awaiting further evaluation.