Safety, pharmacokinetics and efficacy of factor VIIa formulated with PEGylated liposomes in haemophilia A patients with inhibitors to factor VIII – an open label, exploratory, cross‐over, phase I/II study

Abstract

Recombinant activated factor VIIa (FVIIa) is a bypassing agent used to treat bleeding episodes in haemophilia patients with inhibitors to factor VIII (FVIII) and factor IX. The pharmacological effect of FVIIa is short-lived and therefore with the recommended dose of 90 μg kg(-1), a bleeding episode is treated with multiple injections. A long-acting form of FVIIa that can ensure adequate haemostasis with a single infusion, without increasing the thrombotic risk, would therefore be beneficial. PEGylated liposomes (PEGLip) have been shown to bind FVIIa and to improve haemostatic efficacy in preclinical experiments. In the present phase I/II clinical trial, we assessed the safety and efficacy of PEGLip-formulated FVIIa in severe haemophilia A patients (FVIII≤1%) with inhibitors to FVIII. Each patient received one prophylactic infusion of standard FVIIa and one prophylactic infusion of PEGLip-formulated FVIIa. The order of the infusions was randomized and the two infusions were separated by a ten-day washout period. Efficacy assessed by thromboelastography revealed that PEGLip-FVIIa induced significantly shorter clotting times and produced higher clot firmnesses than standard FVIIa. Thrombin generation assays showed that PEGLip-FVIIa induced faster thrombin generation and higher peak levels of thrombin than standard FVIIa. These effects lasted up to 5 h postinfusion. Measurements of D-dimer, prothrombin fragment 1+2 and fibrinogen showed no significant differences between the PEGLip-FVIIa and standard FVIIa treatments. PEGLip-FVIIa therefore showed improved haemostatic efficacy without increased risk of thrombosis and may be further developed for the treatment for bleeding episodes in haemophilia patients with inhibitors.

Predicting dosing advantages of factor VIIa variants with altered tissue factor‐dependent and lipid‐dependent activities

“…) and the rapid decline in response during the first hour after administration observed by Spira et al . (Fig. C).…”

“…Solid lines (red) present FXa integrals obtained in mathematical model simulations in the absence of FVIII and FIX and the presence of FVII (10 n m ). Thrombin generation was measured as follows : (A) platelet‐poor plasma (PPP) supplemented with 3.2 μ m procoagulant lipid (PL) in the presence of 7.16 p m TF; (B) PPP supplemented with 4 μ m PL in the presence of 1 p m tissue factor (TF); (C) PPP supplemented with 4 μ m PL in the absence of TF; and (D) PPP supplemented with 4 μ m PL in the absence of TF. Model concentrations of PL and TF were taken directly from the experimental data, and all simulations were performed with the ex vivo variation of the PK/PD model.…”

Past, present and future of hemophilia: a narrative review

“…Research on longer-acting PEGylated recombinant factor VIIa (rFVIIa) showed the ability of this new product to activate factor X on tissue factor expressing cells [73]. In addition, a recently published phase I/II study comparing the safety and efficacy of the PEGLip rFVIIa (Novo Nordisk, Bagsvaerd, Denmark) with the standard rFVIIa in severe hemophilia A patients with inhibitors found that the PEGylated formulation yielded an improved hemostatic efficacy without increasing the risk of thrombosis [74]. Improved pharmacokinetics properties of coagulation factors have also been obtained through molecule modification by genetic fusion with albumin and the IgG Fc moiety [75,76].…”

Advances in the treatment of inherited coagulation disorders

“…In patients treated prophylactically, randomized infusions of rFVIIa and PEGylated liposomal‐rFVIIa separated by a 10‐day washout period were administered and efficacy was assessed by thromboelastography and the thrombin generation assay. Results showed that PEGylated liposomal‐rFVIIa significantly improved hemostatic efficacy with shorter clotting times, enhanced clot firmness and thrombin generation that had a faster onset and achieved higher peak levels of thrombin compared with rFVIIa . Additionally, no increased risk of thrombosis was observed with PEGylated liposomal‐rFVIIa treatment.…”