Prolonged bleeding-free period following prophylactic infusion of recombinant factor VIII reconstituted with pegylated liposomes

Abstract

IntroductionProphylactic replacement therapy for hemophilia A is based on intravenous infusions of purified factor VIII (FVIII) concentrates. [1][2][3][4][5][6][7][8][9][10] Since the half-life of human FVIII is about 10 to 12 hours, 11 infusions typically need to be repeated every 2 to 3 days to maintain a FVIII level above 1% in patients treated according to the pharmacokinetic (PK) dosing model. 1,[12][13][14][15] The prevention of bleeding episodes, especially in young patients, is of vital importance, as it reduces the occurrence of hemophilic arthropathy, which usually develops secondary to repeated intraarticular bleeding episodes. 3,4,6,7,[16][17][18][19][20][21] Prophylactic infusions performed in order to prevent bleeding episodes can delay the time of onset of hemophilic arthropathy and reduce the severity of pain and sequelae. Patients dosed along PK parameters usually demonstrate very few bleeding episodes and low morbidity. 22 Repeated regular intravenous infusions performed at home every 2 to 3 days over the course of decades places a great burden on patients to be compliant with their therapy. Compliance with treatment directives has been directly linked to the number of infusions given, with compliance increasing as the number of infusions decreased. 23 A FVIII molecule or product formulation that demonstrates increased time in circulation could greatly improve the efficacy and quality of life associated with prophylactic treatment for hemophilia A.The method most commonly used for prolongation of half-life of recombinant proteins, the covalent incorporation of polyethylene glycol (PEG; PEGylation), 24 is not yet available for FVIII. An alternative approach is to incorporate the FVIII protein with a carrier molecule that can be modified by PEGylation, resulting in a prolongation of the time the molecule provides hemostatic efficacy. The advantage with such an approach is that the FVIII molecule would not need to be altered and, provided that the carrier did not confer any conformational changes to the FVIII or act as an adjuvant for the immune system, the risk for FVIII inhibitor development would not be increased compared with standard treatment. Furthermore, since low levels of FVIII have been shown to confer prophylactic efficacy, the goal of maintaining FVIII levels above 1% as in the PK model may not be necessary. [25][26][27][28] Baru et al 29 reported the use of PEGylated liposomes as carriers for recombinant FVIII (Kogenate FS). Synthetic PEGylated liposomes, composed of 90% (wt/wt) palmitoyl-oleoylphosphatidylcholine (POPC) and 1,2-distearoyl-sn-glycero-3-phosphoethanol-amine-N- [poly-(ethyleneglycol) Patients, materials, and methods Study designThe study was conducted in accordance with International Conference on Harmonization Good Clinical Practice (ICH GCP) guidelines. Approval was obtained from the appropriate ethics committees as well as by the Ministry of Health. All patients gave written informed consent prior to participation. The study was designed as a controlled, patient-bl...

Back to the future: a recent history of haemophilia treatment

“…Advances may also materialize through DNA technology that may be able to modify coagulation factor molecules and render them more active and/or less antigenic [60]. Several approaches have been attempted in the laboratories, but at the moment those that are undergoing clinical trials are based upon the PEGylation of factors, or of factor vehicles such as liposomes [54][55][56][57][58][59].…”

“…This would be a significant step forward, considering that in countries that can afford primary prophylaxis, the main obstacles to its widespread adoption are the difficulties of venous access. Several pharmaceutical companies are currently developing factors with longer half-life, which would require less frequent venipunctures [54][55][56][57][58][59]. Advances may also materialize through DNA technology that may be able to modify coagulation factor molecules and render them more active and/or less antigenic [60].…”

Hemophilia: New Protein Therapeutics

“…22 In addition, rFVIII-PEGLip has been examined in patients with severe hemophilia A in a blinded, controlled, crossover, multicenter trial. 16 A single prophylactic infusion of rFVIII-PEG-Lip resulted in a longer bleed-free interval, compared with standard rFVIII. The rFVIII-PEG-Lip formulation was well tolerated, and no significant adverse events were reported during the trial.…”

“…15 Prolonging the half-life of FVIII could greatly reduce the frequency and dose of infusions, thereby improving the efficacy of prophylaxis through better compliance, as well as improve convenience and patient quality of life. 16 The primary determinant of FVIII residence time in plasma is interaction with von Willebrand factor (vWF), which protects it from proteolysis and cellular uptake. Clearance of FVIII has only recently begun to be elucidated.…”

Biological Rationale for New Drugs in the Bleeding Disorders Pipeline

“…In rats, an extended circulation time and reduced clearance (1.4 times slower than free rVIIa) were observed with PEGLip-rVIIa, suggesting decreased clearance. However, despite promising preclinical 41 and phase 1 data, 42 a phase 2 clinical trial of rFVIII conjugated to PEGLip was terminated prematurely due to lack of efficacy. In that study, the PEGLip-rFVIII did not appear to circulate longer than non-PEGLip-rFVIII, and transient mild elevations in total and low density lipoprotein concentrations occurred.…”