First and next generation native rFVIII in the treatment of hemophilia A. What has been achieved? Can patients be switched safely?

Abstract

The introduction of plasma-derived human factor VIII (FVIII) and later human recombinant FVIII (rFVIII) has potentially allowed patients suffering from hemophilia A to have a quality of life and life expectancy similar to the population at large. One of the major achievements in molecular biology over the past 15 years was the sequencing of the gene coding for FVIII, leading eventually to the ability to isolate the human gene for FVIII and transfect cells to produce human rFVIII. The first rFVIII products, which are native full-length FVIII molecules, have proved to have an excellent efficacy and safety profile in patients with hemophilia A. Initial concerns about a potential increased inhibitor formation have not been confirmed so far but long-term pharmacovigilance of inhibitor formation is still ongoing. To date, no transmission of hepatitis or human immunodeficiency virus (HIV) attributable to rFVIII products has been reported. However, a theoretical risk of transmission of infectious disease does exist as long as nonsynthetic proteins are used during the production process. The next-generation native rFVIII has been developed to minimize the exposure of patients to animal or human plasma-derived proteins. This has been achieved through major changes to the process of production of rFVIII from baby hamster kidney cells (BHK). This change has included the introduction of a solvent/detergent step and, of more importance, the introduction of a purification procedure without using albumin as a stabilizer. Finally, the rFVIII (BHK) is formulated using sucrose as the final stabilizer to produce the sucrose formulated rFVIII referred to as rFVIII-FS. This article summarizes the recently published pharmacokinetic, safety, and efficacy data for the native rFVIII-FS and compares its clinical profile with that of the first-generation rFVIII.