Preclinical Evidence Suggests Modified Von Willebrand Factor Extends Factor VIII Half-life In Hemophilia A Model

Baxter Healthcare Corporation announced the presentation of preclinical data from ongoing research studies aimed at developing a novel, longer-acting form of factor VIII, a protein essential for the normal clotting of blood. Preclinical studies suggest that Baxter’s proprietary blood-free factor VIII formulated with chemically modified recombinant von Willebrand factor (rVWF) may extend the half-life of the circulating factor VIII two-to three-fold in mouse models of hemophilia A. Results of these preliminary studies were presented at the American Society of Hematology (ASH) 48th annual meeting held in December (Abstracts 1001, 1002 & 1021).

“These experiments offer proof-of-concept of our ability to improve the pharmacology of recombinant factor VIII (rFVIII) activity and provide early evidence for the potential for these long acting proteins in the treatment of hemophilia A,” said Peter Turecek, Ph.D., senior director of preclinical research and development for Baxter’s BioScience business. “We continue to build upon our proven foundation of blood-free recombinant protein processing with the goal of developing recombinant proteins with longer half-life, which if supported by future clinical trial results, potentially allow for less frequent injections and therefore increase convenience and compliance for patients.”

Baxter scientists presented preclinical results utilizing a novel approach to extend the half-life of factor VIII, based on modifying a rVWF using pegylation (conjugation with synthetic polymers of polyethylene glycol, PEG) or glycosylation technologies. The results suggest that these approaches may make FVIII less susceptible to the body’s breakdown process. Baxter will continue to conduct extensive preclinical research before the modified protein will be available for clinical evaluation.

Pegylation of VWF protein (Abstracts 1002, 1021)
Baxter scientists co-administered pegylated rVWF with rFVIII to mouse models of hemophilia A to evaluate whether the pegylated form of the protein could improve the half-life of administered rFVIII. In the presence of pegylated rVWF, the estimated half-life of rFVIII was 4.4 hours compared to a half-life of 1.2 hours in the presence of unmodified rVWF. In addition, FVIII levels at all time points were substantially higher in the groups co-administered with pegylated VWF.

Glycosylation Modification of VWF (Abstract 1001)
Similar to pegylation, modification of rVWF using glycosylation technology (polysialylation) resulted in a two-fold increase in the lifetime of the polysialylated rVWF as compared to non-modified rVWF when administered to knock-out mice with von Willebrand disease. These early stage data support the potential of glycosylation technology to extend the circulation time of recombinant proteins, and may be used by Baxter to develop a FVIII with an extended half-life.

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