Hemophilia - Extended Half-Life Recombinant VIIa Leads To Longer Biologic Activity

Main Category: Blood / Hematology
Also Included In: Clinical Trials / Drug Trials
Article Date: 04 Jun 2008 - 1:00 PDT

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New data presented at Hemophilia 2008 seen as another step to single dosing regimen of one injection per bleeding event for hemophilia patients with inhibitors

CSL Behring presented results of a pre-clinical study that not only demonstrates the feasibility of genetically fusing factor VIIa to human albumin, but that this therapeutic protein with a prolonged half-life can lead to a longer biologic effect. In the study, which was presented at the Hemophilia 2008 World Congress, the 28th International Congress of the World Federation of Hemophilia, the half-life of recombinant VIIa-albumin fusion protein (rVIIa-FP) was shown to be extended 6-to-9 fold compared to wild type rFVIIa. Additionally, a new FVII depletion animal model showed specifically that rVIIa-FP was still present with full biological activity 16 hours after being injected.

Recombinant factor VIIa (rVIIa) effectively controls bleeding episodes in hemophilia patients with inhibitors. These patients develop an immune response that inhibits the substituted clotting factor from stopping a bleeding episode. However, rVIIa has a short half-life of approximately 2.5 hours. This necessitates multiple injections, which are inconvenient for both physicians and patients, particularly during surgical intervention.

"Extending the half-life of coagulation factors while retaining their hemostatic activity is a major goal in bleeding disorder research," said Dr. Stefan Schulte, Head R&D Marburg, CSL Behring GmbH and lead investigator of the study. "Not only are we are excited that the pharmacological properties of rVIIa-FP have been proven in our study, but that the protein retains this activity many hours after it has been injected. This could one day facilitate a single dosing regimen of one injection per bleeding event, as well as significantly reduce the number of injections hemophilia patients with inhibitors need during surgical interventions."

Recombinant VIIa-FP represents CSL Behring's initial corporate foray into research with recombinant coagulation product technology. The study findings were also published in the April issue of Thrombosis and Haemostasis. The company plans to continue its research, accumulate additional data and validate the results seen in the pre-clinical study of this molecule.

"This study is important news for hemophilia patients with inhibitors, as rVIIa-FP has the potential to increase convenience and compliance for them and the physicians who treat them," said Dr. Andrew Cuthbertson, Chief Scientific Officer at CSL Ltd., parent company of CSL Behring. "CSL Behring is pleased to share this exciting research advance with the coagulation disorders community at Hemophilia 2008 World Congress, as it is consistent with our global leadership in protein therapeutics and our mission to save and improve the quality of patients' lives."

Study Design

Genetic fusion to albumin is an efficient way to extend the half-life of small proteins, but so far it has not been successfully used for the half-life extension of complex proteins. In the presented proof-of-principle study, rVIIa-FP was generated by genetic engineering, expressed in mammalian cell culture, purified and characterized. The rVIIa-FP displayed full biological activity and 6-to-9 fold extended half-life compared to either NovoSeven(R)(1), a recombinant FVIIa, or rVIIa control protein in a pre-clinical rat model. The superior pharmacological properties of the rVIIa-FP could facilitate a single dosing regimen of one injection per bleeding event for treatment of hemophilia inhibitor patients.

In a separate experiment rFVIIa and rVIIa-FP protein coagulation parameter was compared after 16 hours. rFVIIa was not able to correct the clotting time due to its short half-life, but rVIIa-FP corrected clotting values close to the results of healthy controls, indicating the protein was still present at full biological activity.

About Hemophilia with Inhibitors

In some patients with hemophilia, the immune system produces an antibody that blocks the action of the substituted coagulation factor and prevents clot formation. This antibody is known as an inhibitor, and its presence makes treatment of bleeding episodes more difficult. The reason inhibitors develop is unknown, although people with hemophilia have the greatest risk for developing an inhibitor during childhood. The incidence of inhibitors is highest among those with severe hemophilia, followed by moderate and mild deficiency. The risk of inhibitor development is higher if someone in the patient's family also has an inhibitor, and is more frequent among African Americans.(2)

About CSL Behring

CSL Behring is a global leader in the protein biotherapeutics industry. Passionate about saving and improving the quality of patients' lives, CSL Behring manufactures and markets a range of safe and effective plasma- derived and recombinant products and related services. The company's therapies are used in the treatment of rare diseases such as immune deficiency disorders, hemophilia, von Willebrand disease, other bleeding disorders and inherited emphysema. Other products are used for the prevention of hemolytic diseases in the newborn, in cardiac surgery, organ transplantation and in the treatment of burns. The company also operates one of the world's largest plasma collection networks, ZLB Plasma. CSL Behring is a subsidiary of CSL Limited, a biopharmaceutical company with headquarters in Melbourne, Australia. For more information, visit http://www.cslbehring.com.

(1) NovoSeven is a registered trademark of Novo Nordisk Health Care AG.

(2) National Hemophilia Foundation website http://www.hemophilia.org

CSL Behring