Hemophilia is a genetic disease of the blood in which lack of Factor IX (hemophilia B) or lack of Factor VIII (hemophilia A) leads to improper clotting, thus causing patients to suffer from frequent spontaneous bleeding episodes, especially in their joints or soft tissues. With time, hemophilic patients often develop chronic arthropathy or joint dysfunction, and a further percentage of patients suffer permanent disability or even die due to excessive bleeding into the central nervous system.

Hemophilia A affects approximately 17,000 Americans, while hemophilia B, which afflicts one in 30,000 males worldwide, affects some 5,000 Americans. Typical treatment for patients with hemophilia B includes intravenous infusions of factor IX protein concentrates. These infusions are done from between several times per month to several times per week. The cost of this treatment, at up to $125,000 per patient per year, makes hemophilia one of the most expensive of all diseases to treat. Despite the cost and frequency of treatments, Factor IX protein infusions are effective at providing only temporary relief.

Current research into improving treatments for hemophilia is focusing on reducing both cost and inconvenience to patients. Among the companies at the vanguard of hemophilia research are Cell Genesys, Targeted Genetics, Novo Nordisk, and Avigen.

Cell Genesys Inc. (Foster City, CA) and collaborators from the National Institutes of Health (NIH; Bethesda, MD) recently announced at the American Society for Gene Therapy Conference that therapeutic levels of factor IX models of hemophilia B were restored in non-human primates following a single administration of hemophilia gene therapy. The therapy, which was delivered to the liver using Cell GeneSys’ proprietary adeno-associated viral (AAV) gene delivery system, was shown to be safe and well tolerated in a variety of clinical assays. In addition, a potentially harmful immune response against the gene therapy was not observed during the study.

In prior studies, a significant reduction in bleeding episodes in a canine model of hemophilia B was achieved with a single administration of factor IX gene therapy, and treated animals produced the Factor IX protein for more than two years following a single injection.

Also at the American Society of Gene Therapy meeting, Avigen Inc. (Alameda, California) announced that, following positive reports on the Phase I/II clinical trial of AAV-based gene therapy for hemophilia B, its researchers were ready for a second clinical trial of Coagulin-B™. In the current Coagulin-B clinical trial, patients receive an intramuscular injection of Avigen’s AAV vector carrying the gene for factor IX. The proposed second trial would be designed to test the safety and efficacy of infusing the gene therapy into the liver, the normal site of clotting factor production. Avigen has developed an agreement with BTG International Inc. for further development of this therapy.

Taking a different tact than either Avigen or Cell GeneSys, Novo Nordisk A/S (Bagsværd, Denmark) has released a new blood-clotting protein that the company is billing as the first and only coagulation Factor VIIa. Called NovoSeven, the genetically engineered protein sets off a chain reaction that stimulates clotting at the site of injury. NovoSeven is currently in use at The Mount Sinai Medical Center and other academic medical centers, and has most recently been approved for use in Japan.

On the delivery side of the equation, Valentis announced in January 2000 that it was introducing gene delivery systems for secreted proteins that incorporate Valentis’ novel PINC™ (Protective, Interactive, Non-Condensing) polymer muscle delivery system, which is enhanced by electroporation, or the application of an electrical current through the injection site. Valentis’ GeneSwitch™ gene regulation system can be incorporated into some of the secreted protein products to provide precise control over the level and duration of gene expression, and the company believes that the resulting products will provide long-term expression of therapeutic proteins at controllable levels with low manufacturing costs, with an ability to re-dose, and with normal storage characteristics. Valentis is developing this system with varied gene products in mind, including Factor IX for hemophilia B and erythropoietin for anemia.

In February 2000, UroGen Corp announced that the FDA cleared its Investigational New Drug (IND) application for a Phase I human clinical trial of its Factor VIII gene therapy product for the treatment of hemophilia A. UroGen expects to begin the clinical trial later in 2000, following review of the clinical trial protocol by the NIH Recombinant DNA Advisory Committee.

Research supporting the approval of the IND was published in the February 1, 2000, issue of Blood. These studies, performed in mice with hemophilia A, demonstrated sustained production of therapeutic levels of Factor VIII following a single injection of UroGen’s gene therapy product. The expression of the Factor VIII protein continued for approximately one year following the injection; in the researchers’ view, correcting the abnormality.

UroGen’s gene therapy product for hemophilia A is an improved gene delivery system derived from the common cold virus. The product has been genetically modified to replace all the genes responsible for transmitting the virus with therapeutic genes that are responsible for the production of Factor VIII. This product carries the entire human Factor VIII gene sequence and is designed to result in production of Factor VIII in the liver.

In March 2000, American Home Products’ (AHP; Madison, NJ) new hemophilia treatment, ReFacto, was approved by the FDA for prophylactic use. Developed by The Genetics Institute (Cambridge, MA; a division of AHP), ReFacto is said to be the first albumin-free formulated recombinant factor VIII. The elimination of albumin contributes significantly to a reduced risk of viral transmission.

In the same month, Targeted Genetics Corp. (Seattle, WA) announced that its proprietary gene therapy for hemophilia was the subject of a research paper in March 1 issue of Blood. The paper, which was authored by investigators at the University of North Carolina (UNC) Gene Therapy Center and Department of Medicine, demonstrated that AAV can be used to deliver a functional form of the Factor VIII gene. In December 1999, Targeted Genetics had obtained an option to license exclusive rights to proprietary technology from UNC related to the treatment of hemophilia A via gene delivery.

Upcoming Meetings

52nd Annual Meeting of the National Hemophilia Foundation

November 9–11, 2000

Anaheim, CA

http://www.hemophilia.org

Hemophilia 2000

July 16–21, 2000

Montreal, Quebec, Canada

Sponsored by the World Federation of Hemophilia

http://www.wfh.org

Recent Papers of Note:

Moreau, A., et al., “Antibodies to the FVIII Light Chain that Neutralize FVIII Procoagulant Activity are Present in Plasma of Nonresponder Patients with severe Hemophilia A and in Normal Polyclonal Human IgG.” Blood 95(11):3435–41, 2000.

Sabin, C.A., et al., “Cytomegalovirus Seropositivity and Human Immunodeficiency Virus Type 1 RNA Levels in Individuals with Hemophilia.” J. Infect. Dis. 181(5):1800–1803, 2000.

Wiiger, M.T., et al., “Effects of Binding of Ligand (FVIIa) to Induced Tissue Factor in Human

Endothelial Cells.” Thromb. Res. 98(4):311–21,2000.

Huisman, P., et al. “Acquired Hemophilia.” Neth. J. Med. 56(6):229–231, 2000.

Fakharzadeh, S.S., et al., “Correction of the Coagulation Defect in Hemophilia A Mice Through Factor VIII Expression in Skin.” Blood 2000 May 1;95(9):2799-805

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