Avigen: using gene therapy to cure hemophilia

Hemophilia B is a bleeding disease. Victims suffer from prolonged bleeding, spontaneous bleeding, protracted nosebleeds, bruising and bleeding into joints. More severe consequences of the disease include permanent disability, anemia, bleeding in the brain, and death. Caused by a recessive gene on the X chromosome, Hemophilia B affects one out of 34,500 men, with about 5,000 men affected in America. Currently, typical treatments involve IV infusions of Factor IX protein concentrates. Injected several times per week to several times per month, Factor IX replacement injections cost up to $125,000 annually. These expensive shots, however, provide only temporary relief and may include complications, including blood clots in the vein and development of antibodies that block the activity of the injected Factor IX. The need, then, is a therapy that requires fewer injections and costs less. That's where Avigen's gene therapy product comes in.

Despite the small size of the Hemophilia B market, this disease looks like a good target for gene therapy treatment. The Factor IX gene is small and can fit in the smallest of vectors, and only 5-10% of gene expression is required for normal blood clotting. Seeing these points, Avigen decided to develop Coagulin-B as a gene therapy treatment for Hemophilia B using Adeno Associated Virus (AAV) to deliver a working Factor IX gene into patients. AAV is a small parvovirus with a 4.7 kb ssDNA genome. The Factor IX gene is small enough to fit into the virus. AAV has no specific pathology in humans. In fact, >85% of adults are immunopositive for the virus, so AAV could be a safe means of delivering a gene into humans.

To go from platform to clinic, scientists must pass several checkpoints.

Drug Validation
Can the drug be validated? In the dog model system used by Avigen, scientists demonstrated the efficacy and lack of toxicity of Coagulin-B along with long-term expression of Factor IX. Also, the dogs expressed the gene for 2 years following a single injection. And although those results seem promising, it begs the next question.

Model System
How good is the animal model? As a large mammal that is naturally infected by AAV and hemophilia B, the dog seems to be a good model system for humans. This is still no guarantee for good results in human clinical trials, but forms a good foundation for the submission of an Investigational New Drug Application.

Manufacturing
Even with preclinical results, Avigen must also have a plan for manufacturing AAV and scaling it up for full Current Good Manufacturing Protocol compliance by the end of clinical trials. The problems are that AAV is incredibly difficult to manufacture and the sophisticated processes required are difficult to scale-up. But, Avigen has good manufacturing technologies to make the virus and also has a good patent estate to back up those techniques.

Overall solid preclinical data makes Coagulin-B a good drug candidate for Avigen. Despite the small market size of Hemophilia B, the drug’s possible success in clinical trials will poise Avigen at the forefront of the field as the first company to successfully commercialize a gene-therapy based drug. The small market size will also prove useful in clinical trials, as smaller and cheaper patient populations may be used. Further, armed with their strategic alliance with Bayer, Avigen will be able to pursue other applications of the AAV platform without having to worry about running out of money in the clinic with Coagulin-B. Manufacturing worries will also be ameliorated by Bayer’s strong viral manufacturing position. Currently, Avigen is in Phase I Clinical Trials with their Coagulin-B therapy.