This article has been updated from a version posted Nov. 13 to correct the name of the National Hemophilia Foundation.
Biogen Idec and several research advocates have launched a nationwide program to provide free genetic testing to hemophilia patients and their families in order to gain better insight into genetic factors that influence bleeding and therapeutic response.
The National Hemophilia Foundation, the American Thrombosis and Hemostasis Network, Puget Sound Blood Center, and Biogen Idec Hemophilia are partnering in the program. Patients participating in the effort will submit their biological samples, which will be stored in a repository, and have their genotypic and phenotypic data collected in a database. This information will be eventually available to select researchers who apply for access and are selected by a review board.
Biogen Idec is financially supporting the genetic testing service, the development of the DNA sample repository, and the genotype-phenotype database, but the company did not provide an estimate for how much it is spending on the effort. Regardless of its monetary commitment, Biogen Idec will not have any special access to the repository and database, the company said.
Hemophilia is a bleeding disorder that occurs in patients with mutations in either the F8 or F9 genes that lead to a deficiency of the blood-clotting proteins Factor VIII and Factor IX, respectively. Changes in the F8 gene are responsible for hemophilia A, while mutations in the F9 gene cause hemophilia B.
"The mutations across hemophilia are diverse and throughout the gene," Barbara Konkle, director of clinical and translational research at the Puget Sound Blood Center, told PGx Reporter.
Hemophilia A and B are rare, occurring mostly in men. Around 1 in 5,000 males are born with hemophilia A, and 1 in 25,000 men are born with hemophilia B. While most hemophilia-causing gene mutations are inherited, 30 percent of patients have no family history of the condition. Females can be mutation carriers but rarely get the disease.
"One of the major complications, particularly of severe hemophilia A, is that patients develop antibodies to the factor concentrate treatment. We know that that's strongly influenced by the underlying mutation," Konkle said. "We can generally predict how much bleeding they will have based on their factor level, but there is a lot of variability … There are also some issues in terms of response to medication depending on the mutations.
"It would be very helpful to better understand variability in bleeding events … and to be able to have a resource in terms of having DNA for more research and having genotypic and phenotypic data," she added.
Genetic testing for hemophilia is usually conducted for family planning purposes. However, testing is not widely covered by payors. The cost of testing can range from $500 to $3,000 depending on the technique used and the lab performing the service.
In some countries, such as in the UK or Australia, hemophilia patients are genotyped as part of the standard of care, NHF and the other collaborators pointed out in a statement. In the US, however, only 20 percent of hemophilia patients are genotyped currently, and those who choose not to get tested cite reimbursement concerns as their biggest hurdle. Insurers are more likely to cover genetic testing for pregnant women who have a family history of the disease, but, according to Konkle, by that time it's often too late.
"Many insurers have not paid for [genetic testing], and so it's hard for families to have the genotyping done. There is also fear of genetic discrimination," Konkle said, adding that the passage of the Genetic Information Non-discrimination Act has eased some of these fears.
To improve access to genetic testing and to advance research for the condition, Biogen Idec is footing the bill to test between 5,000 and 10,000 hemophilia patients and their families. The firm is currently committed to backing this effort for three years.
Hemophilia A and B are treated by increasing the level of clotting factor in blood through prophylaxis to hinder future bleeds or "on-demand fusions" to stop patients from bleeding during an event. Biogen Idec's hemophilia pipeline is focused on developing clotting factor replacement therapies. Specifically, the company is investigating recombinant factor VIII Fc for hemophilia A and recombinant factor IX Fc for hemophilia B in Phase III studies.
By improving genetic testing access for patients and their families in the US, Biogen Idec and its partners plan to advance research into individualized approaches to therapy.
In addition, Glenn Pierce, Biogen Idec Hemophilia's chief medical officer, was born with hemophilia. The hemophilia community "for the past 15 years has been calling for broad genetic testing of patients and potential carriers," Pierce told PGx Reporter. "While Biogen Idec is not currently developing pharmacogenetic treatments for hemophilia, we hope that the research database will catalyze the development of new treatment options."
Due to the rarity of the disease, relatively few labs in the US perform genetic testing for hemophilia, according to Konkle. Sanger sequencing is commonly performed to detect relevant mutations. "For severe hemophilia A, [which means that] the patient has no detectable Factor VIII, about half of the severe hemophilia is due to the inversions in the Factor VIII gene," Konkle said. "Other than that, there are missense, nonsense insertions, and deletions that are routinely responsible for hemophilia."
In this project, researchers at Puget Sound Blood Center will work with Jay Shendure's lab at the University of Washington's Department of Genome Sciences to identify disease-causing mutations. Shendure's lab will use next-generation sequencing to analyze patient samples, and then researchers at Puget Sound will confirm the mutations in a CLIA-certified lab.
"At the Puget Sound laboratory we'll receive the sample, extract the DNA and make plates for [Shendure's] lab. Then they will return to us a consensus sequence," Konkle explained. "This will allow us to do more genotyping at a lower cost. In our genotyping laboratory, we will confirm the sequence in a separate aliquot"
The American Thrombosis and Hemostasis Network, a nonprofit that runs a database of information on hemophilia patients, is managing the database for this project. The sample repository will be housed at the Puget Sound Blood Center. Researchers interested in gaining access to the database will have to submit project applications, which will be vetted by an ATHN project review committee made up of scientists, patients, and physicians.