More than three million Americans are living with bleeding disorders. These disorders—including hemophilia, von Willebrand disease, and other rare bleeding disorders called rare factor deficiencies—prevent normal blood clotting and can make things like small cuts or routine dental work turn deadly.
Despite being more rare than other bleeding disorders (diagnosed in only roughly 20,000 Americans), hemophilia is perhaps the most well-known. In history, hemophilia was nicknamed the royal disease. Queen Victoria of England, a hemophilia B carrier, passed the condition on to several of her children, grandchildren, and royal families in Spain, Germany, and Russia.
Today, an estimated 400,000 people worldwide live with hemophilia. The condition is more common in men, and there are four types. Three types are inherited: hemophilia A, B, and C. One type, acquired hemophilia, typically develops as a result of illness, medication therapy, or pregnancy.
Von Willebrand disease is the most common bleeding disorder, found in roughly one percent of the world’s population. People with von Willebrand disease can be missing or have deficient von Willebrand disease factor (VWF) but may also have VWF that does not function properly. The von Willebrand disease is typically hereditary but can also be acquired, most commonly in adults 40 and older as a result of a comorbid condition.
Current Bleeding Disorder Therapies
The goal of hemophilia research is to develop a therapy capable of preventing bleeding and its associated complications. Two primary types of therapy are available for hemophilia: factor replacement therapy and nonfactor replacement therapy.
Factor replacement therapies use either recombinant or plasma-derived molecules to increase the amount of clotting factor in a person’s blood. Both standard and extended half-life factor replacement therapies require intravenous infusion. Standard half-life therapies are used primarily to treat hemophilia A and B and some types of von Willebrand disease. Extended half-life therapies have been modified to delay the breakdown of clotting factor in the body and are primarily used as hemophilia A and B treatments.
Nonfactor replacement therapies are intended to prevent bleeding or improve clotting through other methods than clotting factor replacement. These types of treatments include desmopressin acetate for mild hemophilia, a synthetic version of vasopressin available as a nasal spray or injection; aminocaproic acid, an oral medication often used in tandem with clotting factor; and emicizimab, a prophylactic protein that performs the task of Factor VIII in the clotting cascade.
Novel or mechanistic approaches to hemophilia therapy are also being explored, including the use of antithrombin or tissue factor pathway inhibitors, antisense RNA technology like fitusiran, or monoclonal antibodies like concizumab to lower endogenous anticoagulants. These approaches have demonstrated their efficacy, but the associated risk for thrombogenicity means there is still work to be done.
The Future of Hemophilia Gene Therapy
Advances in gene therapy have led to subsequent advances in hemophilia research. Hemophilia occurs as a result of mutations in a single gene. Therefore, many researchers view the disease as an ideal candidate for gene therapy. From an economic standpoint, gene therapy for hemophilia would reduce the financial burden on patients living with hemophilia, many of whom require expensive prophylactic treatments. Due to their inherent complexity, these treatments—in the form of injections and infusions—also have a low adherence rate among teens and adults. Successful gene therapy for hemophilia, then, represents a change in the way people living with hemophilia live their lives.
Researchers hope that, through developing a gene therapy, they will be able to provide long-lasting relief to people with hemophilia through a single dose of treatment. Researchers are optimistic. The nature of hemophilia means that the bleeding phenotype is “responsive to a wide range of factor levels”—in other words, precision isn’t necessary. Specifically, the goal of gene therapy is to establish “continuous endogenous expression” of clotting factors VIII or IX. The recent focus has been on viral vectors, specifically, recombinant adeno-associated viral (AAV) vectors, which have demonstrated the best safety profile. Multiple early-phase clinical studies relying on AAV vectors have demonstrated the efficacy of gene therapy.
Groups like the American Society of Hematology (ASH) are also zeroing in on precision medicine in the hopes that the widespread use of genome sequencing and genomic profiling can increase the efficacy of gene therapy—and soon. ASH is prioritizing a twofold research agenda investigating both immunotherapy and novel immune-based strategies and the molecular profiling of DNA and RNA.
PRA is at the forefront of the important work that may one day change the lives of people living with hemophilia and other bleeding disorders. We’ve worked with sponsors on multiple hemophilia studies and are proud to be doing our part in easing the burden of living with a bleeding disorder.
“We’re thrilled to work with our development partners to bring the next generations of treatments to bleeding disorder communities, such as hemophilia. The complications of having a rare disease are significant, and can impact all aspects of the patients’ lives,” says Amy Raymond PhD, Director of Therapeutic Expertise, Center for Rare Diseases. “As a company focused on putting patients first, it’s incredibly satisfying for us to leverage our expertise and capabilities in rare disease and gene therapy spaces to make clinical research a care option.”
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