Hemophilia B causes a deficiency in factor IX, a protein necessary for blood clotting. Replacement factor IX therapy is the gold standard treatment, but novel and genetic therapies are showing promise in research.
Hemophilia B is a genetic disorder that affects how well the blood clots. Treatment involves supplementing the factor IX protein, but new therapies may offer alternative ways to manage factor IX deficiency.
“Hemophilia” is a broad term for several types of genetic disorders that affect blood clot formation. Hemophilia B is the result of a genetic change in the F9 gene, which causes a deficiency of clotting factor IX.
This article looks at the current treatments for hemophilia B and emerging therapies that could one day support replacement factor IX therapy or be alternatives to it.
Recombinant factor IX is a synthetic protein. It is the current gold standard in
Scientists produce factor IX by cultivating host cells in a laboratory and genetically modifying them. They then extract the protein and use it to create a concentrated infusion that a healthcare professional can administer intravenously (directly into a person’s vein).
The infusion of factor IX back into the body rebalances the clotting cascade for a certain period of time.
Two types of recombinant factor IX are available. They differ according to their half-life, which is how long it takes a person’s body to eliminate half of a substance.
- Standard half-life factor IX: This is a protein with a similar duration to natural factor IX. Healthcare professionals primarily use it to manage acute bleeding in non-severe hemophilia B.
- Extended half-life factor IX: This is a form of factor IX that is modified to stay in the body longer. Healthcare professionals primarily use it in hemophilia B prophylaxis, which involves regular, scheduled infusions for ongoing management of severe hemophilia B.
According to the National Bleeding Disorders Foundation, as many as 75% of people who live with hemophilia B are receiving recombinant factor IX therapy.
When factor IX comes directly from human blood and plasma donations, healthcare professionals refer to it as plasma-derived factor IX concentrates.
Like recombinant factor IX, plasma-derived factor IX provides the body with the factor IX it needs to complete its clotting process.
Plasma-derived factor IX concentrates go through a complex screening and viral inactivation process to ensure that they are free of bloodborne pathogens such as HIV and hepatitis C. They also go through a purification process to limit the blood components that each infusion contains.
Depending on their level of purification, they fall into one of two categories:
- Highly purified plasma-derived products contain mostly factor IX.
- Intermediate-purity infusions may contain other blood components, such as additional clotting factors, that might be useful in treating other conditions.
Because they come from a human donor, plasma-derived factor IX concentrates always carry a small risk of transmitting bloodborne pathogens. For this reason, they are used for hemophilia B only in certain circumstances, such as:
- when there is a shortage of recombinant products
- when factor IX is needed in an emergency situation
- when a person develops antibodies to recombinant treatments (also known as developing inhibitors)
- when the cost of recombinant factor IX is too high
Fresh frozen plasma is a blood product that comes from human donors and is used in various medical circumstances. It
Fresh frozen plasma is not virally inactivated, and it poses a higher risk of bloodborne pathogen transmission than factor IX concentrates do. It is also inefficient at keeping factor IX at a therapeutic level and is used only when other standard factor IX therapies are unavailable.
Healthcare professionals may use transfusions and surgery to manage secondary complications of hemophilia B.
A blood transfusion involves the administration of whole blood or blood concentrates, such as red blood cells, platelets, or plasma. This may be necessary if bleeding episodes have caused major blood loss.
As a result of ineffective clotting processes, hemophilia B can cause chronic bleeding throughout the body. Over time, this bleeding and inflammation can lead to damage or scarring (for example, within the joints) that may require surgical intervention.
In rare cases, severe hemophilia might cause bleeding episodes that result in excessive blood loss. In this situation, a blood transfusion may be necessary to restore levels of other blood components, such as red and white blood cells.
Investigative therapies that are not part of current treatment guidelines are called novel therapies because they offer a potentially innovative approach to medical treatment.
Researchers are currently studying several novel agents for the potential treatment of hemophilia B, including those below.
Bispecific antibodies (emicizumab)
Emicizumab is already being used to treat hemophilia A, but researchers are now investigating whether it can be used in hemophilia B.
These antibodies promote the activity of factor X, the protein activated by factor IX. By focusing on factor X, they allow the clotting process to continue even when factor IX levels are low.
Non-factor replacement therapies (fitusiran)
Non-factor replacement therapies use non-clotting factor molecules that enhance thrombin (clotting factor) generation and fibrin (clotting protein) production. Both thrombin and fibrin help the blood to clot.
Anti-TFPI inhibitors (concizumab)
Anti-TFPI inhibitors are antibodies that block tissue factor pathway inhibitor (TFPI), a substance that regulates the clotting process. When TFPI is blocked, thrombin and fibrin production can increase.
Bypassing agents (FEIBA, NovoSeven, SevenFact)
Bypassing agents bypass the traditional clotting cascade. These unique substances start the clotting process through alternative routes when the body has developed inhibitors to traditional therapies.
Clinical trials
Novel agents are an area of ongoing research. People who are interested in participating in a clinical trial for one of these therapies can find current opportunities by visiting ClinicalTrials.gov and www.centerwatch.com.
Gene therapy is a medical treatment that involves adding, removing, or modifying genetic material. For hemophilia B, researchers are exploring several gene therapies to potentially restore the genetic function of F9 or work around its limitations by enhancing or regulating other genetic features.
Among the gene therapies in current research, the use of Adeno-associated virus (AAV) vectors has gained significant traction. Vectors are particles that help transport genetic material into targeted parts of a cell.
When vectors are used to encode functional factor IX genes within certain cells, the body may be able to produce higher levels of factor IX naturally.
In 2023, researchers completed phase 3 of the HOPE-B clinical trial for the AAV vector-transported genetic variant etranacogene dezaparvovec. The findings suggested that genetic therapy was superior to traditional factor IX replacement in the prevention of bleeding, with a favorable safety profile.
Although hemophilia B is not curable, treatment is available to manage it. With an early intervention of standard factor IX replacement therapy,
More research is needed to understand the long-term outcomes of novel and genetic therapies. While many of these emerging treatments are promising, long-term data is necessary to determine their success rates, safety, and feasibility.
Ultimately, a person’s outlook with hemophilia B can depend on many factors, such as:
- the severity of hemophilia B
- any co-occurring conditions
- a person’s age
- treatment adherence
- inhibitor development
- individual treatment response
Recombinant factor IX replacement therapy is the primary treatment for hemophilia B. It involves using infusions to reintroduce factor IX protein into the body to stabilize the clotting process.
While many people experience success with traditional hemophilia B treatments, researchers are exploring novel agents and genetic therapies as promising alternative or supportive options.
