What is Gene Therapy?
Your genetic information is composed of multiple parts. Genes are the part of your DNA that provides instructions for your cells to make specific proteins, like factor proteins. Gene therapy is a treatment that provides your cells with a working copy of a gene. For hemophilia, gene therapy provides your cells with a working copy of the factor VIII (8) gene for hemophilia A or the factor IX (9) gene for hemophilia B, which allows your body to produce functioning clotting factors on its own, leading to long-term factor expression.
The corrected gene is delivered to the cells in something called a “vector.” A vector is like a package that carries the functional gene to the cells that need it. A vector is a structure that originally came from a virus but has been modified to remove the parts that could cause illness. Once the vector is inside the body, it targets the specific cells that need the working gene: in hemophilia, these are your liver cells. The functional gene is then processed by your cells to produce working clotting factor proteins. Gene therapy does not change your own DNA but adds a healthy copy of the factor gene to your cells. Current therapies use adeno-associated viral (AAV) vectors, but there are multiple vector types, and there may be other delivery vectors in the future.
After the vector has done its job and delivered the working gene, the added gene remains within the liver cells, and the vector leaves the body naturally through urine, feces, blood, saliva, and semen. This is called vector shedding.
The goal of gene therapy is to enable a patient’s body to make its own clotting factor to prevent bleeds, avoid regular prophylactic infusions, prevent further damage, and improve quality of life. Gene therapy can provide sustained and near-normal factor levels for years and eliminates the need for routine prophylaxis in the majority of patients who receive treatment.
What gene therapy treatments are available?
As of mid-2023, two gene therapy products have been approved for the treatment of hemophilia in the United States and Europe. ROCTAVIAN (valoctocogene roxaparvovec) is approved for the treatment of hemophilia A,1-4 and HEMGENIX (entranacogene dezaparvovec) is approved for the treatment of hemophilia B.5-7 Both use the AAV serotype 5 vector. There are several other gene therapies in clinical trials for the treatment of hemophilia A and hemophilia B.
Each type of gene therapy has unique features that can affect how well it works in your body and whether it’s the right choice for you. Your healthcare team can help you understand the different treatment options and how gene therapy might impact your life. Your healthcare team will consider your medical history, the severity of your hemophilia, and your personal preferences and goals to help you make an informed decision about gene therapy.
How is the mechanism of action for gene therapy different from other treatments for hemophilia?
The main treatment types for hemophilia are clotting factor replacement therapy (standard half-life (SHL) and extended half-life (EHL)), bispecific antibodies, re-balancing agents, and gene therapy. All these treatments help the blood clot more efficiently, but they all work in different ways.
Clotting factor replacement therapy provides a short-term increase in factor levels by injecting the needed clotting factor protein directly into the blood of a person with hemophilia.
Bispecific antibodies are Y-shaped proteins that act as a bridge between factor IXa and factor X, which helps the blood to clot more efficiently. This antibody bridge mimics the function of the missing activated factor VIII (i.e., factor VIIIa-mimetic).
Rebalancing therapies restore the disrupted balance between the levels of anticoagulation (i.e., anti-clotting) factors and clotting factors in the blood, thereby improving blood clotting.
Gene therapy introduces a working copy of the gene that provides instructions for missing the clotting factor protein. Once the gene is introduced, the body can produce the missing protein and maintain adequate clotting factor levels, on its own, for an extended time.
How will I know if gene therapy is the right treatment choice for me?
Deciding to pursue treatment with gene therapy is an important decision that should be made after discussing your options with your healthcare team and loved ones. The decision should be based on the available evidence, your health history, your life goals, and your treatment preferences. Make sure you understand the possible benefits and risks associated with gene therapy. Take your time to think, reflect, and discuss your options with your healthcare team and others you trust.
Gene therapy is not for everyone. Some people will not be eligible, and some will not have access. If you are eligible and it is available to you, it is not guaranteed that you will respond to gene therapy. If you do respond to gene therapy, it is not possible to predict your level of response. At this time, you cannot re-do gene therapy, but if your therapy is not successful you can safely return to your prior treatment regimen or consider other treatment options. Keep in mind that gene therapy for hemophilia A and for hemophilia B are different, with different benefits and risks associated with treatment. For example, after gene therapy treatment, most patients with hemophilia A (~80%) and some with hemophilia B (~20%) require treatment with additional medications (e.g., corticosteroids or other immunosuppressive medications) for several weeks to months for the treatment of immune reactions in the liver. There can be significant side effects associated with taking these medications, and your healthcare team is equipped to help you manage these side effects.
Who is eligible to receive gene therapy?
Gene therapy is not for everyone. Treatment with gene therapy should be discussed in detail with your healthcare team. ROCTAVIAN (valoctocogene roxaparvovec) is approved for use in adults with hemophilia A in the United States and Europe.1,2 Patients must not have pre-existing antibodies against the AAV5 vector and must not have a history of factor VIII (8) inhibitors.
New gene therapies may also be available through clinical trials. Generally, patients eligible for clinical trials are adults with severe or moderately severe hemophilia who are at least 18 years old; have been treated with factor replacement therapy or other types of treatment; have no evidence of advanced liver dysfunction and are otherwise healthy. If you meet these criteria, you may be able to participate in a clinical trial if your Hemophilia Treatment Center is involved in an ongoing clinical trial. Participation should be discussed with your healthcare team.
How is gene therapy administered?
Gene therapy is administered at a hemophilia treatment center by a single infusion into a vein in your arm. The infusion typically takes 1–4 hours, but you should plan for a full day at the treatment center. After the infusion, you will be monitored for several hours to make sure you are okay before going home.
What is the treatment frequency for gene therapy?
Gene therapy is a one-time-treatment and you will not require repeat infusions. If you do not respond to gene therapy, you are not currently eligible to receive gene therapy again, but you can return to other prophylactic therapies for treatment of your hemophilia.
How will clotting factor levels be affected?
The effects of gene therapy will begin to appear approximately 3-4 weeks after treatment.3,4,7 If the treatment was successful, at 3-4 weeks your clotting factor levels will begin to increase. After a few months, clotting factor levels will stabilize. Everyone responds differently to gene therapy, and it is not possible to predict what factor level someone will achieve or how long they will maintain that factor level.
After treatment with ROCTAVIAN for hemophilia A, average factor levels were 42% after 1 year, 23% after 2 years, and 15% after 3 years1. Studies are in progress to determine whether the factor levels will continue to decline or will remain stable beyond 3 years. Longer-term data are available and could be discussed with your healthcare team.
| expression1 | Year 1 (N = 134) | Year 2 (N = 134) | Year 3 (N = 19) |
|---|---|---|---|
| 0–3% | 10% | 15% | 26% |
| 3–5% | 2% | 10% | 11% |
| 5–15% | 17% | 34% | 42% |
| 15–40% | 34% | 26% | 5% |
| >40% | 31% | 13% | 16% |
How will gene therapy affect my annual bleeding rate?
In phase 3 clinical trials for ROCTAVIAN, people with hemophilia A had very few bleeding events and averaged 2.6 bleeds per year,2 with 0.8 bleeds per year requiring treatment.1 Most people (74%) had zero bleeds requiring treatment.1
How will gene therapy affect my use of prophylaxis?
Patients will continue prophylactic treatment until they produce their own factor, which typically takes a few weeks. Not all patients will produce enough factor to stop prophylactic treatment. In clinical trials, 96% of patients who received ROCTAVIAN still did not need to restart prophylaxis 2 years after treatment.1
How long can I expect the effects of gene therapy to last?
We do not know how long the effects of gene therapy will last. As of June 2023, patients have been followed for three years for hemophilia A and two years for hemophilia B in clinical trials. There are differences in how long gene therapy lasts between hemophilia A and hemophilia B, please discuss the latest data with your healthcare team.
Is gene therapy safe?
Clinical trials evaluate whether new treatments are safe and effective. In the case of gene therapy for hemophilia, clinical trials have been run to make sure that the treatment is safe for people to use. ROCTAVIAN is approved for use in the United States and Europe for the treatment of Hemophilia A. Gene therapy has known warnings and precautions that should be discussed with your healthcare team prior to deciding on a treatment plan.
What are the possible side effects (adverse reactions) of gene therapy?
The most common side effects (adverse reactions) following treatment with ROCTAVIAN were nausea, fatigue, headache, infusion related reactions, vomiting, and abdominal pain.1,2,4 The most common laboratory abnormalities included increases in ALT, AST, and factor VIII activity.
Infusion-related reactions included hypersensitivity reactions, anaphylaxis, nausea, fatigue, and headache. Patients are closely monitored during the infusion and these symptoms, which may temporarily interrupt treatment, can be treated, and usually resolve quickly.
Are there any known serious side effects of gene therapy?
Some important side effects are known and can be controlled. Most people with hemophilia A (80%)1,2 will experience abnormal increases in liver enzyme levels following gene therapy. These liver changes can be controlled with additional medications (e.g., corticosteroids or other immunosuppressive medications) for several weeks to months. There can be significant side effects associated with taking these medications, however they are generally manageable and reversible; your healthcare team is equipped to help you manage these side effects.
Because of these liver changes, it is recommended that patients abstain from alcohol for at least one year, and thereafter limit their alcohol use.
What are the long- term side effects of gene therapy?
Longer-term risks include potential impacts to liver health.8 Clinical trials are ongoing, and current available data is limited to 8 years; therefore the long-term risks are not fully known. No known cancers related to gene therapy have been observed to date.
How often will you need follow up and monitoring after gene therapy?
Treatment with gene therapy requires regular follow-ups. The typical follow-up schedule in year one is 1–2 times per week for the first six months and every 1–4 weeks for the next 6 months. Most of these visits will be laboratory visits that may only require a blood draw. In year 2, visit frequency may decrease to once every three months. After year 2, visit frequency may decrease to once every six months. Visits may be more frequent for patients with factor levels less than 5%. These visits will help your healthcare team monitor your health and factor levels to make sure the treatment is still working effectively
You will need to continue to see your healthcare team for regular check-ups even after the initial follow-up period is over to ensure that you continue to receive the best possible care and support for your hemophilia.
Do I need to register in a patient registry after gene therapy?
The best way for researchers to monitor how well gene therapy works over the long-term is for all patients who receive gene therapy to be followed in a registry. The WFH Gene Therapy Registry (GTR) is designed so that every patient, no matter where they live, can participate.9 Participation in the registry is voluntary but recommended. You can ask your healthcare team to sign you up for the WFH GTR.
Can I stop gene therapy?
Once gene therapy has been administered, the added gene cannot be stopped or removed. It is important to carefully consider the potential benefits and risks of gene therapy before deciding to undergo the treatment.
Will I still have hemophilia after gene therapy?
Gene therapy is not a cure for hemophilia, but successful treatment can eliminate the burden of prophylaxis, reduce bleeding, and improve quality of life. Studies have shown that gene therapy increases factor levels in most, but not all, patients, sometimes even to normal levels. This can help reduce or eliminate bleeding and the need for regular factor infusions. While curative levels may be achieved by some, for others, the severity of hemophilia may be improved.
If gene therapy is not successful, can I return to my prior treatment regimen?
If gene therapy for hemophilia is not successful, you will be able to safely return to your prior treatment regimen or another standard of care treatment.
Will I still need to use other treatments for hemophilia?
It is possible that you may not need to use regular prophylaxis or factor replacement therapy once your factor levels reach a level where most bleeds would stop. The majority of people in clinical trials did not need to resume prophylaxis or take treatment for bleeding events in clinical trials.
It is recommended that you continue to work closely with your healthcare team and follow their recommendations for managing your hemophilia. In some cases, such as bleeding, trauma, and surgeries, additional treatment may still be necessary.
Will gene therapy heal my existing joint damage?
Gene therapy is unlikely to reverse existing structural joint damage, but may reduce other joint symptoms.
How will my quality of life be affected by gene therapy?
Gene therapy for hemophilia has the potential to improve a patient’s quality of life. Many, but not all, patients who have undergone gene therapy report increased freedom and improved ability to engage in physical activities without fear of bleeding.
With successful gene therapy, patients may no longer require regular prophylaxis and may experience a significant reduction in bleeding episodes.
What will happen in the event of a bleed or injury or if I need surgery?
The need for treatment following a bleed, injury, or because of surgery will depend on how much factor your body is producing. Each person’s response to gene therapy is different, and impossible to predict. There is also no guarantee that every bleed or injury will have the same treatment needs. This should be discussed with your health care team. In most cases, you are advised to treat a bleed with usual replacement therapy products and record all details.
Can the effects of gene therapy be passed on to my future children?
Gene therapy for hemophilia provides a functional copy of the factor VIII (8) gene to the liver. Gene therapy does not change the DNA in your reproductive cells and therefore, hemophilia can still be passed on to future children. This means that if a person with hemophilia receives gene therapy, their children will not inherit the working gene. Gene therapy only helps the person who receives it, not their future children.
Will gene therapy impact my ability to have children?
Men: No, gene therapy will not affect your ability to have children. However, the vector may be present in semen (as it is released from the body) for a varying period of time after receiving gene therapy. Although there is very little risk that it affects semen, it is recommended that men use contraceptive measures to prevent pregnancies until the vector is no longer present (i.e., 6 to 12 months).
Women: No data are available to recommend the duration of contraceptive measures in women of childbearing potential. While women are eligible for gene therapy, it is not recommended in women of childbearing potential. Gene therapy is also not recommended in women who are pregnant or breastfeeding.
What is the World Federation of Hemophilia Gene Therapy Registry (WFH GTR)?
The WFH GTR is a prospective, observational, and longitudinal registry designed to collect long-term data on people with hemophilia who receive gene therapy globally.9 Participation in the registry after receiving gene therapy is voluntary but recommended. This registry is the best way to capture long-term data on gene therapy and ensure the safety of gene therapy for patients.
WWhere can I find more information on gene therapy or gene therapy for hemophilia?
Society of Gene and Cell Therapy
A Guide for Patients and Caregivers. All About Hemophilia
Gene Therapy. Canadian Hemophilia Society.
EHC Gene Therapy A Practical Guide Book
ISTH: Gene Therapy
National Hemophilia Foundation. Frequently Asked
Questions
WFH Gene Therapy Registry
The Hemophilia Gene Therapy Patient Journey: Questions
and Answers for Shared Decision-Making.
Wang M, Negrier C, Driessler F, Goodman C, Skinner MW
WFH Shared Decision Making Tool: THERAPY Fact Sheet
DownloadWhat is Gene Therapy?
Your genetic information is composed of multiple parts. Genes are the part of your DNA that provides instructions for your cells to make specific proteins, like factor proteins. Gene therapy is a treatment that provides your cells with a working copy of a gene. For hemophilia, gene therapy provides your cells with a working copy of the factor VIII (8) gene for hemophilia A or the factor IX (9) gene for hemophilia B, which allows your body to produce functioning clotting factors on its own, leading to long-term factor expression.
The corrected gene is delivered to the cells in something called a “vector.” A vector is like a package that carries the functional gene to the cells that need it. A vector is a structure that originally came from a virus but has been modified to remove the parts that could cause illness. Once the vector is inside the body, it targets the specific cells that need the working gene: in hemophilia, these are your liver cells. The functional gene is then processed by your cells to produce working clotting factor proteins. Gene therapy does not change your own DNA but adds a healthy copy of the factor gene to your cells. Current therapies use adeno-associated viral (AAV) vectors, but there are multiple vector types, and there may be other delivery vectors in the future.
After the vector has done its job and delivered the working gene, the added gene remains within the liver cells, and the vector leaves the body naturally through urine, feces, blood, saliva, and semen. This is called vector shedding.
The goal of gene therapy is to enable a patient’s body to make its own clotting factor to prevent bleeds, avoid regular prophylactic infusions, prevent further damage, and improve quality of life. Gene therapy can provide sustained and near-normal factor levels for years and eliminates the need for routine prophylaxis in the majority of patients who receive treatment
What gene therapies treatments are available?
As of mid-2023, two gene therapy products have been approved for the treatment of hemophilia in the United States and Europe. ROCTAVIAN (valoctocogene roxaparvovec) is approved for the treatment of hemophilia A,1-4 and HEMGENIX (entranacogene dezaparvovec) is approved for the treatment of hemophilia B.5-7 Both use the AAV serotype 5 vector. There are several other gene therapies in clinical trials for the treatment of hemophilia A and hemophilia B.
Each type of gene therapy has unique features that can affect how well it works in your body and whether it’s the right choice for you. Your healthcare team can help you understand the different treatment options and how gene therapy might impact your life. Your healthcare team will consider your medical history, the severity of your hemophilia, and your personal preferences and goals to help you make an informed decision about gene therapy.
How is the mechanism of action for gene therapy different from other treatments for hemophilia?
The main treatment types for hemophilia are clotting factor replacement therapy (standard half-life (SHL) and extended half-life (EHL)), bispecific antibodies, re-balancing agents, and gene therapy. All these treatments help the blood clot more efficiently, but they all work in different ways.
Clotting factor replacement therapy provides a short-term increase in factor levels by injecting the needed clotting factor protein directly into the blood of a person with hemophilia.
Bispecific antibodies are Y-shaped proteins that act as a bridge between factor IXa and factor X, which helps the blood to clot more efficiently. This antibody bridge mimics the function of the missing activated factor VIII (i.e., factor VIIIa-mimetic).
Rebalancing therapies restore the disrupted balance between the levels of anticoagulation (i.e., anti-clotting) factors and clotting factors in the blood, thereby improving blood clotting.
Gene therapy introduces a working copy of the gene that provides instructions for missing the clotting factor protein. Once the gene is introduced, the body can produce the missing protein and maintain adequate clotting factor levels, on its own, for an extended time.
How will I know if gene therapy is the right treatment choice for me?
Deciding to pursue treatment with gene therapy is an important decision that should be made after discussing your options with your healthcare team and loved ones. The decision should be based on the available evidence, your health history, your life goals, and your treatment preferences. Make sure you understand the possible benefits and risks associated with gene therapy. Take your time to think, reflect, and discuss your options with your healthcare team and others you trust.
Gene therapy is not for everyone. Some people will not be eligible, and some will not have access. If you are eligible and it is available to you, it is not guaranteed that you will respond to gene therapy. If you do respond to gene therapy, it is not possible to predict your level of response. At this time, you cannot re-do gene therapy, but if your therapy is not successful you can safely return to your prior treatment regimen or consider other treatment options. Keep in mind that gene therapy for hemophilia A and for hemophilia B are different, with different benefits and risks associated with treatment. For example, after gene therapy treatment, most patients with hemophilia A (~80%) and some with hemophilia B (~20%) require treatment with additional medications (e.g., corticosteroids or other immunosuppressive medications) for several weeks to months for the treatment of immune reactions in the liver. There can be significant side effects associated with taking these medications, and your healthcare team is equipped to help you manage these side effects.
Who is eligible to receive gene therapy?
Gene therapy is not for everyone. Treatment with gene therapy should be discussed in detail with your healthcare team. HEMGENIX (entranacogene dezaparvovec) is approved for use in adults with hemophilia B in the United States and Europe.5,6 Treatment is indicated in patients who currently use factor IX (9) prophylaxis or have a current or historical life-threatening hemorrhage or have repeated serious spontaneous bleeding episodes.
New gene therapies may also be available through clinical trials. Generally, patients eligible for clinical trials are adults with severe or moderately severe hemophilia who are at least 18 years old; have been treated with factor replacement therapy or other types of treatment; have no evidence of advanced liver dysfunction and are otherwise healthy. If you meet these criteria, you may be able to participate in a clinical trial if your Hemophilia Treatment Center is involved in an ongoing clinical trial. Participation should be discussed with your healthcare team.
How is gene therapy administered?
Gene therapy is administered at a hemophilia treatment center by a single infusion into a vein in your arm. The infusion typically takes 1–4 hours, but you should plan for a full day at the treatment center. After the infusion, you will be monitored for several hours to make sure you are okay before going home.
What is the treatment frequency for gene therapy?
Gene therapy is a one-time-treatment and you will not require repeat infusions. If you do not respond to gene therapy, you are not currently eligible to receive gene therapy again, but you can return to other prophylactic therapies for treatment of your hemophilia.
How will clotting factor levels be affected?
The effects of gene therapy will begin to appear approximately 3–4 weeks after treatment.3,4,7 If the treatment was successful, at 3–4 weeks your clotting factor levels will begin to increase. After a few months, clotting factor levels will stabilize. Everyone responds differently to gene therapy, and it is not possible to predict what factor level someone will achieve or how long they will maintain that factor level.
After gene therapy with HEMGENIX for hemophilia B, average factor levels were 42% after 1 year, 37% after 18 months, and 37% after 2 years.5 Studies are ongoing to determine whether factor levels continue to be maintained over the long term. Longer-term data are available and could be discussed with your healthcare team.
How will gene therapy affect my annual bleeding rate?
In phase 3 clinical trials of HEMGENIX, people with hemophilia B who responded to treatment averaged 1.1 bleeds per year,5 with 0.8 bleeds per year requiring treatment.6 Most people (64%) had zero bleeds.
How will gene therapy affect my use of prophylaxis?
Patients will continue prophylactic treatment until they produce their own factor, which typically takes a few weeks. Not all patients will produce enough factor to stop prophylactic treatment. In clinical trials, 96% of patients who received HEMGENIX still did not need to re- start prophylaxis 2 years after treatment.
How long can I expect the effects of gene therapy to last?
We do not know how long the effects of gene therapy will last. As of June 2023, patients have been followed for three years for hemophilia A and two years for hemophilia B in clinical trials. There are differences in how long gene therapy lasts between hemophilia A and hemophilia B, please discuss the latest data with your healthcare team.
Is gene therapy safe?
Clinical trials evaluate whether new treatments are safe and effective. In the case of gene therapy for hemophilia, clinical trials have been run to make sure that the treatment is safe for people to use. HEMGENIX is approved for use in the United States and Europe for the treatment of Hemophilia B. Gene therapy has known warnings and precautions that should be discussed with your healthcare team prior to deciding on a treatment plan.
What are the possible side effects (adverse reactions) of gene therapy?
The most common side effects (adverse reactions) following treatment with HEMGENIX were increases in ALT and blood creatine kinase levels, flu-like symptoms, infusion related reactions, fatigue, malaise, and elevated AST levels.
Infusion related reactions include hypersensitivity reactions, anaphylaxis, chest tightness, headaches, abdominal pain, light headedness, flu-like symptoms, shivering, flushing, rash, and hypertension. Patients are closely monitored during the infusion and these side effects, which may temporarily interrupt treatment, can be treated, and usually resolve quickly.
Are there any known serious side effects of gene therapy?
Some important side effects are known and can be controlled. Approximately 20% of patients with hemophilia B5,6 will experience abnormal increases in liver enzyme levels following gene therapy. These liver changes can be controlled with additional medications (e.g., corticosteroids or other immunosuppressive medications) for several weeks to months. There can be significant side effects associated with taking these medications, however they are generally manageable and reversible; your healthcare team is equipped to help you manage these side effects.
Because of these liver changes, it is recommended that patients abstain from alcohol for at least one year, and thereafter limit their alcohol use.
What are the long- term side effects of gene therapy?
Longer-term risks include potential impacts to liver health.8 Clinical trials are ongoing, and current available data is limited to 8 years; therefore the long-term risks are not fully known. No known cancers related to gene therapy have been observed to date. SDMWFH SHARED DECISION
How often will you need follow up and monitoring after gene therapy?
Treatment with gene therapy requires regular follow-ups. The typical follow-up schedule is once per week for the first three months and once every three months for the rest of year one. In year two, visit frequency may decrease to one every six months, and in year three visit frequency may decreases to one every 12 months. Visit frequency may be adjusted based on your response to treatment. These visits will help your healthcare team monitor your health and factor levels to make sure the treatment is still working effectively.
You will need to continue to see your healthcare team for regular check-ups even after the initial follow-up period is over to ensure that you continue to receive the best possible care and support for your hemophilia
Do I need to register in a patient registry after gene therapy?
The best way for researchers to monitor how well gene therapy works over the long-term is for all patients who receive gene therapy to be followed in a registry. The WFH Gene Therapy Registry (GTR) is designed so that every patient, no matter where they live, can participate.9 Participation in the registry is voluntary but recommended. You can ask your healthcare team to sign you up for the WFH GTR
Can I stop gene therapy?
Once gene therapy has been administered, the added gene cannot be stopped or removed. It is important to carefully consider the potential benefits and risks of gene therapy before deciding to undergo the treatment.
Will I still have hemophilia after gene therapy?
Gene therapy is not a cure for hemophilia, but successful treatment can eliminate the burden of prophylaxis, reduce bleeding, and improve quality of life. Studies have shown that gene therapy increases factor levels in most, but not all, patients, sometimes even to normal levels. This can help reduce or eliminate bleeding and the need for regular factor infusions. While curative levels may be achieved by some, for others, the severity of hemophilia may be improved.
If gene therapy is not successful, can I return to my prior treatment regimen?
If gene therapy for hemophilia is not successful, you will be able to safely return to your prior treatment regimen or another standard of care treatment.
Will I still need to use other treatments for hemophilia?
t is possible that you may not need to use regular prophylaxis or factor replacement therapy once your factor levels reach a level where most bleeds would stop. The majority of people in clinical trials did not need to resume prophylaxis or take treatment for bleeding events in clinical trials.
It is recommended that you continue to work closely with your healthcare team and follow their recommendations for managing your hemophilia. In some cases, such as bleeding, trauma, and surgeries, additional treatment may still be necessary.
Will gene therapy heal my existing joint damage?
Gene therapy is unlikely to reverse existing structural joint damage, but may reduce other joint symptoms.
How will my quality of life be affected by gene therapy?
Gene therapy for hemophilia has the potential to improve a patient’s quality of life. Many, but not all, patients who have undergone gene therapy report increased freedom and improved ability to engage in physical activities without fear of bleeding.
With successful gene therapy for hemophilia B, most patients no longer require regular prophylaxis and experience a significant reduction in bleeding episodes.
What will happen in the event of a bleed or injury or if I need surgery?
The need for treatment following a bleed, injury, or because of surgery will depend on how much factor your body is producing. Each person’s response to gene therapy is different, and impossible to predict. There is also no guarantee that every bleed or injury will have the same treatment needs. This should be discussed with your health care team. In most cases, you are advised to treat a bleed with usual replacement therapy products and record all details.
Can the effects of gene therapy be passed on to my future children?
Gene therapy for hemophilia provides a functional copy of the factor IX (9) gene to the liver. Gene therapy does not change the DNA in your reproductive cells and therefore, hemophilia can still be passed on to future children. This means that if a person with hemophilia receives gene therapy, their children will not inherit the working gene. Gene therapy only helps the person who receives it, not their future children.
Will gene therapy impact my ability to have children?
Men: No, gene therapy will not affect your ability to have children. However, the vector may be present in semen (as it is released from the body) for a varying period of time after receiving gene therapy. Although there is very little risk that it affects semen, it is recommended that men use contraceptive measures to prevent pregnancies until the vector is no longer present (i.e., 6 to 12 months).
Women: No data are available to recommend the duration of contraceptive measures in women of childbearing potential. While women are eligible for gene therapy, it is not recommended in women of childbearing potential. Gene therapy is also not recommended in women who are pregnant or breastfeeding.
What is the World Federation of Hemophilia Gene Therapy Registry (WFH GTR)?
The WFH GTR is a prospective, observational, and longitudinal registry designed to collect long-term data on people with hemophilia who receive gene therapy globally.9 Participation in the registry after receiving gene therapy is voluntary but recommended. This registry is the best way to capture long-term data on gene therapy and ensure the safety of gene therapy for patients.
WWhere can I find more information on gene therapy or gene therapy for hemophilia?
Society of Gene and Cell Therapy
A Guide for Patients and Caregivers. All About Hemophilia
Gene Therapy. Canadian Hemophilia Society.
EHC Gene Therapy A Practical Guide Book
ISTH: Gene Therapy
National Hemophilia Foundation. Frequently Asked
Questions
WFH Gene Therapy Registry
The Hemophilia Gene Therapy Patient Journey: Questions
and Answers for Shared Decision-Making.
Wang M, Negrier C, Driessler F, Goodman C, Skinner MW
WFH Shared Decision Making Tool: GENE THERAPY Fact Sheet
DownloadWhat are hemostatic rebalancing therapies?
Hemostatic rebalancing therapies belong to the non-factor therapy class and can be used to treat hemophilia A and hemophilia B, with and without inhibitors.
To understand how these medications work, we need to know more about how a blood clot forms. When we are injured, our body’s natural system stops the bleeding through activation of the clotting factors already present in the blood and thrombin generation. People with hemophilia have no or low levels of clotting factor VIII (hemophilia A), or factor IX (hemophilia B) and low thrombin generation, so their blood cannot effectively clot. In other words, in people with hemophilia, there is an imbalance between the factors that help the blood clot (clotting factors) and the factors that prevent clotting (anticoagulation factors).
Rebalancing therapies help to restore this balance by decreasing the anticoagulation factor levels, which helps prevent bleeding events and restore normal blood clotting
What are the different types of hemostatic rebalancing therapies?
As of April 2023, one hemostatic rebalancing therapy, concizumab (ALHEMO), has been approved for use in Canada for people with hemophilia B with inhibitors.2 Other rebalancing therapies are in phase 3 clinical trials1, including fitusiran3 and marstacimab.
Concizumab and marstacimab are humanized monoclonal antibodies that target a natural anticoagulation factor called tissue factor pathway inhibitor (TFPI). By inhibiting TFPI (also known as anti-TFPI) these medications increase thrombin generation and blood clotting in people with hemophilia A and B, with and without inhibitors.
Fitusiran works differently. Fitusiran is a small interfering RNA (siRNA) that inhibits the production of another coagulant, antithrombin. This increases thrombin generation and results in increased blood clotting in people with hemophilia A and B, with and without inhibitors.
How is the mechanism of action of hemostatic rebalancing therapies different from other treatments for hemophilia?
The main treatment types for hemophilia are clotting factor replacement therapy (standard half-life (SHL) and extended half-life (EHL)), bispecific antibodies, re-balancing agents, and gene therapy. All these treatments help the blood clot more efficiently, but they all work in different ways.
Clotting factor replacement therapy provides a short-term increase in factor levels by injecting the needed clotting factor protein directly into the blood of a person with hemophilia.
Bispecific antibodies are Y-shaped proteins that act as a bridge between factor IXa and factor X, which helps the blood to clot more efficiently. This antibody bridge mimics the function of the missing activated factor VIII (i.e., factor VIIIa-mimetic). FA C T S H E E T Hemostatic Rebalancing Therapy
(continued)
Rebalancing therapies restore the disrupted balance between the levels of anticoagulation (i.e., anti-clotting) factors and clotting factors in the blood, thereby improving blood clotting.
Gene therapy introduces a working copy of the gene that provides instructions for missing the clotting factor protein. Once the gene is introduced, the body can produce the missing protein and maintain adequate clotting factor levels, on its own, for an extended time.
Who is eligible to use rebalancing agents?
Hemostatic rebalancing therapies are being developed for people with hemophilia A and B, including those with inhibitors. Concizumab is currently approved in Canada for use in people aged 12 years and older with hemophilia B, who have inhibitors and require prophylaxis.
How are prophylactic rebalancing therapies administered?
Rebalancing therapies are administered by subcutaneous injection under the skin. The injection takes approximately one minute and can be done at home or at a clinic.
What is the treatment frequency for prophylaxis with hemostatic rebalancing therapies?
Prophylactic treatment with hemostatic rebalancing therapies is administered on a daily to bi-monthly basis and is determined by the medication type. Concizumab is the only approved rebalancing therapy and is administered daily.
Can hemostatic rebalancing therapies be used in combination with other hemophilia treatments?
In some cases, additional treatments (clotting factor replacement therapies or bypassing agents) may be required. It is important to discuss with your healthcare team how to treat breakthrough bleeding as the dosing of other therapies may need to be adjusted.
How will clotting factor levels be affected?
Hemostatic rebalancing therapies will not change the clotting factor levels. Studies show that the effect of hemostatic rebalancing therapies is similar to having mild hemophilia.
How will hemostatic rebalancing therapies affect my annual bleed rate?
Any form of regular prophylactic treatment is likely to reduce your annual bleed rate. In clinical trials for concizumab, people with hemophilia A or B with inhibitors had very few bleeding events and averaged less than 2 bleeds per year during the first year following treatment,2 and people with hemophilia A without inhibitors had approximately 5 bleeds per year during the first year following treatment. SDMWFH SHARED DECISION
What are the possible side effects of hemostatic rebalancing therapies?
The most common side effects to concizumab are reactions related to the injection.2 Other reported side effects include joint pain (arthralgia), upper respiratory tract infection, and headache.
Are there any known serious side effects?
Thromboembolic events (blood clots in the veins or arteries), which can be dangerous and life threatening have been reported in patients taking concizumab and fitusiran (not yet approved). Therefore, it is important to discuss with your healthcare team how you will treat bleeding, injury, and/or surgery while taking hemostatic rebalancing therapies.
How often will you need follow up and monitoring with hemostatic rebalancing therapies?
AAs with all hemophilia treatment classes, regular monitoring by your health care team is recommended. Clinical review should be conducted every 6 months and as needed.
What will happen in the event of a bleed, injury, or surgery?
In the event of a bleed, injury, or planned surgical procedure, additional therapies may be required. The use of on-demand bypassing agents should be discussed with your health care team.
WFH Shared Decision Making Tool: HEMOSTATIC REBALANCING THERAPY Fact Sheet
DownloadWhat are bispecific antibody therapies?
Bispecific antibody therapies belong to the non-factor replacement therapy class and are used to treat hemophilia A.
Antibodies are Y-shaped proteins that can selectively bind to other proteins. Bispecific antibodies can bind to two different proteins at the same time. In hemophilia A, the antibody acts as a bridge between two important proteins in the body, factor IXa (9a) and factor X (10), which helps the blood clot more efficiently: this mimics the function of the missing factor VIII (8), and therefore, these therapies are also referred to as factor VIII(a)-mimetics.
What are the different types of bispecific antibody therapy?
One bispecific antibody therapy, emicizumab (HEMLIBRA), a factor VIIIa mimetic, has been approved for the treatment of hemophilia A.1 Mim8 is another factor VIIIa mimetic in phase 3 clinical trials.
How is the mechanism of action of bispecific antibodies different from other treatments for hemophilia?
The main treatment types for hemophilia are clotting factor replacement therapy (standard half-life (SHL) and extended half-life (EHL)), bispecific antibodies, re-balancing agents, and gene therapy. All these treatments help the blood clot more efficiently, but they all work in different ways.
Clotting factor replacement therapy provides a short-term increase in factor levels by injecting the needed clotting factor protein directly into the blood of a person with hemophilia.
Bispecific antibodies are Y-shaped proteins that act as a bridge between factor IXa and factor X, which helps the blood to clot more efficiently. This antibody bridge mimics the function of the missing activated factor VIII (i.e., factor VIIIa-mimetic).
Rebalancing therapies restore the disrupted balance between the levels of anticoagulation (i.e., anti-clotting) factors and clotting factors in the blood, thereby improving blood clotting.
Gene therapy introduces a working copy of the gene that provides instructions for missing the clotting factor protein. Once the gene is introduced, the body can produce the missing protein and maintain adequate clotting factor levels, on its own, for an extended time.
Who is eligible to use bispecific antibodies?
Bispecific antibodies work by mimicking the effects of activated factor VIII and are therefore only available for people with hemophilia A. Emicizumab is approved for use in people with factor VIII inhibitors and people without inhibitors who have severe disease (FVIII activity <1%) or moderate disease (FVIII activity between 1 and 5%) with severe bleeding phenotype.1,2 Emicizumab can be used in all age groups (newborn and older).
How are prophylactic bispecific antibody therapies administered?
Bispecific antibody therapies are administered by subcutaneous injection directly under the skin; there is no need to find a vein. The injection takes approximately one minute and can be done at home or at a clinic.
What is the treatment frequency for prophylaxis with bispecific antibody therapies?
Prophylactic treatment with bispecific antibody therapies (specifically emicizumab) is administered every 1, 2, or 4 weeks depending on your personal preference.1 There is an initial loading dose period (4 weeks) with weekly treatment.
Can bispecific antibody therapies be used in combination with other hemophilia treatments?
In some cases, additional therapies (clotting factor replacement therapies or bypassing agents) may be required, especially during traumatic breakthrough bleeding or surgical procedures. This should be discussed with your healthcare team.
How will clotting factor levels be affected?
Bispecific antibodies will not change the clotting factor levels. Studies show that the effect of factor VIIIa-mimetic therapies is similar to having mild hemophilia.
How will bispecific antibody therapies affect my annual bleed rate?
Any form of regular prophylactic treatment is likely to reduce your annual bleed rate. Clinical trials for emicizumab reported a median annual bleed rate of 1.5 for patients taking 1.5 mg/kg every week and 1.3 for patients taking 3 mg/kg every two weeks; 55.6% and 60% patients reported zero bleeds.
What are the possible side effects of bispecific antibody therapies?
The most common side effects reported for emicizumab include injection site reactions, headache, and joint pain (arthralgia), which occured in about 1 in 10 patients.
Are there any known serious side effects or long-term risks?
No major safety concerns with emicizumab have been detected when used in hemophilia A without inhibitors. However, in people with inhibitors, there is a risk of severe and potentially life-threatening thromboembolic events (blood clots in the veins or arteries) when used in combination with an activated prothrombin complex concentrate.
How often will you need follow up and monitoring with bispecific antibody therapies?
As with all hemophilia treatment classes, regular monitoring by your health care team is recommended. Clinical review should be conducted annually and as needed.
What will happen in the event of a bleed, injury or surgery?
In the event of a bleed, injury, or planned surgical procedure, additional treatments may be required. This should be discussed with your health care team.
WFH Shared Decision Making Tool: BISPECIFIC ANTIBODY THERAPY Fact Sheet
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