Acute health events in adult patients with genetic disorders: The Marshfield Epidemiologic Study Area
Your Guide To Treatment Options For Hemophilia B
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.
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.
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:
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:
Fresh frozen plasma is a blood product that comes from human donors and is used in various medical circumstances. It naturally contains clotting factors (including factor IX), plasma proteins, electrolytes, and other nutrients.
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, most people can have an average life span and a good quality of life.
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:
What Is Factor X?
Factor X is a protein in your blood that helps with clotting. Blood clotting is important because that is what helps you to stop bleeding when you get a cut or bruise. Factor X deficiency is a genetic disorder when you are born without this protein. You can also develop the condition later in life.
Other names for factor X deficiency include:
Factor X deficiency is a condition that leads to a bleeding disorder. The symptoms of factor X deficiency include:
The severity of factor X deficiency varies from person to person. Your body still produces 40% or more of the normal amount of factor X in mild cases. You may have no symptoms or only very minor ones.
Your body produces 10% to 40% of the usual amount of factor X if you have a moderate case of the deficiency. It is considered severe if you have less than 10% of the normal amount of factor X.
Factor X deficiency is a rare disorder. It only occurs in 1 out of every 500,000 to 1 million people. People of any gender have an equal chance of getting it.
Genes. Some people inherit factor X deficiency. This is called congenital factor X deficiency.
Congenital factor X deficiency is caused by a mutation to the F10 gene. This gene is a protein-coding gene that controls the process that creates factor X in your blood. Your body produces less of the factor when a mutation occurs. This leads to difficulty with blood clotting.
Genetic factor X deficiency means that both of your parents have at least one copy of the mutated gene and have both passed one on to you. They are just carriers if each parent has only one copy of the gene. This means they would not have any symptoms.
Certain conditions. Acquired factor X deficiency is when you have not inherited it. Causes of acquired factor X deficiency include:
Doctors diagnose factor X deficiency in the following ways:
Cogadex. Doctors typically treat excess bleeding when it happens. The main treatment for a bleeding episode is a drug called Cogadex. It is a version of factor X that people with factor X deficiency can take to either prevent a bleeding episode or stop bleeding after it has already started.
Your doctor may also recommend this drug if you are going to have surgery and you have factor X deficiency.
PPC. Another option for treatment is prothrombin plasma concentrate (PPC). This product contains factor X along with factors II, VII, and IX. But most people only lack one of these clotting factors. So this treatment may be less ideal than Cogadex. Using PPC may also increase the risk of blood clots due to excess amounts of the wrong clotting factor.
Plasma. Treatment with fresh frozen plasma is another option for a bleeding episode. There are some minor risks, like viral infections. However, doctors screen blood to lower this risk.
Antifibrinolytic agents. Your doctor may recommend other treatments, like nosebleed powder or antifibrinolytic agents for mild symptoms. These are drugs that help your blood to clot.
Your doctor may recommend a supplement if your factor X deficiency is caused by a lack of vitamin K. They may recommend genetic testing or counseling before you decide to have children if factor X deficiency runs in your family.
People with severe clotting factor deficiencies should generally avoid high-impact activities where the potential for injury is greater.
There are 12 other factors in addition to X that are important in blood clotting. All of them have Roman numerals and are numbered I to XIII. Each one represents a different protein involved at some stage of blood clotting or coagulation.
You can have a deficiency in many of the other 12 factors. Each one has a different name. But the symptoms may be similar. All of the factor deficiencies cause excessive bleeding.
U.S. FDA Approves Pfizer's HYMPAVZI™ (marstacimab-hncq) For The Treatment Of Adults And Adolescents With Hemophilia A Or B Without Inhibitors
"HYMPAVZI is Pfizer's second hemophilia treatment to receive FDA approval this year and is the latest meaningful scientific advancement in our more than 40-year commitment to improve care for people living with hemophilia," said Aamir Malik, Chief U.S. Commercial Officer and Executive Vice President, Pfizer. "We look forward to launching this latest medical breakthrough and to now offer three distinct classes of hemophilia medicines – an anti-TFPI, gene therapy, and recombinant factor treatments – that can meet the unique treatment needs of a wide range of patients."
Results from the Phase 3 BASIS trial (NCT03938792) supported the approval of HYMPAVZI in the U.S. In adults and adolescents with hemophilia A or B without inhibitors. In the study, HYMPAVZI reduced the annualized bleeding rate (ABR) for treated bleeds by 35% and 92% after a 12-month active treatment period compared to routine prophylaxis (RP) and on-demand (OD) treatment, respectively, in patients with hemophilia A or B without inhibitors. The safety profile for HYMPAVZI was consistent with Phase 1/2 results. The most commonly reported adverse reactions (≥3% of patients) in the study were injection site reactions, headache, and pruritus.
"The hemophilia community continually seeks advancements in care that can improve quality of life for our community members," said Phil Gattone, President and CEO, National Bleeding Disorders Foundation. "We greatly appreciate Pfizer's innovative efforts in developing this novel treatment option that addresses some of the ongoing challenges faced by people with hemophilia A and B. The availability of this therapy represents a powerful step forward in advancing care for more individuals and families in the bleeding disorders community."
The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion for marstacimab for the routine prophylaxis of bleeding episodes in adults and adolescents 12 years and older with severe hemophilia A without FVIII inhibitors, or severe hemophilia B without FIX inhibitors. In addition to HYMPAVZI, Pfizer recently received regulatory approvals for its hemophilia B gene therapy BEQVEZ™ (fidanacogene elaparvovec) in the U.S., EU, and Canada, and announced positive results from a Phase 3 program investigating its hemophilia A gene therapy (giroctocogene fitelparvovec).
About HYMPAVZI (marstacimab-hncq)
Discovered by Pfizer scientists, HYMPAVZI is a rebalancing agent that targets the Kunitz 2 domain of tissue factor pathway inhibitor (TFPI), a natural anticoagulation protein that functions to prevent the formation of blood clots and restore hemostasis.
HYMPAVZI is approved in the U.S. For routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and pediatric patients 12 years of age and older with hemophilia A (congenital factor VIII deficiency) without factor VIII inhibitors, or hemophilia B (congenital factor IX deficiency) without factor IX inhibitors.
About the BASIS study
The pivotal BASIS study is a global Phase 3, open-label, multicenter study to evaluate the efficacy and safety of HYMPAVZI in adolescent and adult participants ages 12 to <75 years with severe hemophilia A (defined as FVIII <1%) or moderately severe to severe hemophilia B (defined as FIX activity ≤2%) with or without inhibitors.
The FDA approval is based on results from the BASIS study that included 116 people living with hemophilia without inhibitors who were treated with HYMPAVZI during a 12-month active treatment period (ATP) versus an RP and OD intravenous regimen with FVIII or FIX, administered as part of usual care in a six-month observational period. During the ATP, participants received prophylaxis (a 300 mg subcutaneous loading dose of HYMPAVZI, followed by 150 mg subcutaneously once weekly) with potential for dose escalation to 300 mg once weekly.
HYMPAVZI reduced the ABR for treated bleeds by 35% and 92% after a 12-month ATP compared to RP and OD treatment, respectively, in patients with hemophilia A or B without inhibitors. In the OD group, superiority (p<0.0001) of HYMPAVZI was demonstrated across all bleeding-related secondary endpoints – spontaneous bleeds, joint bleeds, target joint bleeds, and total bleeds. In the RP group, HYMPAVZI demonstrated non-inferiority to these secondary efficacy endpoints.
The safety profile for HYMPAVZI was consistent with Phase 1/2 results and treatment was generally well-tolerated. The most commonly reported adverse reactions (≥3% of patients) were injection site reactions, headache, and pruritus.
The inhibitor cohort of the BASIS trial is ongoing, with results expected in the third quarter of 2025. Pfizer is also conducting BASIS KIDS, an open-label study investigating the safety and efficacy of marstacimab in children 1 to <18 years of age with severe hemophilia A or moderately severe to severe hemophilia B with or without inhibitors.
About Hemophilia
Hemophilia is a family of rare genetic blood diseases caused by a clotting factor deficiency (FVIII in hemophilia A, FIX in hemophilia B), which prevents normal blood clotting. Hemophilia is diagnosed in early childhood and impacts more than 800,000 people worldwide.1 The inability of the blood to clot properly can increase the risk of painful bleeding inside the joints, which can cause joint scarring and damage. People living with hemophilia can suffer permanent joint damage following repeated bleeding episodes.2,3
For decades, the most common treatment approach for hemophilia A and B has been factor replacement therapy, which replaces the missing clotting factors. Factor replacement therapies increase the amount of clotting factor in the body to levels that improve clotting, resulting in less bleeding.5,6
In a survey of people in the U.S. Receiving prophylaxis for hemophilia A or B, nearly one-third of those that receive treatment and have high compliance – defined as taking 75% or more of their prescribed infusions – stated that the time-consuming nature of prophylaxis was the most significant challenge of the regimen.7,8 Nearly 60% of those that took less than the prescribed number of infusions reported that the time commitment was the primary reason for missing infusions.
HYMPAVZI (marstacimab) U.S. Important Safety Information
Important: Before you start using HYMPAVZI, it is very important to talk to your healthcare provider about using factor VIII and factor IX products (products that help blood clot but work in a different way than HYMPAVZI). You may need to use factor VIII or factor IX medicines to treat episodes of breakthrough bleeding during treatment with HYMPAVZI. Carefully follow your healthcare provider's instructions regarding when to use factor VIII or factor IX medicines and the prescribed dose during your treatment with HYMPAVZI.
Before using HYMPAVZI, tell your healthcare provider about all of your medical conditions, including if you:
have a planned surgery. Your healthcare provider may stop treatment with HYMPAVZI before your surgery. Talk to your healthcare provider about when to stop using HYMPAVZI and when to start it again if you have a planned surgery.
have a severe short-term (acute) illness such as an infection or injury.
are pregnant or plan to become pregnant. HYMPAVZI may harm your unborn baby.
Females who are able to become pregnant:
Your healthcare provider will do a pregnancy test before you start your treatment with HYMPAVZI.
You should use effective birth control (contraception) during treatment with HYMPAVZI and for at least 2 months after the last dose of HYMPAVZI.
Tell your healthcare provider right away if you become pregnant or think that you may be pregnant during treatment with HYMPAVZI.
Tell your healthcare provider about all the medicines you take, including prescription medicines, over‑the‑counter medicines, vitamins, and herbal supplements.
What are the possible side effects of HYMPAVZI?
HYMPAVZI may cause serious side effects, including:
blood clots (thromboembolic events). HYMPAVZI may increase the risk for your blood to clot. Blood clots may form in blood vessels in your arm, leg, lung, or head and can be life‑threatening. Get medical help right away if you develop any of these signs or symptoms of blood clots:
swelling or pain in arms or legs
redness or discoloration in your arms or legs
shortness of breath
pain in chest or upper back
fast heart rate
cough up blood
feel faint
headache
numbness in your face
eye pain or swelling
trouble seeing
allergic reactions. Allergic reactions, including rash and itching have happened in people treated with HYMPAVZI. Stop using HYMPAVZI and get medical help right away if you develop any of the following symptoms of a severe allergic reaction:
swelling of your face, lips, mouth, or tongue
trouble breathing
wheezing
dizziness or fainting
fast heartbeat or pounding in your chest
sweating
The most common side effects of HYMPAVZI are injection site reactions (itching, swelling, hardening, redness, bruising, pain at the injection site), headache, and itching.
These are not all the possible side effects of HYMPAVZI. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
The full Prescribing Information can be found here. If it is not currently available via this link, it will be visible as soon as possible as we work to finalize the document. Please check back for the full information shortly.
About Pfizer: Breakthroughs That Change Patients' Lives
At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world's premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For 175 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at www.Pfizer.Com. In addition, to learn more, please visit us on www.Pfizer.Com and follow us on X at @Pfizer and @Pfizer_News, LinkedIn, YouTube and like us on Facebook at www.Facebook.Com/Pfizer/.
Category: Prescription Medicines
Disclosure notice
The information contained in this release is as of October 11, 2024. Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments.
This release contains forward-looking information about HYMPAVZI, an anti-tissue factor pathway inhibitor, and Pfizer's other hemophilia approved and investigational products, including their potential benefits, that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risks and uncertainties include, among other things, uncertainties regarding the commercial success of HYMPAVZI and Pfizer's other hemophilia products; the uncertainties inherent in research and development, including the ability to meet anticipated clinical endpoints, commencement and/or completion dates for our clinical trials, regulatory submission dates, regulatory approval dates and/or launch dates, as well as the possibility of unfavorable new clinical data and further analyses of existing clinical data; whether or when the inhibitor cohort of the BASIS trial will be successful; the risk that clinical trial data are subject to differing interpretations and assessments by regulatory authorities; whether regulatory authorities will be satisfied with the design of and results from our clinical studies; whether and when any applications may be filed with regulatory authorities in particular jurisdictions for HYMPAVZI or any other products or product candidates; whether and when any such applications that may be pending or filed for HYMPAVZI or any other products or product candidates may be approved by regulatory authorities, which will depend on myriad factors, including making a determination as to whether the product's benefits outweigh its known risks and determination of the product's efficacy and, if approved, whether HYMPAVZI or any such other products or product candidates will be commercially successful; decisions by regulatory authorities impacting labeling, manufacturing processes, safety and/or other matters that could affect the availability or commercial potential of HYMPAVZI or any such other products or product candidates; uncertainties regarding the impact of COVID-19 on our business, operations and financial results; and competitive developments.
A further description of risks and uncertainties can be found in Pfizer's Annual Report on Form 10-K for the fiscal year ended December 31, 2023 and in its subsequent reports on Form 10-Q, including in the sections thereof captioned "Risk Factors" and "Forward-Looking Information and Factors That May Affect Future Results", as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at www.Sec.Gov and www.Pfizer.Com.
1 World Federation of Hemophilia. World Federation of Hemophilia Global Report on the Annual Global Survey 2022. Https://www1.Wfh.Org/publications/files/pdf-2399.Pdf.2 Srivastava A, Santagostino E, Dougall A, et al. WFH guidelines for the management of hemophilia, 3rd Edition; 2020. Haemophilia. 26(S6), 1–158. Https://doi.Org/10.1111/hae.14046.3 Franchini M, Mannucci PM. Past, present and future of hemophilia: a narrative review. Orphanet J Rare Dis. 7, 24 (2012). Https://doi.Org/10.1186/1750-1172-7-24.4 Ohmori T, Mizukami H, Ozawa K, et al. New approaches to gene and cell therapy for hemophilia. J Thromb Haemost. 2015;13(Suppl 1): S133-142.5 Centers for Disease Control and Prevention. Hemophilia. Last Reviewed: April 2023. Https://www.Cdc.Gov/ncbddd/hemophilia/.6 Weyand AC, Pipe SW. New therapies for hemophilia. Blood. 2019;133(5):389–398. Doi: https://doi.Org/10.1182/blood-2018-08-872291.7 Thornburg CD, Duncan NA. Treatment adherence in hemophilia. Patient Prefer Adherence. 2017;11:1677-1686. Https://doi.Org/10.2147/PPA.S139851.8 Hacker MR, Geraghty S, Manco-Johnson M. Barriers to compliance with prophylaxis therapy in haemophilia. Haemophilia. 2001;7(4):392-6.
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