Novel Therapies

The standard of care for hemophilia is life-long prophylaxis with replacement clotting factor concentrates (CFCs) starting as early as the first year of life. Access to these products is restricted in many countries. In countries where access to factor concentrates is not an issue, the frequent infusions are a significant burden on people with hemophilia and on healthcare systems.

A key limitation of factor replacement products is the immediate rise in factor levels after an infusion followed by a drop to low levels before the next infusion (the saw-tooth response, see figure below). The lack of stable factor levels results in a decrease in ability to form clots and therefore to prevent and stop bleeds (hemostasis), which can lead to bleeds and joint damage between infusions.

Replacement clotting factor concentrates (CFCs), including extended half-life (EHL) concentrates,
are effective at raising but not stabilizing factor levels and hemostatic ability.

Inhibitors are a serious potential complication of hemophilia caused by an immune response to CFCs that inhibit the effectiveness of replacement factor to treat and prevent bleeds. While some treatment options do exist for inhibitors, the challenges of managing hemophilia in the presence of inhibitors also contributed to the interest in developing novel therapies to treat bleeding disorders.

Updated November 2019

Non-factor replacement products are innovative treatment options for hemophilia that aim to rebalance hemostasis without the need for replacing the clotting factor that is missing. They target different points in the coagulation cascade, other than simply replacing the missing factor VIII (hemophilia A) or factor IX (hemophilia B). One non-factor replacement product has been approved in multiple countries, a bispecific antibody that can replace factor VIII in the clotting cascade. It is available for people with hemophilia A with and without inhibitors.

Gene therapy is a promising treatment option for hemophilia. Instead of using factor concentrates to raise factor levels and prevent bleeds, hematologists may be able to use gene therapy to provide the individual with a defective gene with a healthy copy. This means that an individual’s body could then produce enough clotting factor on its own to prevent bleeds and reduce the need for factor infusion. No gene therapies for hemophilia are approved yet, although some are nearing completion of phase 3 clinical trials.

Updated November 2019

Overview

The hemostatic balance is a fine balance between too much clotting (thrombosis) and not enough clotting (bleeding). In hemophilia, an essential clotting factor is lacking, and the hemostatic balance is tipped toward too much bleeding. The goal of non-factor replacement products is to prevent bleeds by raising hemostatic potential (how likely the blood is to clot if a blood vessel is injured), rather than by raising factor levels.

Figure adapted, with permission, from Novel approaches to haemophilia therapy: successes and challenges. Arruda VR, Doshi BS, and Samelson-Jones BJ, Blood 2017;130(21):2251-2256.

The goal of non-factor replacement products is different to the goal of gene therapy, which attempts to achieve stable factor levels by getting the body to produce the clotting factor that is missing. Ideally, non-factor replacement therapies are administered at a dose that gives rise to a very stable hemostatic level (to prevent bleeds), even though it does not involve a change in factor level.

The non-factor replacement product, emicizumab, has been approved for people with hemophilia A with and without inhibitors, and other products in this class are currently in clinical trials for similar indications. The treatment of people with hemophilia and inhibitors has been the greatest unmet need in hemophilia treatment products, with bypassing agents constituting the mainstay of this treatment. This new class of products that rebalance hemostasis in people with inhibitors provides a promising alternative. While emicizumab is the only non-factor replacement product that has been approved at this time, others currently in clinical trials include anti-TFPI antibodies and fitusiran, a small inhibitory RNA that can block anti-thrombin.

Factor VIII substitution therapy

Factor VIII substitution therapy is a type of non-factor replacement hemophilia product that takes the place of factor VIII in the series of reactions that leads to clotting (coagulation cascade). Emicizumab is a bispecific monoclonal antibody, which means it has been manufactured in a laboratory and designed to recognise and bind to 2 different targets.

Emicizumab is a bispecific antibody that binds to activated factor IX (FIXa) on one arm and to factor X (FX) on the other arm. By doing so it carries out the natural function of activated factor VIII (FVIIIa, missing or defective in hemophilia A) that is needed for effective clotting. Since it does not replace the function of missing factor IX it cannot be used to treat hemophilia B.

Factor VIII substitution therapy with emicizumab is the first non-factor replacement product to be approved in a number of countries for the prophylactic treatment of people of all ages with hemophilia A with or without inhibitors. Some countries have not approved the use of emicizumab while other countries have not approved this entire indication. Consult your local regulatory agency for the latest details in your region.

Although emicizumab is highly effective at preventing bleeds, it cannot be used to treat bleeds. Healthcare professionals experienced in the treatment of hemophilia must determine the appropriate dosing of agents, such as bypassing agents and factor VIII, to treat different kinds of bleeds in someone who is taking emicizumab. People with hemophilia should carefully follow the urgent action plan they establish with their hemophilia specialist to treat breakthrough bleeds. A few people using specific combinations of high doses of activated prothrombin complex concentrates (aPCCs) and emicizumab have experienced serious and potentially life-threatening side effects including thrombotic microangiopathy and thromboembolism. Hemophilia specialists should avoid using aPCCs and emicizumab at the same time unless no other treatment options, such as factor VIIa, are available.

Emicizumab interferes with certain laboratory tests that measure how well a person’s blood clots, leading to false readings. Before undergoing laboratory tests that measure blood clotting, people with hemophilia should inform any healthcare professionals that they are taking emicizumab. It is important for them to know so that they do not misinterpret the results of the tests, which could affect management decisions.

To learn more about the specific tests that are impacted, please consult the Non-factor Replacement Hemophilia Therapies eLearning module.

Releasing the brakes on hemostasis

The body has several processes in place to prevent coagulation running longer than necessary or starting when it should not, to avoid too much blood clotting. One of these mechanisms includes natural anticoagulants that act as brakes to limit clotting.

Research is ongoing into innovative non-factor replacement products that target a number of natural anticoagulants, including antithrombin (AT) and tissue factor pathway inhibitor (TFPI), and release the brakes on hemostasis, which could tip the balance back towards more clotting. Research is exploring the impact of reducing or blocking these, and other, anticoagulants to restore hemostatic balance.

Removing the brakes on coagulation, by using non-factor replacement products that block or remove anticoagulants, has shown potential for rebalancing hemostasis in hemophilia without replacing the missing clotting factor.

Impact on people with hemophilia

The potential of non-factor replacement products is to rebalance hemostasis, in people with hemophilia A or B, without the need for infusions of clotting factor concentrates (CFCs). While non-factor replacement products reduce the severity of hemophilia, these products do not provide a cure and occasional on-demand treatment for breakthrough bleeds may be required.

People with hemophilia who are taking a non-factor replacement product should:

Non-factor replacement hemophilia therapies are used strictly prophylactically to prevent bleeds, making them fundamentally different from clotting factor concentrates (CFCs) that can also be used to treat a suspected bleed. The “if in doubt, treat” approach must not be applied to these products. The products are administered subcutaneously and may not act quickly enough to promote blood clotting, and the efficacy and safety of taking high doses of these products is unknown. They are not to be administered intravenously. Combining them with different products that promote coagulation may, in some cases, even tip the balance in their body too far towards more clotting (thrombosis).

Non-factor replacement products are very new hemophilia treatment options and their full safety profile is not yet known. They do not have decades of safety history like factor replacement products and it will be important to continue to gather information about potential safety issues as non-factor replacement products gain widespread use. Only one non-factor replacement product has been approved for use in people with hemophilia A, emicizumab. Others are in clinical trials.

Updated August 2020

Overview

Gene therapy is a promising experimental technique that uses genes rather than drugs or surgery to treat genetic diseases, including hemophilia. The most common form of gene therapy involves introducing a healthy copy of a mutated (altered) gene to restore normal function.

Hemophilia A and B are simply due to a defect in a single gene (and therefore its protein product) and are ideally suited to gene therapy. Decades of treatment infusing replacement factor VIII or factor IX have shown that a wide range of factor levels can promote hemostasis (the cessation of bleeding) and even small increases in factor VIII and factor IX substantially improve the symptoms of people with severe hemophilia.

The ultimate goal of gene therapy for hemophilia is a one-time administration that achieves a stable increase in factor levels over long periods of time such that no bleeds occur and regular factor infusions are no longer required.

Gene therapy techniques

Researchers have harnessed the natural ability of viruses to infect cells to deliver gene therapy. Carefully selected viruses are modified by replacing viral genetic material with the human gene of interest. These vehicles or genetically engineered vectors, therefore, do not cause disease.

Adeno-associated virus (AAV) and lentivirus have shown the greatest promise in human gene therapy trials. AAV vectors in particular have emerged as a safe and efficient tool for gene delivery for hemophilia. Gene transfer can be achieved by directly injecting vector containing the new gene into the body. The vectors selected for hemophilia gene therapy target the liver, which is where factor VIII and factor IX are normally produced by the body.

Gene transfer can be achieved by directly injecting vector containing the new gene into the body. Individual cells take up the vector and transport (via vesicles—small enclosed structures in the cell) the new gene to their nucleus. Here, the information stored in genes is converted into instructions for making proteins through a tightly regulated process called gene expression.

Current gene therapy techniques do not modify a person’s existing genetic sequence. The new gene is simply used by the cell that also contains the original defective gene. Current trials for hemophilia use an approach that targets non-sex cells, not eggs or sperm cells. This means that the effects of gene therapy on the person receiving the treatment will not be passed onto subsequent generations. People with hemophilia who receive this kind of gene therapy should achieve stable factor levels, avoiding the saw-tooth patterns seen with infusions of clotting factor concentrates (CFCs), but they can still pass the gene that causes hemophilia on to their children.

Gene therapy techniques are relatively new and some of the risks may be unpredictable. Researchers, institutions, and public authorities that regulate the quality and efficacy of medical products are working to ensure that gene therapy research is as safe as possible. Current techniques also cannot accurately predict the level of factor protein that will be expressed, if at all, from the new gene, or how long that factor expression level will last. While several advanced clinical trials of gene therapy in hemophilia A and B are ongoing, no hemophilia gene therapy product has been approved by a regulatory agency, at the time of publication of this text.

Impact on people with hemophilia

While gene therapy has the potential to improve the health and quality of life of people with hemophilia, researchers and clinicians are still gathering data on the long-term safety and effectiveness of this treatment approach. Although a specific threshold level of factor produced has not been defined for gene therapy success, even small increases in factor levels can substantially improve a person’s quality of life. Naturally, people with hemophilia, and the people who care for them, would like gene therapy to deliver normal, or near normal, levels of factor VIII or factor IX.

Gene therapy is a significant treatment decision and not everyone who might like to participate in a clinical trial will meet the strict eligibility criteria. Not being accepted into a clinical trial can have important psychosocial consequences. Psychosocial issues related to the life-long burden of hemophilia and the damage done to the body, especially the joints, prior to gene therapy remain even if a person is eligible for gene therapy and if their gene therapy is successful.

Continued comprehensive care and engagement with the bleeding disorders community remains important for people with hemophilia following gene therapy. Life-long follow-up is crucial to understanding the real promise and impact of gene therapy and to ensuring the optimal management of the person’s overall health.

Summary

Gene therapy for hemophilia is an evolving area of research. The type of gene therapy for hemophilia that is closest to approval is somatic, which means that the person receiving the treatment can still pass hemophilia on to their children. Gene therapy remains an experimental technique and much more research into its safety and efficacy is required. No hemophilia gene therapy product has been approved by a regulatory agency, at the time of publication of this text.

People with hemophilia should follow-up with their healthcare provider to further discuss gene therapy and other novel therapies, as these are also advancing.

For more information, please consult the Gene Therapy for Hemophilia eLearning module.

Updated November 2019

While one factor VIII substitution product is approved for use in people with hemophilia A, other innovative non-factor replacement products are currently being evaluated in clinical trials. People with hemophilia should consult their primary hematologist if they wish to start using emicizumab or other non-factor replacement products if they are approved by regulators and available. Non-factor replacement products should only be used precisely as described by hemophilia specialists.

The bleeding disorders community has decades of experience with the infusion of replacement clotting factor and the safety and efficacy of clotting factor concentrates (CFCs) are well understood. Unlike CFCs, which are largely interchangeable with the exception of differences in half-lives, these non-factor replacement therapies have unique mechanisms of action. They are used prophylactically only, not for treating bleeds. Any breakthrough bleeds must be treated with CFCs or bypassing agents, following very specific rules.

For more information, please consult the Non-factor Replacement Hemophilia Therapies eLearning module.

Updated November 2019