© 2024 World Federation of Hemophilia
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.
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.
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.
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.
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 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.
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.
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.
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.
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.