Treating a person with an inhibitor, especially one whose immune system is mounting a potent and sustained immune response to replacement therapy, is often a very complicated and challenging endeavor. The patient and the healthcare team are often compelled to approach the inhibitor on two tracks by managing the bleeding episode itself and tackling the inhibitor response itself. The inhibitor response can take months or even years to resolve.
Best Case Scenario – A Low Responding Inhibitor
For people who have low responding inhibitor levels, continued therapy with factor replacement is often effective. In many instances this approach is enough to control both minor and more severe bleeds. To overcome the presence of inhibitors in these cases, a physician may opt to increase the size and frequency of factor dosing.
It’s Complicated – High Responding Inhibitors
A patient’s situation becomes much more complicated in cases of a high responding inhibitors as even large doses of infused factor are often rendered ineffectual by the sheer potency of the antibody response.
In these cases, treatment is based on several things including the type of hemophilia and the nature of the bleed. During a life or limb-threatening bleeding episode, physicians can remove antibodies from the body using a process called plasmapheresis, which lowers the level of antibodies to allow treatment with factor concentrate to treat the bleed. However, this is only a temporary solution, as within a few days the body will produce large amounts of new antibodies.
For the person with a high responding inhibitor, there are therapies that can effectively treat bleeds by circumventing the need to replace FVIII or FIX.
Several of these products, commonly referred to as bypassing agents (BPAs), include activated prothrombin complex concentrate (aPCC) and recombinant activated factor VIIa concentrates These bypassing products contain other factors that can stimulate the formation of a clot and stop bleeding.
FEIBA® (Takeda) is a human plasma derived product that contains activated factors IIa, VIIa, IXa and Xa that are, in combination, effective at promoting hemostasis. The product is treated with vapor steam heat and nanofiltration to eliminate viruses.
There are also currently two FDA-approved recombinant factor VIIa (rFVIIa) products that are manufactured with DNA technology:
NovoSeven® RT (Novo Nordisk), was first approved in 1999 for use in patients with inhibitors to factor VIII or IX, has been shown to be effective in the treatment of both minor and life-threatening bleeding. Multiple doses can be required to stop bleeding depending on the situation.
Sevenfact® (LFB) was approved in the Spring of 2020 for the treatment and control of bleeding episodes occurring in adults and adolescents 12 years of age and older with hemophilia A or B with inhibitors. Sevenfact is unique in that its active ingredient, a recombinant analog of the human FVII protein, is expressed in the mammary gland of genetically engineered rabbits.
Another therapy that does not function by FVIII or IX replacement is Hemlibra® (Genentech), a novel laboratory-engineered protein that works by performing a key function in the clotting cascade – bridging activated factor and factor X – that is normally carried out by the FVIII protein. It is approved specifically for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children with hemophilia A with factor VIII inhibitors. While existing factor therapies are delivered intravenously, this product is unique in that it is administered subcutaneously via an injection just under the skin.
It is important to note that the proper diagnosis and treatment of inhibitors is complex. There are many variables affecting choice of therapies and the timing of treatment as no two patients’ circumstances or clinical scenarios are identical. Decisions relevant to inhibitor treatment should be reached in close coordination with the patient and the hemophilia treatment center care team.
For expert guidance and recommendations on treatment you can refer to MASAC Recommendations Concerning Products Licensed for the Treatment of Hemophilia and Other Bleeding Disorders, the council’s enduring and most broad-based treatment document, which includes descriptions of, and recommendations for, the use of all therapies currently approved by the U.S. Food and Drug Administration (FDA) to treat bleeding disorders. This document is accompanied by a list of these therapies, organized by bleeding disorder type. NOTE: The list includes hyperlinks to the FDA webpage dedicated to each approved product. View Products Licensed in the U.S.
Copyright National Hemophilia Foundation
Last Updated March 2021