Bayer has a long history of research and development in the area of hemophilia. Hemophilia is a genetic defect and is inherited recessively on the X chromosome, so it primarily affects men. These patients lack a protein that among others causes the blood to clot as part of the natural wound-healing process. In hemophilia A, which affects 80-85 percent of patients with hemophilia, it is the blood clotting factor VIII that is lacking. Severe hemophilia is characterized by spontaneous bleeding into joints, muscles and various organs, even if there are no external injuries. This bleeding can lead to permanent disability or even death at any age.
Recombinant factor VIII
Modern therapies enable patients to lead a virtually normal, active life: the missing clotting factor is replaced by a 'recombinant factor', which is manufactured using genetically modified mammalian cells. When administered intravenously, the recombinant factor helps to stop acute bleeding at an early stage or may prevent it altogether by regular prophylaxis. The recombinant factor VIII developed by Bayer for treating hemophilia A was one of the first products of its kind. It was launched in 1993.
Prophylaxis which involves regular intravenous injections of clotting factors is currently the only effective treatment to prevent regular spontaneous bleeds and joint damage in patients with severe hemophilia. In some cases, these injections are necessary on an every other day basis from toddler age. Therefore, there is still a high medical need for better therapies.
Bayer research in the area of hemophilia concentrates on four different approaches:
- improving replacement treatment of clotting factors to decrease the frequency of injections,
- gene therapy to find a way of inducing the body’s own production of factor VIII,
- developing bypass approaches (in case of neutralizing antibodies to factor VIII) and
- inhibiting fibrinolysis to prevent breakdown of a clot once it is formed.
Improving replacement therapy
Improving replacement therapy for severe hemophilia A includes reducing the number of preventive injections needed. The aim is that the factor administered remains in the bloodstream for a longer period of time, and is eliminated slowly from the body (has a prolonged elimination half-life). One approach to achieve this is by site-specific pegylation, in which a large polyethylene glycol (PEG) molecule is attached at a well identified site on the recombinant factor VIII molecule. The pegylation leads to a slow down of the clearance of factor VIII in the body, thus prolonging the time the factor remains in circulation. A longer elimination time may allow decreasing the number of injections per week necessary for effective prophylaxis. For the patient, fewer injections could mean less stress, better adherence to regular prophylaxis and better quality of life. Half-life extension of clotting factors, however, may also be achieved by other means and Bayer scientists are working on additional innovative research platforms to further improve the effective circulation time of the molecule.
A complication of hemophilia A therapy in about 30 percent of previously untreated patients is the development of inhibitors, i.e. neutralizing antibodies, against factor VIII protein inhibiting its function. As a result, these patients are no longer responding to factor VIII substitution treatment and, thus, are at high risk of suffering severe potentially fatal bleedings. Bayer scientists are looking into finding ways to prevent or attenuate the immune response after factor administration.
A particularly new approach for the treatment of hemophilia is gene therapy: here, the aim is to deliver the gene responsible for the expression of the missing clotting factor using a non-disease producing virus to transport the gene into hepatocytes where the factor VIII is expressed (viral vectors). To achieve this Bayer has entered into collaboration with Dimension Therapeutics, a company focused on developing novel adeno-associated virus (AAV) based gene therapy for rare disease indications. Using this approach may have the potential to obviate the need for intravenous replacement injections for many years.
Besides improving the existing treatments, hematology research at Bayer is also looking into alternative approaches that bypass factor VIII replacement altogether. Here, scientists are evaluating the possibilities of, for instance, inhibiting natural anti-coagulation modulators.These novel approaches bypass the need for coagulation factor replacement, circumventing the battle against the mechanisms participating in the rapid clearance of factor VIII protein. Developing agents that act as pro-coagulants could provide options to stop bleeding even in patients with normal coagulation status under life threatening conditions such as post-partum hemorrhage or intracranial bleeding.
Inhibition of fibrinolysis
Inhibition of the processes leading to the breakdown of a stable blood clot by anti-fibrinolytic agents is another approach to influence blood coagulation. Fibrinolysis is a process which maintains the natural balance of hemostasis by stopping the growth of blood clots by breaking down fibrin meshing via plasmin. Inhibiting plasminogen and or plasmin leads to reduced bleeding, a principle which can be used under emergency bleeding conditions or also in patients with rare bleeding disorders either alone or in combination with clotting factor replacement.