Concizumab: New bleeding prophylaxis for hemophilia
To treat the hereditary disease hemophilia, drugs that replace the missing clotting factor are usually used. However, patients often develop antibodies against them, which can render the therapy ineffective. / © Getty Images/Alena Butusava
The development of inhibitors is a serious complication in the treatment of patients with hemophilia. The resulting inhibitors neutralize the substitute factor preparations, causing them to lose significant effectiveness or even become completely ineffective. This affects approximately 30 percent of patients with severe hemophilia A and 1 to 5 percent of those with severe hemophilia B. Immunotolerance therapy attempts to permanently eradicate the inhibitors. However, this is not always successful, so new approaches to treating inhibitor hemophilia are needed.
Concizumab is an antibody against the tissue factor pathway inhibitor (TFPI). TFPI inhibits the extrinsic coagulation cascade by blocking the active site of factor Xa (FXa). By reversing the inhibitory effect of TFPI on blood coagulation, concizumab increases the availability of free FXa. The increased FXa activity prolongs the activation phase of the coagulation cascade and allows for sufficient thrombin generation for effective hemostasis. Concizumab acts independently of factor VIII and factor IX, the factors lacking in hemophilia A and B, respectively.
Concizumab (Alhemo®, Novo Nordisk) is approved for the routine prophylaxis of bleeding episodes in adolescents and adults 12 years of age and older with hemophilia A or B and inhibitors. Treatment should be initiated when the patient is free of bleeding. Furthermore, prior treatment with bypass medications must be discontinued: rFVIIa at least 12 hours prior, and aPCC (activated prothrombin complex concentrate) at least 48 hours prior.
The antibody is injected subcutaneously once daily. The recommended dosing regimen is a loading dose of 1 mg/kg on the first day, followed by an initial daily dose of 0.2 mg/kg, followed by an individualized daily maintenance dose. After four weeks of treatment, the dose is adjusted based on the concizumab concentration in the blood.
Alhemo is a prefilled multidose pen that can be self-injected by patients after training. / © Novo Nordisk
After training, patients can inject themselves, preferably into the abdomen or thigh. The injection site should be changed daily. Before first use, Alhemo should be stored in a refrigerator at 2 to 8°C. Afterward, the pre-filled pen can be stored for up to four weeks at temperatures up to 30°C. This should be done with the cap in place to protect the solution from light, but not with the needle attached.
Concizumab should be discontinued at least four days before major surgery. Treatment can be resumed 10 to 14 days after surgery at the same maintenance dose without a new loading dose.
Allergic hypersensitivity reactions occurred within the first few weeks of treatment, including hospitalization and permanent discontinuation of therapy. If symptoms of hypersensitivity occur, the patient should discontinue use of Alhemo and consult a physician.
The development of neutralizing anti-concizumab antibodies has been observed in some patients, but this usually does not result in loss of efficacy. Clinical signs of loss of efficacy may include an increase in breakthrough bleeding. If this occurs, patients should be evaluated to assess the etiology and consider other therapeutic options.
The risk of thrombosis may increase with the use of concizumab. For example, patients with coronary heart disease, venous or arterial thrombosis, or those with acute severe illness associated with elevated tissue factor expression are at increased risk. If thromboembolic events are suspected, the antibody should be discontinued. It should be regularly and carefully assessed whether the potential benefit of concizumab treatment outweighs the potential risk in patients at high risk for thromboembolic events.
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