Concizumab shows promising results for hemophilia patients

Concizumab shows promising results for hemophilia patients

For people with the blood clotting disorder hemophilia, life can seem like a constant state of alertness. If they accidentally cut their finger while chopping vegetables, they must immediately administer the clotting factor protein, which their body is either missing or not producing in sufficient quantities. A normal visit to the dentist, which can be accompanied by light bleeding, can pose a high risk for a hemophiliac.

We are aware of cases where a person whose hemophilia was untreated or inadequately treated bled to death after a tooth extraction.”

Hermann Eichler, Professor of Transfusion Medicine and Clinical Hemostaseology, Saarland University and Director, Institute for Clinical Hemostaseology and Transfusion Medicine, Saarland University Hospital

Eichler is the head of one of only around 30 centers in Germany that specialize in the treatment of severe forms of hemophilia. The institute offers comprehensive medical treatment for people born with a deficiency in certain clotting factors. However, this type of advanced medical treatment comes with costs, namely around 200,000 euros per year per patient. Clotting factors (clotting factors) are proteins in the blood that cause the blood to clot when necessary. In contrast, inhibitors (anticoagulant factors) serve to control the clotting reaction and thus prevent the formation of potentially life-threatening thrombi (blood clots). “You can imagine it like a precisely balanced set of scales,” said Hermann Eichler. “On the one hand, there are the proteins that promote blood clotting – the crucial first step in ensuring the wound closes.” On the other hand, there are anticoagulant factors that ensure that the blood in the circulation does not clot.” If this delicate balance is disturbed, one side dominates the other, leading to either thrombosis or unstoppable bleeding.

The situation is particularly serious in people who lack coagulation factors 8 and 9. If these coagulation factors are completely missing, those affected suffer from severe hemophilia, which can lead to spontaneous bleeding, often in large joints. Currently, conventional treatment requires patients to inject the missing clotting factor 8 or 9 into a vein one to three times a week to prevent bleeding. “With this type of prophylactic treatment, the patient only receives enough clotting factor to prevent spontaneous bleeding,” explains Professor Eichler. “But that doesn’t mean they’re completely healthy in terms of blood clotting.” “It's not ideal, but at least the patients no longer suffer from spontaneous joint bleeding, which would lead to chronic joint damage with long-term treatment,” says Eichler, describing the current status of hemophilia treatment.

However, this type of treatment can only really delay the onset of the most serious consequences of hemophilia. “In most patients, joint damage or, in the most severe cases, joint degeneration only occurs in adulthood,” explains Hermann Eichler. However, patients with severe hemophilia often suffer from chronic joint pain and a severely reduced quality of life up to the age of 40.

Relief could now come in the form of concizumab, a new drug from the Danish multinational pharmaceutical company Novo Nordisk. Hermann Eichler and his team were significantly involved in the clinical development and were able to demonstrate its effectiveness and tolerability in a recently published study. While traditional treatments aim to replace the missing clotting factors 8 or 9 in the patient's blood, concizumab - a therapeutic monoclonal antibody - offers a different approach to treating hemophilia. “Instead of adding the missing clotting factors to the blood, we essentially block an anticoagulant factor, so that the delicate balance between the factors that promote clotting and those that inhibit it is restored,” explained Professor Eichler.

Specifically, concizumab inhibits the function of the anticoagulant factor TFPI (tissue factor pathway inhibitor). In healthy people, TFPI ensures that too much of the central clotting enzyme thrombin is not produced at the injury site during the wound healing process. Thrombin essentially controls the formation of fibrin, a protein arranged in long fiber chains. These fibrin strands combine to form a fibrous network that traps blood cells, especially platelets, and ultimately forms a stable clot. Instead of adding the missing coagulation factors 8 or 9 directly to the patient's blood, the researchers use concizumab to block the production of TFPI. When the action of the thrombin inhibitor is blocked in this way, enough thrombin can be produced so that clotting occurs and the bleeding stops. “This development is of great importance for hemophilia patients,” explains Hermann Eichler. “By blocking TFPI, thrombin production at the injury site is significantly increased, allowing blood clotting to begin and wound closure.”

The Phase 3 clinical trial, recently published in the prestigious journal The Lancet Hematology, included data from a total of 148 people suffering from severe hemophilia A or B (that is, people who lack clotting factors 8 or 9, respectively). “The bleeding rate was significantly lower in study participants who received concizumab and the drug, which is injected under the skin with a disposable pen in a similar way to diabetics, is very well tolerated,” says Eichler, summarizing the encouraging results of the clinical study. This new treatment approach may prevent the serious complications associated with hemophilia, such as degenerative joint disease, but this still needs to be confirmed in long-term studies. “In contrast to previous therapeutic approaches, blocking the action of TFPI normalizes thrombin formation in hemophilia patients – something we normally only observe in people with healthy blood clotting,” said Hermann Eichler.

Eichler illustrated what these scientific results mean in practice with the following impressive example: “One of the patients participating in the study recently suffered a serious fall from a bicycle and sustained a large wound.” Without hemophilia treatment, the man would almost certainly have suffered a serious bleeding complication. But now, just a few days later, he is sitting there just like you and me and his wounds are healing normally.”

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