Clinical trial demonstrates efficacy and tolerability of new drug for haemophilia patients

For people with the bleeding disorder haemophilia, life can seem like one continuous state of alertness. If they accidentally cut their finger while chopping vegetables, they have to immediately administer the clotting factor protein that their body either lacks or does not produce enough of. A normal visit to the dentist, which may well be accompanied by a small amount of bleeding, can be highly risky for a haemophiliac. 'We know of cases in which a person whose haemophilia is untreated or has not been adequately managed has bled to death after a tooth extraction,’ explained Hermann Eichler, Professor of Transfusion Medicine and Clinical Haemostaseology at Saarland University and Director of the Institute for Clinical Haemostaseology and Transfusion Medicine at Saarland University Medical Center.

Eichler is the head of one of only about 30 centres in Germany that specialize in the treatment of severe types of haemophilia. The institute provides comprehensive medical treatment to individuals born with a deficiency in certain coagulation factors. But this type of advanced medical treatment comes at a cost, specifically around €200,000 per year per patient. Coagulation factors (clotting factors) are proteins in the blood that ensure that the blood coagulates when needed. Inhibitors (anticoagulant factors) in contrast serve to control the clotting response and so prevent the formation of potentially life-threatening thrombi (clots). 'You can think of it like a pair of precisely balanced scales,' said Hermann Eichler. 'On the one side, you have the proteins that promote blood coagulation – the vital first step in ensuring that the wound will close. On the other, you have the anticoagulant factors, which ensure that the blood in the bloodstream does not clot.’ If this delicate balance is disturbed, one side outweighs the other, leading either to thrombosis or to unstoppable bleeding.

The situation is particularly serious in those individuals who lack coagulation factors 8 and 9. If these clotting factors are completely absent, the individuals concerned suffer from severe haemophilia that can result in spontaneous bleeding, not infrequently in the large joints. At present, conventional treatment requires patients to inject the missing clotting factor 8 or 9 into a vein between one and three times a week to prevent bleeding. ‘In this type of prophylactic treatment, the patient only receives enough of the coagulation factor to prevent spontaneous bleeding,’ explained Professor Eichler. 'But that doesn’t mean that they are fully healthy from a blood clotting perspective. It's not ideal, but at least the patients no longer suffer from spontaneous joint bleeds, which, if left untreated over the long term, would result in chronic joint damage,' said Eichler, describing the current state of haemophilia treatment.

But this type of treatment can only really delay the onset of the most serious consequences of haemophilia. 'In most patients, joint damage or, in the most severe cases, joint degeneration, doesn't occur until adulthood,’ explained Hermann Eichler. Nevertheless, by the time they have reached the age of 40, patients with severe haemophilia will very often be suffering from chronic joint pain and a severely reduced quality of life.

Relief may well now come in the form of concizumab, a new drug from the Danish multinational pharmaceutical company Novo Nordisk. Hermann Eichler and his team played a major role in its clinical development and were able to demonstrate its efficacy and tolerability in a recently published study. While conventional treatments aim to replace the missing coagulation factors 8 or 9 in the patient's blood, concizumab – a therapeutic monoclonal antibody – offers a different approach to treating haemophilia. 'Rather than adding the missing clotting factors to the blood, we essentially block an anticoagulant factor so that the delicate equilibrium between the factors that promote coagulation 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 individuals, TFPI ensures that not too much of the central clotting enzyme thrombin is produced at the injury site during the wound healing process. Thrombin essentially controls the formation of fibrin, a protein arranged in long fibrous chains. These fibrin strands interlink to create a fibrous mesh that traps blood cells, particularly platelets, eventually forming 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. Blocking the action of the thrombin inhibitor in this way allows enough thrombin to be generated, so that clotting occurs and bleeding stops. ‘This development is of major significance for haemophilia patients,’ explained Hermann Eichler, 'By blocking TFPI, thrombin production at the injury site is significantly increased, which allows blood clotting to begin and the wound to close.’

The clinical phase 3 trial, which was recently published in the highly respected journal The Lancet Haematology involved data from a total of 148 people suffering from severe haemophilia A or B (i.e. individuals missing clotting factors 8 or 9 respectively). 'The bleeding rate was significantly lower in trial participants who received concizumab, and the drug, which is injected under the skin with a disposable pen similar to those used by diabetics, is very well tolerated,’ said Eichler, summarizing the encouraging clinical trial results. This new treatment approach may well make it possible to avoid the serious complications associated with haemophilia, such as degenerative joint disease, but this still needs to be confirmed by long-term studies. ‘In contrast to previous therapeutic approaches, blocking the action of TFPI normalizes thrombin formation in haemophilia patients – something we typically only see in individuals with healthy coagulation,’ said Hermann Eichler.

Eichler illustrated what these scientific results mean in practice with the following striking example: 'One of the patients who took part in the trial recently suffered a bad fall from his bicycle and sustained a large wound. Without haemophilia 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 quite normally.’