It is mainly men who suffer from it. Its essence is the lack of a blood clotting factor, which is the cause of, among others, bleeding time, both external and internal. How are patients with hemophilia treated in Poland? Do the newest therapies offer a chance of a full recovery?
We talked about the treatment of hemophilia in Poland with prof. dr hab. n. med. Tomasz Urasiński, Head of the Department of Paediatrics, Hemato-Oncology and Pediatric Gastroenterology, Independent Public Clinical Hospital No. prof. Tadeusz Sokołowski of the Pomeranian Medical University in Szczecin.
Editorial: Since hemophilia is a sex-linked genetic disease, it is not possible to treat it causally. So how is hemophilia treated today, and what is it for?
Prof. dr hab. n. med. Tomasz Urasiński: And here I will surprise you; the causal treatment of hemophilia is possible precisely because it is a genetic disease, or more precisely, a monogenic disease. I am thinking of gene therapy, especially in haemophilia B. It has been proven in clinical trials that it is possible to introduce into the liver cell, in which clotting factors IX (and also VIII) are produced, the correct gene encoding the factor, using specially selected viruses with affinity. into the liver cell (we call them hepatotropic viruses). In clinical trials involving patients with severe hemophilia B, it turned out that such a genetically “manipulated” liver cell starts with the synthesis of coagulation factor IX, and its blood activity increases to several percent and is maintained for a longer period of time (in severe hemophilia B factor activity is less than 1 percent). This means that the effect of gene therapy is the transformation of the severe form of the disease into a mild form, in which bleeding occurs only after major injuries, e.g. during surgery. Similar attempts are also made in cases of haemophilia A, although this is more difficult because the factor VIII gene is much larger than that of factor IX. I believe gene therapy is the near future of hemophilia treatment.
Gene therapy is without doubt a hope for patients suffering from hemophilia. Currently, however, injections have become very popular. On average, how many clotting factor injections do a patient per week? Is there any alternative to injections to limit the number of injections?
For children with severe haemophilia A, for prophylaxis of bleeding, 3-4 injections per week are intravenous, for haemophilia B it is 2 injections per week. An alternative are preparations with a prolonged half-life (the half-life is the time from the injection to the moment when the activity of the factor drops to half the initial value). By using such preparations, the number of intravenous injections can be reduced to two per week in patients with haemophilia A and even to one per week in patients with haemophilia B. Unfortunately, in Poland, patients with haemophilia do not have access to these preparations. There are also so-called non-reagent drugs, e.g. emicizumab. This drug is administered subcutaneously at a frequency of once every two weeks and even once every four weeks. This drug is available in Poland for selected patients with haemophilia A – those who have developed an inhibitor (antibody against factor VIII) who is not subject to the immunotolerance procedure. In Poland, 12 children are currently treated with emicizumab; there could be more of them, but for reasons I do not understand, the qualification procedures were suspended. We filed the application for our patient about six months ago.
What is the difference between plasma-like and recombinant drugs?
Origin. Plasma-derived drugs are produced from plasma from multiple donors, recombinant drugs are drugs produced by genetic engineering. Their effectiveness in preventing and treating bleeding is very similar. Recently, I had the opportunity to compare the results of bleeding prophylaxis in Polish children with haemophilia A in two groups: those who received plasma-like drugs and those who received recombinant drugs. They were found to be of equal effectiveness in preventing bleeding. The advantage of recombinant drugs is that their use does not carry the risk of transmitting viral infections. The older generation of hemophiliacs still remember what happened in the XNUMXs and XNUMXs. Then there was a mass infection of patients with hemophilia HIV and hepatitis C virus (diseases then and now often fatal) contaminated by these viruses with clotting factor concentrates. And although the improved technologies for the production of clotting factor concentrates today guarantee practically complete safety of their use, the memory of this in the environment of hemophiliacs is still alive – patients prefer recombinant factors. Finally – and this is a very important argument – there is a shortage of plasma for the production of concentrates in the world. We are, in a way, doomed to use recombinant factors.
So what is non-substitution treatment and what are the effects?
Let’s start with the word “substitution”. It is giving the patient a substance that his body is unable to produce sufficiently. In haemophilia, substitution involves the administration of plasma-derived or recombinant coagulation factors. Non-substitutive drugs are drugs that, while not being coagulation factors, are able to restore normal blood clotting (normal hemostasis). The aforementioned emicizumab is such a drug. It is a monoclonal antibody that combines with factors IX and X on the surface of the plate, activating the latter, and this activates the final part of the clotting cascade. I have to say here, however, that the drug only partially restores clotting “normal”; it is rather the conversion of a severe form of hemophilia into a very mild form of the disease, although it does not change my conviction that Midori Shioma, who invented this drug, deserved the Nobel Prize. The same applies to the use of other non-reagent drugs, e.g. conccizumab or phytusiran. These drugs are in clinical trials and have not yet been used in children.
According to your Professor, how has the experience of treating patients with hemophilia changed in recent years and how has this influenced their quality of life?
The main breakthrough in our country was the introduction of the bleeding prevention program. Every Polish child with a severe form of hemophilia, as well as children with moderate hemophilia, the so-called the malignant bleeding phenotype is covered by this program. Trained parents, and often elderly patients at home, administer the agent intravenously on a regular basis, 3-4 times a week. The agent is delivered “to the doorstep” of their homes, medical waste is regularly collected from them: concentrate packages, used needles, etc. bleeding, which we – doctors – having Internet access to this information – can track in real time. Finally – after performing the pharmacokinetic analysis on our patient, we enter its result into the application, thanks to which the patient can see on the device screen what the activity of the factor in his blood is at the moment. We call it personalized prophylaxis – tailored to the individual needs of the patient and interactive prophylaxis, because the application tells the patient what level of physical activity he can afford at the moment. Haemophilia used to be a life-threatening disease, damaging the joints and leading to significant motor disabilities, but I think that these times are over forever. The life of a boy with hemophilia slowly begins to resemble that of his healthy peer.
What is the most important for patients during treatment – the form of drug administration, its effectiveness, frequency of application, or maybe all these elements?
I think that all these elements are important to our patients, but effectiveness is the overriding value, which translates into the quality of life. A boy with hemophilia wants to be like his disease-free peer and is willing to accept many austerities to achieve this goal. Not so long ago, I proposed to one of my preschool patients to increase the number of injections to four per week, according to a pharmacokinetic analysis. In response, I heard that he is looking forward to that fourth injection, because then on Sunday he will be able to do what he wants.
Is there any prophylactic treatment for people genetically burdened with the disease?
A genetically burdened person with hemophilia is simply a person suffering from hemophilia. For such patients, especially those with a severe form of the disease, the best course of action is undoubtedly prophylaxis, i.e. regular and systematic administration of missing coagulation factor concentrate to prevent bleeding. It is indisputably the best course of action to prevent the development of haemophilic arthropathy – the progressive destruction of joints caused by recurrent bleeding. All Polish children with severe hemophilia are covered by the NHF-funded bleeding prevention program, and we really have nothing to be ashamed of.
What is the future for hemophilia treatment? Is there a drug in the course of clinical trials that could be hope for patients?
I believe in gene therapy, but it is still, though probably – especially in haemophilia B, however, that the “song of the future” was not far away. Non-reagent drugs are a prospect for patients with an inhibitor that has not been eradicated (eliminated). For most patients, substitution treatment will remain that future; I hope that recombinant clotting factor concentrates with a prolonged half-life will become available to our patients. Their use is effective in preventing bleeding, and the quality of life of patients is improved due to the fact that, although intravenously, they are administered less frequently. The introduction of oral drugs that restore normal hemostasis would be a revolution, but we will have to wait a little longer for that.