Advances in the Treatment of Hemophilia and von Willebrand Disease

In total, several dozen representatives of patient organisations and physicians from many European countries attended the meeting, as well as a representative of the World Federation of Hemophilia from the USA. The weekend was packed with presentations in several sessions, each followed by an open discussion on the topics covered.

Replacement Therapy

Replacement therapy is the longest-used form of hemophilia treatment. It involves supplementing the missing factor, which is obtained either from human plasma or from modified cell cultures in the case of recombinant products. A disadvantage of this type of treatment is the relatively short time during which the body breaks down the factor administered in the medicinal product. Another disadvantage is the necessity of intravenous administration.

Manufacturers are trying to overcome the first disadvantage by adding auxiliary substances to the clotting factor itself that help keep it in the bloodstream for longer -- we then speak of extended half-life (EHL) drugs. Much more significant prolongation of the effect is being achieved with factor IX and thus in the treatment of hemophilia B, where current extended half-life products allow prophylactic treatment with an administration frequency of once every one or even two weeks. The half-life of these drugs is roughly 3-5 times longer compared to drugs with a standard half-life.

In hemophilia A and factor VIII, such an extension has not been achieved; typically, the half-life is approximately 1.5-1.6 times longer compared to standard half-life drugs. For prophylactic treatment, an administration frequency of at least twice a week remains necessary to ensure that the factor level in the body does not drop below the minimum level at which the risk of spontaneous bleeding arises.

Currently, a product designated BIVV001 is in the final phase of clinical trials for the treatment of hemophilia A, where results from the initial trial phases on patients show a 3-4 times half-life extension compared to standard products. This is therefore a very promising drug that could reduce the frequency of applications in prophylactic treatment of hemophilia A. With a higher administration frequency maintained, the product could help keep FVIII levels close to those of a healthy person throughout the entire period.

Non-Factor Therapy

The second disadvantage of replacement therapy -- the necessity of intravenous administration -- is successfully eliminated by drugs from the non-factor therapy category. In their case, the missing factor is not administered directly into the body, but rather a different substance that has a similar effect within the cascade leading to blood clot formation. One of these is the so-called "bispecific antibody".

Currently, the substance Emicizumab is already used in clinical practice for the treatment of hemophilia A, administered subcutaneously. In the case of prophylactic treatment, one injection at a relatively long interval (one, two, or even four weeks depending on the prescribed dosage) is sufficient to maintain a level of the active substance in the body throughout the period between doses, corresponding to a factor VIII level of approximately 10-15%.

An advantage of this drug, besides subcutaneous administration, is that the active substance level remains constant between individual applications when the prescribed dosage is followed -- there is no sharp increase followed by a rapid decrease, as we know from replacement therapy.

This fact is simultaneously a certain disadvantage of this type of treatment, since the mentioned substance level may not be sufficient to prevent bleeding for people with a very active lifestyle, or in the case of injury or surgery. In such cases, it is necessary to supplement the missing factor level with a standard replacement drug.

Conversely, one of the advantages is that the effect of Emicizumab in the body is not affected by the possible presence of a FVIII inhibitor, and for people with an inhibitor, it often represents the only effective treatment option.

Experience from around the world and from our country shows very good results with minimal side effects even in prophylactic treatment of patients with severe hemophilia A without an inhibitor. In one of the presentations, a physician from the Belgian Saint-Luc Hospital shared his experience, where 72% of patients (both adults and children) with severe hemophilia A at his workplace are already being treated with this drug, and the therapeutic effect is very good in the majority of them.

Currently, a new drug based on a similar principle, designated Mim8, is again in the final phase of clinical trials. This product should be usable, among other things, in individuals who have developed antibodies against Emicizumab, although this is a very rare occurrence.

Rebalancing Therapy

An entirely new approach to hemophilia treatment is brought by the products Fitusiran and Concizumab, which are also in the clinical trial phase. While all previously mentioned products aim to increase the level of blood coagulation, drugs from this category take a completely opposite approach, which may surprise many. However, upon closer examination, it makes sense.

The degree of blood coagulation in a healthy person depends on the balance between factors that promote clotting and, on the other hand, those that inhibit it. Both categories are normally present in the body, and their balance enables the formation of a blood clot. However, if the balance is disrupted due to a missing pro-coagulant factor, we can help by also reducing the production of anticoagulant substances that prevent blood clot formation. This restores the balance, and blood coagulation can function almost as well as in a healthy person.

Both mentioned drugs again have the advantage of subcutaneous administration with a relatively long interval between doses (up to 4 weeks). Another interesting fact is that this is the first drug with subcutaneous administration that also works in patients with hemophilia B. However, this treatment does carry certain risks, which will certainly be more precisely determined once the appropriate clinical studies are completed.

Gene Therapy

In almost all presentations, great attention was devoted to gene therapy for hemophilia, which has made great progress in recent times. Products aiming to treat both hemophilia A and B are now in the final phase of clinical trials. The principle of this therapy is to deliver the genetic blueprint for producing the missing factor into the body. The most commonly used carrier for this genetic blueprint is a virus from the AAV family, which can deliver the genetic information all the way into the liver cell, where factor synthesis subsequently takes place. Treatment of this type is typically administered as a single infusion.

In August of this year, the European Medicines Agency (EMA) approved the first drug of this type under the name Roctavian for use in patients with hemophilia A. The drug has received conditional approval pending the results of further clinical trials. These are now continuing in a study called GENEr8-3, which was launched in 2020 and includes 22 people. It is planned to run until January 2027.

Close to approval in Europe is also the product EtranaDez, aimed at treating hemophilia B. The third phase of clinical trials (under the name HOPE-B) of this product began as early as 2018 and involves 67 patients. Final results should be known in 2025, but approval by the EMA could come as early as 2023. As of the publication date of this article, 23 November 2022, the product was in fact approved by the US Food and Drug Administration (FDA).

The results so far from both studies (and their previous phases) show that the fundamental goal -- a true cure for hemophilia (rather than the current therapy consisting of replacing the missing factor) -- is achievable. At the same time, however, it is already clear that there are many questions to which we do not yet have a definitive answer, and treatment of this type is still associated with a greater or lesser degree of risk.

The first major finding is that the amount of factor produced in the patient's body after gene therapy application varies greatly between individual patients. The range varied from 0% in patients where gene therapy did not work at all for an unknown reason, to hundreds of percent in some individuals. This variability is much more pronounced in the study of the product for hemophilia A; in hemophilia B, the variation was within a narrower range and the maximum values did not reach such extreme levels.

Another problem is that the effect of the treatment decreases over time. This manifests as a gradual decline in the factor level produced by the body. This decline is again much more pronounced with the product targeting factor VIII and thus hemophilia A. It can be expected that within a time horizon of approximately 8 years, the treatment effect will completely disappear. With the product for hemophilia B, no significant decline was observed during the monitored period (24 months).

It is not entirely clear whether the differences in the results of both studies are related to the difference between the diagnoses or rather to the difference in the medicinal products themselves.

There are also many other weaknesses currently associated with gene therapy. These may include, for example, antibodies against AAV viruses, which are commonly found in the population and are currently considered an exclusion criterion for this type of treatment. The treatment is also not yet applicable in children. In many patients in clinical trials, an immune response occurred that had to be managed with higher doses of corticosteroids for up to 8 months. Corticosteroid treatment is then associated with many side effects. The application of gene therapy also requires very detailed monitoring of the patient for a minimum of 12 weeks after application.

Last but not least, this type of treatment is also associated with a much higher cost compared to existing treatment. Models of financing are still being sought that would enable its application in clinical practice under conditions acceptable to the entities that pay for the treatment. One of the presentations at the workshop, for example, dealt with constructing an economic model that compares the benefits and costs of gene therapy and current treatment, which could serve as a basis for discussions about its reimbursement.

The question of which facilities will have sufficient qualifications to apply this type of treatment to patients is also being actively addressed.

Although the first drug has already received approval from the European Medicines Agency and the second is likely to follow soon, their path to routine clinical practice will still be very long.

Treatment of von Willebrand Disease

Compared to the rapid development in hemophilia treatment in recent years, it might seem that almost no progress has been made in the treatment of von Willebrand disease. However, this is not entirely true, and the coming years should bring new options for patients with this diagnosis as well.

Currently, products made from human plasma are used for the treatment of vWD, either in the form of a pure von Willebrand factor concentrate or a combination of FVIII and vWF. However, the first recombinant vWF concentrate has already appeared on the market.

Conclusion

In recent years, we have witnessed a truly unprecedented development of new possibilities in the treatment of rare bleeding disorders, led by hemophilia. New forms of established drugs as well as entirely new types of medicinal products have the potential to fundamentally improve the quality of life of people with these conditions. Each product has its own specifics, and it is therefore absolutely essential that not only physicians but also patients are well-informed about the treatment options. The choice of the most suitable therapy is then the result of assessing many factors and the specific case. The final say in choosing a specific product must always rest with the physician, who can assess not only the patient's condition and needs but also all known facts, risks, benefits, and experience with the given drug, as well as the recommendations for hemophilia treatment issued by professional societies, the World Federation of Hemophilia, and the European Haemophilia Consortium based on the latest scientific findings.