‘Goal of treating hemophilia is to normalize life like a non-patient’

The history of hemophilia treatment over the past 100 years has been remarkable, from plasma transfusions to the development of clotting factors and to the advent of antibody and gene therapies.

The goal of hemophilia treatment, which was once urgent to save lives, has been upgraded with various therapies to normalize patients’ lives to those of non-patients and even cure them completely.

Advances in clotting factors, especially the development of extended half-life products, have been a major pillar of the history of hemophilia treatment. They have recently gained renewed attention due to their new role in joint health, one of the main goals of hemophilia treatment.

Korea Biomedical Review sat down with Dr. Leonard A. Valentino, professor of pediatrics at Rush University School of Medicine in New York, who was invited to present at the International Congress of the Korean Society of Hematology (ICKSH 2024) late last month to learn more about the history and evolution of hemophilia treatment innovations, as well as the new roles and prospects for clotting factor products that have recently been rediscovered.

Dr. Valentino is a world-renowned expert in hemophilia treatment and one of the founders of prophylaxis with clotting factor products.

Question: The evolution of hemophilia treatments has led to the development of a wide range of treatment options, from clotting factor agents to antibody and gene therapies. That has likely improved the ultimate goal of treatment for hemophilia.

Answer: The primary goal of hemophilia treatment is to prevent all bleeding, including asymptomatic bleeding. That’s because frequent bleeding in people with severe hemophilia can cause joint damage, which can lead to arthritis, a potentially permanent disability. However, the burden patients feel is not only physical but also psychological and emotional. Patients who experience complications other than bleeding can experience strong psychological depression. There are also socioeconomic costs associated with treating joint-related complications.

Looking back, 20, 30, and 40 years ago, the goal of hemophilia treatment was focused on "saving lives," as treatment for people with hemophilia was limited by high costs. Today, the goal of hemophilia treatment has evolved to improve the quality of life so that people with hemophilia can lead normal lives. The goal of hemophilia treatment has evolved to include "health equity," which means that people with hemophilia can live the same life as people without hemophilia based on the best possible treatment outcomes.

Consider, for example, the advent of extended half-life formulations following standard half-life formulations. The innovation of reducing the number of infusions with extended half-life formulations has reduced the physical, psychological, and emotional burden on patients. Prophylaxis with these therapies also saves money, as they prevent bleeding and joint damage, the most common complications for patients with existing severe or moderate hemophilia. Joint damage can lead to severe arthritis, which drives up the cost of orthopedic surgeries, joint replacements, and other societal costs.

Advances in treatment have made it possible for people with hemophilia to lead better lives. From clotting factors to gene therapies to monoclonal antibody therapies, treatment innovations are bringing us closer and closer to the goal of living a normal life like the rest of the population.

Q: Factor VIII has recently been revitalized with the discovery of its direct role in joint health.

A: Much progress has been made in the last two years in demonstrating the important role factor VIII plays in joint health. Intra-articular bleeding caused by a lack of factor VIII in the body has three potentially devastating consequences: first, bleeding in the joints can lead to "angiogenesis," stimulating blood vessel formation by iron in the blood. This rapid proliferation of blood vessels also increases the likelihood of synovial membrane proliferation. The synovial membrane is a tissue composed of inflammatory cells in the joint that tends to increase very quickly. Finally, enlarged synovium increases the likelihood and frequency of bleeding, which, in turn, can lead to cartilage degeneration, which is the loss and destruction of cartilage.

Factor VIII preparations can contribute to normalizing joint function by preventing the three consequences. The PROPEL clinical study, which evaluated prophylaxis with factor VIII in patients with congenital hemophilia A, showed that by administering higher levels of factor VIII than traditionally used, all three key biomarkers that were high at the start of the study were reduced -- abnormal blood vessel formation, synovial membrane proliferation, and joint and cartilage degeneration.

A link between factor VIII and the lymphatic system has also been discovered. While blood vessels carry blood and iron to the joints, lymphatic vessels are responsible for carrying it out of the joints, and a lack of factor VIII causes lymphatic vessels to become disorganized and lose their function. In preclinical studies in mouse models of hemophilia, only factor VIII-deficient mice showed impaired lymphatic vessel formation that contributes to the removal of hemoglobin from the synovial membrane and deposited hemoglobin that was not removed. Direct supplementation of factor VIII in these mice also stabilized the lymphatic vessels and moved blood out of the joint.

This confirms the importance of factor VIII in the healing process after joint bleeding. Considering the additional normalization of joint health beyond hemostasis, it suggests that patients treated with non-clotting factor agents also need factor VIII therapy to restore normal function to joints, cartilage, and lymphatic vessels.

Q: Is combining antibody therapy with a factor VIII agent possible?

A: Yes. As mentioned earlier, treatment goals for hemophilia patients include preventing bleeding and promoting joint health. A lack of factor VIII in the body leads to thinning bones and osteoporosis, which increases the risk of fractures. Therefore, even if other mechanisms control bleeding, factor VIII is essential to improve patients' joint and bone health.

Developing and actively utilizing new therapeutic agents is essential to achieving optimal patient outcomes and moving toward personalized care. I think we need to be exploratory in combining different drugs to prevent bleeding and improve complications in the joints.

Q: Speaking of personalized treatment, hemophilia patients in Korea know their pharmacokinetic (PK) profile and use it to guide their treatment. What is the situation in the United States?

A: For people with hemophilia, PK is a key tool for measuring and understanding how their body processes factor VIII. For personalized prophylaxis with factor VIII, measuring the half-life of factor VIII in the body after treatment is important. Still, it is even more important to determine how high factor VIII activity rises after administration and how long it stays there.

Let's use a car as an example. You wouldn't start driving your car if the fuel gauge was empty, or if you have an electric car, you want to know the level of the battery to avoid discharging it. The same is true for PK. PK monitoring gives patients proactive information to protect them from bleeding risks.

Personalized treatment involves more than just PK. The patient's lifestyle, exercise habits, genetics, and interactions with the environment surrounding them are also important. When and what sports patients participate in, the intensity of their exercise, and how well they adhere to their treatment are also very important variables.

I believe that modern hemophilia treatment is moving in the same direction as precision medicine for cancer. Precision medicine considers the patient's genetic background, medications, and the environment in which the patient lives. In the U.S., we are moving toward treatments that consider the environment of care, including social determinants, such as a patient's payment system and access to the healthcare system.

Q: You mentioned access to treatment, but the current reimbursement threshold for factor VIII in Korea is set for "patients with less than 1 percent factor VIII activity in their blood," making it difficult to meet the 3-5 percent level of factor VIII activity recommended by the World Federation of Hemophilia.

A: Data from studies in the U.S. and Germany show that patients treated with only the lowest 1 percent level still experience severe joint disease, often lasting for decades. If this is the case in Korea, we need to get data from Korean patients, analyze it, and quickly discuss with the government the need to set a higher factor VIII activity threshold. No one wants children as young as two or three years old to live with severe joint disability.

Data is a valuable asset on which to base the discussion. It doesn't have to be expensive. Patient surveys are a good example. They are a great way to understand how patients feel about their treatment outcomes, burdens, and daily experiences with hemophilia. These cost-effective tools should be utilized to generate data that can be used to initiate change discussions with health authorities.

Q: What do you see as the ultimate goal for hemophilia treatment? Is it a cure or normalization of daily life like the non-patients?

A: A complete cure is the ultimate goal. However, it is still very far, decades or more away. Gene editing has recently been introduced into treating hemophilia, but it does not change the genetic predisposition to hemophilia. Parents who carry the hemophilia gene will still pass it on to their children, so the current direction of treatment is focused on "health equity," where everyone has the same access to a high quality of life. We aim to enable people with hemophilia to lead the same normal lives as those without hemophilia.