Discussing a Novel Factor VIII Replacement Therapy for Patients With Hemophilia

Barbara Konkle, MD, professor of medicine, Division of Hematology, University of Washington; research director, Washington Center for Bleeding Disorders; and director, Hemostasis, Platelet Immunology and Genomics Laboratory at Bloodworks Northwest, reviews the types of hemophilia and offers insight into how efanesoctocog alfa differs from other factor VIII replacement therapies.

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Welcome back to PopHealth Perspectives, a conversation with the Population Health Learning Network where we combine expert commentary and exclusive insight into key issues in population health management and more.

In the first part of this podcast, Dr Barbara Konkle discusses the types of hemophilia and treatment with efanesoctocog alfa.

I'm Dr Barbara Konkle. I am a professor of medicine in the Division of Hematology at the University of Washington, and the research director for the Washington Center for Bleeding Disorders. I've been caring for patients with hemophilia for almost 40 years now.

Can you briefly define the different types of hemophilia and how prevalent each of them are? What symptoms do patients experience?

There's hemophilia A and hemophilia B. Hemophilia A is caused by missing or abnormal levels of clotting factor VIII, and for hemophilia B it’s clotting factor IX. Both of those are critical in developing a blood clot. 

The prevalence of hemophilia in the United States is about 30,000 to 35,000 individuals. Most hemophilia is hemophilia A, about 80%, and the rest is hemophilia B. The symptoms are the same. The treatment is different. And today, we'll be talking about treatment for hemophilia A. 

In terms of symptoms, there are different levels of deficiency, and those with severe hemophilia have basically none of the clotting factor that's involved. Hemophilia A is due to lack of the factor VIII, which is located on the X chromosome, so it's an X-linked disorder. Because of that, hemophilia A affects males more than females. Females may still have bleeding symptoms, usually milder, but they can occasionally have severe hemophilia as well. 

The major cause of death in hemophilia is intracranial bleeding. The major cause of morbidity is bleeding into joints and muscles. Our goal in hemophilia, and the standard of care, is to give treatment to prevent bleeding so that those complications do not occur.

What led you and your team of researchers to conduct the XTEND-1 study?

The standard of care in hemophilia is what's called prophylactic factor. So factor VIII is a very large molecule, and original treatment was through blood products. It circulates in the blood. 

With the development of recombinant factor VIII, it is still a product that is given intravenously (IV), so that can obviously be done in the hospital. But a key to treatment is that patients and parents learn how to do IV infusions at home. And the standard factor concentrate to obtain an adequate response may require every-other-day infusions, which is a real challenge for people and families. These infusions are started at a very young age, so you can imagine the challenge of having a young child and infusing them every other day. With recombinant technology, the idea was now we can modify the protein so that it lasts longer, so there will be fewer infusions and, overall, we'll get better care.

This was done pretty quickly for factor IX. There are modified factor IX products where the infusions are given once a week or once every two weeks. But factor VIII was a challenge. And the reason factor VIII was a challenge is that it is bound to another blood clotting protein, von Willebrand factor, in circulation, and then is released with activation to form the blood clot. But factor VIII’s half-life depends on von Willebrand factor, and in essence has the half-life of von Willebrand factor. There are extended half-life factor VIII products, but they weren't extended nearly as long as the factor IX products—only about 1.5 times. Now, administration every other day or twice per week is an advantage, but there was a desire to extend that further. Efanesoctocog alfa is unique in that they added some things to extend the half-life, and also added the factor VIII binding portion of von Willebrand factor, which is released with activation.

This makes factor VIII independent of the von Willebrand factor that's circulating in the person's body. This actually provided two things. One, as we found in studies including the XTEND-1 study, it did significantly improve the half-life about 4- to 5-fold. 

It also produced a very predictable response. Von Willebrand factor levels in normal people and in the patients in the study vary a lot, from about 50% to 150%. We know that a person's response to factor VIII, how long it lasts, and how they have to dose depends on their von Willebrand factor level. So if someone's not responding well, we would look at their von Willebrand factor level. Efanesoctocog alfa is independent of that, so it gives a more consistent response.

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