People living with hemophilia are looking for treatments that last longer and make life more predictable and manageable. That’s why scientists are investigating three different approaches to preventing bleeds in people with missing or insufficient blood-clotting factors:

  • Protein engineering: In clinical studies, we’re investigating a new class of factor VIII replacement therapy. It's designed to sustain high protection from bleeds in people with hemophilia A, with factor levels in the normal to near-normal range for most of the week.
  • RNA technology: Our goal is to help people live more active lives and think about their treatments less. That’s why we’re working to provide extended protection with minimal treatment burden. We’re studying a treatment that’s based on small interfering RNA (siRNA). It’s designed to rebalance the missing blood-clotting factors in people with hemophilia A and B, with or without inhibitors (antibodies that attack replacement factors), potentially offering prophylaxis with as few as 6 injections per year.
  • Gene therapy: Researchers are exploring ways to correct the single DNA mutation that prevents patients from producing enough blood-clotting factor. 

What is hemophilia?

Hemophilia is a rare, genetic condition. People with hemophilia A don’t produce enough blood-clotting factor VIII. People with hemophilia B don’t produce enough blood-clotting factor IX. The result is spontaneous or prolonged bleeding, often into the joints and soft tissues. This can be painful and dangerous, impacting joint health and quality of life.

1. Factor replacement therapies: protein engineering at work

Without enough factor VIII or IX, the body can’t produce enough thrombin to activate clotting.1,2 To solve this problem, many people are treated with replacement factors, given by intravenous (IV) injection. These replacement factors circulate in the blood until they’re either metabolized or activated to help stop bleeding.

But factor proteins are cleared from the body so quickly that many people with hemophilia A need to inject replacement factor several times a week.

Extended half-life factor replacement therapies keep factor VIII or IX proteins circulating longer. This is possible thanks to earlier innovations in protein engineering. To protect the replacement factors from being metabolized too quickly, scientists designed them to “hitch a ride” on proteins that are recycled more slowly.

Breaking the 19-hour limit

But there’s a limit: clotting factor VIII can only circulate in the blood for between 15 and 19 hours. That’s because factor VIII usually travels with a companion protein called von Willebrand factor (vWF). vWF protects factor VIII from being broken down3,4 but every 15-19 hours, half of it gets cleared from the blood, taking the factor along with it.

The challenge for scientists: to develop a factor VIII replacement therapy that keeps these clotting proteins circulating for longer.

Illustration of factor VIII protected by von Willebrand Factor

Caption: von Willebrand factor (purple) protects factor VIII (pink) from being broken down by certain proteins (green and blue).

An alternative to von Willebrand Factor?

We’ve been developing a replacement factor VIII that enjoys the kind of protection vWF gives, without getting caught up in the vWF recycling pathway.5

  • A small fragment of vWF is attached to the replacement factor as a decoy, designed to trick the body’s own vWF into ignoring it. A “linker” molecule releases the decoy when the factor is needed for clotting.
  • Another molecule, XTEN®, acts as a shield, fending off other proteins to protect the replacement factor from being metabolized. An antibody domain helps the factor stay in circulation longer.

The ambition of this novel design, which is still being investigated, is to sustain factor VIII levels in the normal to near-normal range for more than half the week.

Illustration of factor VIII protected by von Willebrand Factor

Caption: When replacement factor VIII (yellow) is bound to a vWF domain (blue), the vWF circulating in the blood (blue and gray) cannot bind to it.

2. RNA technology and hemophilia

mRNA has gained widespread attention for its role in vaccines, but other RNA technologies are also opening up new possibilities for healthcare. For example, our teams aim to improve blood clotting in people with hemophilia by using small interfering RNA (siRNA).6,7,8 It can be designed to help slow the body's manufacture of a protein called antithrombin-3.

Antithrombin is a protein that helps keep blood flowing by limiting the amount of thrombin the body generates. People with less antithrombin in their blood generate more thrombin than others. Recently, scientists discovered that having lower levels of antithrombin-3 restores some thrombin production in people with hemophilia, making clotting more effective.9,10,11

How can we slow down antithrombin-3 production?

The body uses mRNA templates to produce proteins, such as antithrombin-3.12 Without those mRNA templates, the proteins can’t be made. Our teams are studying an siRNA /enzyme complex that intercepts mRNA templates for antithrombin-3 and destroys enough of them to slow down protein production.13,14 That means antithrombin-3 levels could potentially remain low, leaving more thrombin available to initiate blood clotting. 

This is the idea behind a potential prophylactic treatment for people with hemophilia A or B, with or without inhibitors.15,16,17 This type of treatment may result in even fewer treatment cycles for the patient.

mRNA finds siRNA

1. The siRNA lures an mRNA molecule on its way to deliver antithrombin-3 templates to a protein-building factory

mRNA binds to siRNA

2. The mRNA binds to the siRNA

Enzymes break down mRNA

3. Enzymes break down the mRNA and clear it… 

Protein template is destroyed

4. leaving the siRNA strand free to attract another mRNA  

3. Gene therapies

In hemophilia research, the goal of gene therapy is to cure the disease by correcting the single DNA mutation that prevents patients from manufacturing enough factor VIII or IX. We're exploring experimental approaches to gene therapy that we hope will one day improve the lives of people with hemophilia and their families.18,19

This article refers to therapies that are being investigated in research and development programs. The safety and efficacy of the investigational medicines described here have not been evaluated by any regulatory authority.

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References

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MAT-GLB-2001505 v2.0 | July 2022