Hemophilia: Our Approach to New Therapeutics

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 down^3,4but 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.

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.

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.

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.