Summer 2003 - Factor Nine News

• Inhibitors
• NHF Gala - Honor’s Bruce Lee Evatt, MD
• Adirondack “SPIN”Tacular-September 13
• Aventis Behring Assurance Programs

The care of patients who develop inhibitors is one of the most challenging aspects of hemophilia treatment. Inhibitors are antibodies that develop in the bloodstream of some hemophiliacs and inactivate factor IX. The immune system normally produces antibodies to protect the body from viruses, bacteria or other foreign materials including proteins. The problem is that when factor IX is injected into some hemophiliacs their immune system does not recognize it as a normal component of their blood. Instead their immune system treats it as a foreign invader, something potentially harmful that needs to be neutralized and eliminated.

Inhibitors develop in up to one-third of hemophilia A patients, but it is much less common in Hemophilia B patients, most studies quote a number of 5%. The proportion is higher for patients with severe hemophilia and also varies among ethnic groups. If an inhibitor is going to develop, it usually happens within a few weeks after a child is first started on factor IX products. However, inhibitors can develop in older patients who have been receiving factor IX injections for longer periods of time.

One serious complication for hemophilia B patients with inhibitors is that they can also experience anaphylactic reactions to factor IX. These are severe allergic reactions that can be life threatening if not treated quickly. For this reason, many physicians recommend that a child’s first few factor IX injections be given in a medical facility where help is available immediately.

In the past, it was thought that the manufacturing method used to produce a factor concentrate or its purity might influence the development of inhibitors. Therefore, whenever a new factor concentrate was developed, there was always concern that it might increase the number of patients developing inhibitors. This was especially a concern when the recombinant products were first developed. However, except in a few cases this has not proven to be the case.

More recently, studies have shown that inhibitor development depends to a large extent on the type of genetic mutation causing the hemophilia. Some hemophiliacs produce factor IX molecules that have small defects, which cause the protein to be dysfunctional. Because their factor IX looks very similar to fully functional factor IX, their immune systems are less likely to see the factor IX from a concentrate as a foreign protein. Other hemophiliacs produce factor IX molecules that have large defects or produce no factor IX at all.

They have a greater tendency to develop inhibitors because their immune systems are not used to seeing any factor IX.

Over the years a number of methods have been developed to deal with inhibitors. The best treatment depends partly on the concentration of inhibitor antibodies in the blood. The inhibitor level is measured using a special blood clotting test, and the result is expressed in Bethesda Units (BU). Inhibitor levels of less than 5 to 10 BU are called low titer inhibitors. Hemophiliacs who develop low titer inhibitors are called low responders and can often simply be given larger amounts of factor IX, enough to overwhelm the inhibitor. However, for high responders with inhibitor levels above 10 BU, it becomes prohibitively expensive to use enough factor IX to overcome the inhibitor.

High responders may be treated with specially activated clotting factor concentrates. In the bloodstream, most of the clotting factors circulate as inactive proteins. When an injury occurs, components are released from the damaged cells that activate the clotting factors and start the clotting process. The activated concentrates used to treat inhibitor patients contain clotting factor proteins that are already activated. These activated concentrates are sometimes called bypassing agents because they start the clotting process at a step that bypasses the step that involves factor VIII and factor IX. Bypassing that step eliminates some of the control built into the clotting process, but works effectively for many inhibitor patients.

“Inhibitors are much less common in people with Hemophilia B, most studies quote 5%. The proportion is higher for people with severe Hemophilia B.”

The actual mechanism by which the activated concentrates work is not completely understood, but there is some evidence that it involves the activated form of factor VII. Because of this NovoSeven, a recombinant version of activated factor VII was developed in Europe and has been available in the U.S. for several years.

NovoSeven appears to work effectively and has the same safety advantages as other recombinant factor concentrates, so it has become widely used in the treatment of Hemophilia B inhibitor patients. Unfortunately, its half-life is short and therefore treatment with NovoSeven is often more expensive.

Of course, the best treatment would be to permanently eliminate the inhibitor. A method called immune tolerance therapy has been shown to do that in about half of the patients who try it. Immune tolerance therapy involves the periodic infusion of large amounts of factor IX over a long period of time. It may also include the use of drugs and other treatments that suppress the immune system. There is no single method of immune tolerance therapy that has been shown to work the best. Various factor IX doses have been used with infusions given anywhere from several times a day to once a week with treatment lasting from several months to several years. Immune tolerance therapy is not without challenges. It is expensive, the routine injections can become a real burden for the hemophiliac and his family, and there are several possible complications such as the development of kidney problems. However, when it works, it can completely eliminate an inhibitor.

Inhibitor development might also be a problem in gene therapy. Gene therapy is a treatment that may eventually provide a complete cure for hemophilia by introducing new factor IX genes into the body to allow it to produce its own functional factor IX. Just as some patients develop inhibitors to factor IX injected as a concentrate, patients could also develop inhibitors to the factor IX produced by the new genes. However, one recent study in animals has shown that the continuous production of factor IX by new factor IX genes implanted in the liver may provide a kind of internal immune tolerance therapy. As the study progressed, animals gradually stopped producing inhibitor antibodies, allowing the factor IX produced by the new genes to work effectively. Thus, although the gene therapy patient who develops inhibitors might still need additional treatment by conventional methods for a period of time, there is hope that his inhibitor would eventually be eliminated. ****

June 7, 2003, Waldorf Astoria Hotel, New York. Over 300 people gathered at this gala event to celebrate Dr. Bruce Lee Evatt, Chief of the Hematologic Diseases Branch, at the Center for Disease Control and Prevention, for his outstanding research contributions to the hemophilia community.

While working for the Center for Disease Control in 1982, Dr. Evatt connected HIV/AIDS to the death of hemophilia patients and began an intensive campaign to educate the hemophilia community, the general public and the government of widespread implication. By 1984 he developed a heating method to inactivate viruses from blood products and received the Public Health Service Commendation Medal.In 1985 the AIDS epidemic was successfully halted in hemophilia patients.

With nearly 300 published articles in journals and textbooks, Dr. Evatt still finds time to travel as a medical advisor for the World Federation of Hemophilia. He travels to Chile, Uruguay, Costa Rica, Egypt and other places, visiting hospitals and patient groups and working with local health authorities.

Congratulations Dr. Evatt on your success and thank you for all your hard work and dedication to the hemophilia community.****

There will be a BBQ, Private Auction, Music and entertainment. All families are welcome. Corporate donations are being accepted and will be acknowledged in the Adirondack Spintacular Program which will be distributed to all participants. For more information please contact Lisa or Carol at (518) 863-2668

King of Prussia, June 19, 2003, Aventis Behring L.L.C today launched two new programs in the United States that are designed to help ensure that qualified people who rely on recombinant and plasma-derived therapies can continue to receive these life-saving treatments, even if they experience a lapse in third-party, private health insurance. The Choice Assurance Program will serve the bleeding disorder community, and the Gammar-PIV Assurance Program will focus on the needs of people who rely on intravenous immune globulin (IVIG) Therapy.

For more information please call Choice Assurance Hotline (866) 415-2164, website www.ChoiceAssurance.com or Gammar-PIV Assurance Hotline at (866) 415-2165, website www.GammarpivAssurance.com.