Spring 1997 - Factor Nine News

In a recent issue we described prophylactic treatment and the health benefits it can provide. However, we also described some of the practical problems involved in getting a FIX injection every day, especially with young children. Drug delivery scientists at the Red Cross and other organizations have been working to solve these problems. They are developing systems that provide FIX or another drug continuously and without the need for constant injections. In fact, continuous delivery of FIX, being much more like the way the body normally works, should be an improvement over once-a-day prophylactic treatment and provide additional health benefits.

The Red Cross is adapting currently-available implantable pumps for continuous long-term delivery of FIX. These pumps have been developed by other manufacturers for various treatments such as delivery of chemotherapy drugs to cancer patients and delivery of insulin to diabetics. They are implanted in the abdomen, completely inside the body. This eliminates the problem of infection seen with the catheters sometimes used in prophylaxis. Anytime a device passes through the skin it provides a place for infection to enter the body. The pumps work in various ways, some are mechanical run by batteries, and one is run by gas pressure. Once of the electrical pumps can even be controlled by remote control like a TV. All of the pumps have a reservoir that holds the drug being administered and that reservoir is typically refilled about once a month by an injection. Thus instead of daily injections, a hemophiliac with an implantable pump would receive a FIX injection once a month to refill the pump reservoir. The electrical pumps must have the batteries changed every few years which involves a surgical procedure while the gas pressurized pump is recharged every month when the drug reservoir is refilled.

One of the major challenges involved in adapting these pumps for delivery of FIX is finding ways to keep the FIX stable and active for a month. Unlike many of the drugs that have been used with these pumps previously, proteins like FIX tend to degrade and lose activity over time, especially when they are dissolved in a solution. This is the reason that FIX normally comes as a freeze-dried powder which is much more stable. Even freeze-dried, FIX often must be refrigerated because proteins degrade more slowly at lower temperatures.

Finding a way to keep FIX active for a month in solution at body temperature has not been trivial. Red Cross has been doing extensive biophysical characterization of FIX to see what causes it to lose activity and what materials can be included in a formulation to maintain stability. The formulation is the mixture of compounds included with a drug. With an injectable drug like FIX these compounds,

called excipients, are included mainly to improve stability. Red Cross scientists have succeeded in developing a formulation that is stable for a month. They are currently developing methods for

evaluationof pumps with the stable FIX formulation in dogs. If that work is successful, that is, if the method appears safe and effective, the next step would be to test the pumps in human volunteers.

Another practical challenge in prophylactic treatment of individuals with hemophilia B is that it takes a lot of FIX. Even though studies have shown that the lower lifetime cost of health care for hemophiliacs on prophylactic treatment more than makes up for the cost of the additional FIX required, FIX is currently relatively expensive and the amount available from plasma is limited. Because of this the Red Cross and other organizations have been working to find other sources of FIX. The first such product, a recombinant FIX made by genetic engineering was recently licensed by the FDA. This product tradenamed BeneFIX , is made by Genetics Institute in Cambridge, MA. BeneFIX is made by cell culture, that is the gene for human FIX is inserted in animal cells which causes them to produce FIX. These cells are grown in the laboratory (”cultured”) to produce FIX which can be purified to produce a therapeutic product. This method potentially solves the supply problem because an unlimited number of cells can be grown up to produce as much FIX as is needed.

The Red Cross is approaching the development of a genetically engineered FIX in a different way. Instead of working with individual animal cells grown in the laboratory, Red Cross is genetically engineering whole animals to produce proteins like FIX in their milk. These “transgenic animals” are

produced by inserting the gene for human FIX in the egg cell of an animal. Then when the egg grows into an animal, that animal will have the gene for human FIX in every cell of its body. The trick is that the original FIX gene includes another piece of genetic material that only causes the FIX to be produced in mammary tissue, that is, to be produced in the animal’s milk. The FIX can then be purified from the milk. This has the potential to make much larger quantities of FIX, or any other protein, available than could be produced from plasma and potentially at a much lower cost. Working with the engineering and agriculture schools at Virginia Polytechnic Institute and State University (Virginia Tech), the Red cross has produced pigs that produce human plasma proteins in their milk. In addition to FIX, erythropoietin, protein C, and other coagulation factors have also been produced in transgenic animals.

Finally, of utmost importance is the safety of any therapeutic product. The current plasma-derived products have a very good safety record because of the viral inactivation methods developed over the last decade. Recombinant products are newer but so far appear to be free of human viruses, as expected. The Red Cross and other manufacturers continue to devote major resources to improving viral inactivation and removal methods. The Red Cross is currently studying the use of iodine and gamma irradiation for viral inactivation. In addition, much emphasis is being placed on studies of prion diseases. These are fatal diseases such as “Mad Cow Disease” in animals and Creutzfeld-Jakob Disease (CJD) in humans. Some scientists believe that these diseases are caused by viruses while others think they may be caused by an abnormal protein they call a prion. No one knows for sure whether these diseases can be transmitted by blood or blood products. To be safe the Red Cross currently does not distribute any product made from plasma from a donor diagnosed with CJD. Currently the Red Cross is collaborating with outside scientists to determine whether CJD can be transmitted by plasma products and to develop methods to prevent any such infectivity.

RECOMBINANT FACTOR IX IS NOW AVAILABLE! Genetics Institute, Inc. (GI) has introduced the first and only plasma-free, albumin-free recombinant factor IX, BeneFIX Coagulation Factor IX (Recombinant). BeneFIX is the only factor IX product without blood or plasma. BeneFIX contains no albumin and, for added viral safety, includes a nanofiltration step in its purification process. BeneFIX is the latest creation of scientists at GI , who have been pioneers in recombinant technology with a 17 year history of developing recombinant products.

Recombinant Technology means “Recombined”. It uses the science of genetic engineering to identify a specific gene (like factor IX). Then scientists remove the gene and insert it into the DNA of a special production cell. These “Recombined” production cells then grow and multiply to produce factor IX.

For over a decade recombinant technology has created many diverse and exciting therapies that have been used in over 100 million treatments worldwide without a single report of viral transmission. Recombinant products are currently used to treat diabetes, anemia, hemophilia, multiple sclerosis, cystic fibrosis, heart attacks and more.

For more information please call Genetic Institute’s toll free number at 888-999-2349, visit their Internet site - http://www.genetics.com or E-mail - info@genetics.com.

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