A Very Happy Christmas for Patients with Christmas Disease

SRxA’s Word on Health couldn’t resist this story. Not only did it provide us with a seasonal healthcare title but it allowed me to blog about a condition that I have been passionate about for most of my life. As a college student, one of my friends and mentors had hemophilia. He taught me a lot about the disease, about courage and dignity and hope and despair. His death from AIDS left me saddened but determined to pursue a career in healthcare. A few years later I had the opportunity to head up a hemophilia research project in the UK. One thing led to another and I spent the next 20 years of my life involved with transfusion medicine and blood products therapies. Although I’m no longer working directly in that field, later today, I will be running a training course on hemophilia.  I guess you could say it’s in my blood!

For those of you wondering what the above recollections have to do with Christmas Disease, let me explain.

Hemophilia B, a deficiency of coagulation factor IX (FIX) is also known as Christmas disease. Hemophilia is an inherited, potentially life-threatening disorder affecting an estimated 20,000 Americans, almost all of them males. Their blood doesn’t clot properly because of a faulty gene. In severe cases, they can spontaneously start bleeding . Internal bleeding in the joints leads to debilitating movement problems and intense pain.

Unlike most diseases that were named after the doctor that discovered them, hemophilia B is rather special because it was named for the first patient described to have it. Stephen Christmas was born in London, UK in 1947.  He emigrated to Canada at a young age and was diagnosed with hemophilia at age two by Toronto’s Hospital for Sick Children. The family returned to London in December 1952 to visit relatives and, during the trip, young Stephen was admitted to hospital. A sample of his blood was sent to the Oxford Hemophilia Centre where it was discovered that he was not deficient in Factor VIII, which is normally decreased in classic hemophilia A, but a different protein, which received the name Christmas factor in his honor (and later Factor IX).

Now, almost 60 years later, scientists have described the first unequivocal evidence of successful gene therapy for hemophilia. Past gene therapy experiments improved blood-clotting for only a few weeks.

This week, the New England Journal of Medicine reports that a single intravenous injection of an adenovirus-associated virus (AAV) vector that expresses FIX  was successfully used to treat 6 patients  with hemophilia B for more than a year. This is a remarkable breakthrough, given that patients normally need to infuse FIX two or more times every week.

The six men each got a single, 20-minute infusion of AAV. Each saw the amount of clotting proteins in their blood increase from less than 1% of normal levels to at least 2%, and in one case as much as 11%.  Although that may not seem like a lot, it was enough to allow all the men to cut back on the number of regular FIX treatments, and four stopped conventional treatment altogether.

Because their prophylactic use of factor concentrate was either eliminated or reduced, dramatic cost savings were achieved. In the United States, annual costs for a single adult patient with hemophilia B are approximately $300,000. Over a lifetime this adds up to a staggering $20 million. Whereas, the AAV is estimated to cost $30,000 per patient

An editorial that accompanied the study asked: Should the practicing hematologist rush to order this gene therapy vector if it is approved by the Food and Drug Administration?

Their answer – “probably yes!”  Still, they caution that the risks of this procedure are not yet totally clear. In one patient, liver enzyme levels were found to be about five times the upper limit of normal 2 months after gene therapy.

Nevertheless this gene therapy trial for hemophilia B is truly a landmark study, since it is the first to achieve long-term expression of a blood protein at therapeutically relevant levels. If further studies determine that this approach is safe, it may not only replace the cumbersome and expensive protein therapy currently used for patients with hemophilia B, but also translate into applications for other disorders, such as alpha₁-antitrypsin deficiency, and hyperlipidemias.

Now, that really would be a Christmas gift.

High hopes for long-term hemophilia B therapy

Investigators from St Jude Children’s Research Hospital and University College London recently announced extremely encouraging preliminary results of a Phase I/II gene therapy trial in patients with hemophilia B.

Hemophilia B, is a deficiency of Factor IX (FIX), one of the proteins necessary for normal clot formation. The disease affects about 1 in 30,000 people.  Without treatment, people with hemophilia B are at risk for uncontrolled, disabling and potentially fatal episodes of both internal and external bleeding.

The FIX gene is carried recessively on the X chromosome, and as a result the disorder, just like hemophilia A (FVIII deficiency), is almost exclusively seen in males, though it is carried by females.  Patients with severe hemophilia B, must normally inject themselves intravenously with FIX twice a week.

For such patients, gene therapy offers the enticing prospect of a near normal life, but previous studies have yielded disappointing results.

This study, presented last week at the American Society of Hematology annual meeting, was designed primarily to evaluate the toxicological safety study of low and intermediate doses. Because of the low dose used, researchers anticipated that trial subjects would produce little or no detectable FIX. So it was something of a positive surprise when the first patients FIX levels rose from <1% to 2% of normal, after infusion of the experimental vector.

While this rise, may not sound all that impressive, for a person with hemophilia it means the difference between severe and moderate disease.

Even more surprisingly, the patient’s FIX production remains elevated more than nine months later. Since the infusion the patient has also not suffered any spontaneous joint bleeds or needed prophylactic treatment.

Work on the vector began more than 10 years ago. An adeno-associated virus (AAV) vector known as AAV8 was picked because the incidence of natural infection with AAV8 is low and, like although it targets liver cells it does not integrate into the patient’s DNA. Participants received no immune suppressing drugs prior to infusion of the experimental vector.  The results so far suggest the experimental vector does not trigger the T-cell mediated immune response seen in a previous hemophilia B gene therapy trial.

The highest dose of the novel gene-vector combination is scheduled to be infused into the fifth and sixth study participants by mid-January. Investigators will then decide whether to expand the trial to include four more adults with severe hemophilia B.

As always SRxA’s Word on Health will be watching closely and will bring you news of further developments as they are announced.