A Cure for Hemophilia?

In 1964, a laboratory breakthrough sent hopes soaring that a cure for hemophilia A and B was a possibility. That was the year Judith Graham Pool, PhD, professor of medicine at Stanford University, discovered how to derive factor-rich cryoprecipitate from human plasma in large quantities. For the first time, blood-clotting factors could be produced cost-effectively and consistently.

Today, researchers have discovered how to manufacture factor products derived from plasma, as well as synthetic factor products using recombinant technologies that do not require human plasma. Factor can be concentrated and mass-produced to create stable products that can be used prophylactically to prevent bleeds.

“Now we have a lifelong replacement therapy,” says Steven W. Pipe, MD, associate professor of pediatrics and pathology at the University of Michigan Medical School. He is also pediatric medical director of its Hemophilia and Coagulation Disorders Program. “Patients are liberated from treatment in hospital settings. Now they can self-manage their disease at home. It is not, strictly speaking, a cure, but similar to the way people in the 1920s considered insulin to be a cure for diabetes.”

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The definition of “curing” a chronic disease varies widely. The question, “What does a ‘cure’ mean for you?” was posed to consumers attending the 2006 annual meeting of the Lone Star Chapter of the National Hemophilia Foundation (NHF) in Houston by Rita R. Gonzales, NHF board member and the mother of two sons with hemophilia. “It was very informal,” says Gonzales. “I surveyed about 20 people and encouraged them to speak freely about their ideas. Their responses were all over the ­ballpark.”

The answers ranged from “getting the body to express factor” to the simple expectation of “my son not having to infuse twice a week” to the hopeful notion of “a permanent fix or reversal of the genetic defect.” The latter interviewee added, “But we have to be realistic and ask what is achievable in the near future. There will be steps along the way.”

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Defining Moments

“In my mind, the definition of a cure has changed significantly since our son was born,” says Richard Metz, MD, a Los Angeles primary care physician and father of an adult son with severe hemophilia A. Metz is a former member of the NHF board. “A long time ago, a cure was thought of as nothing less than changing the gene—getting rid of the deficiency so that subsequent generations would not be affected. But as time has gone on, we’ve seen so many issues and problems in gene therapy research, and it’s taking a lot longer than expected.” Meanwhile, many safe, innovative therapies have emerged to improve the lives of those with hemophilia.

When Michael Metz was born in 1987, physicians were just beginning to treat hemophilia with safer, viral-inactivated­, plasma-derived concentrates. “Then recombinant products came out, along with safer clotting factor, and that was another huge step toward a cure,” says Richard Metz. A major burden was alleviated, and it changed Michael’s future. “He rarely bleeds, leads a fairly normal lifestyle and is doing quite well.”

Eliminating hemophilia won’t happen soon, because about one-third of cases involve a random—not inherited—gene mutation, according to NHF. Also, several different mutations can cause low factor levels. “It’s not just one disease, and it’s not going to be completely wiped out,” says NHF board member Eileen Bostwick, PhD. She is the mother of a college-aged son with severe hemophilia A. “But for a lot of laypeople, this is what they think of when they hear the word ‘cure.’”

Deciphering the meaning of “cure” is important to the bleeding disorders community at large, since public support for chronic disease research funding often focuses on eradication. An NHF working group met in 2007 to begin hammering out its own definition of a cure. “We want donors to understand very specifically what we are going after,” says Bostwick. With Metz, she served on the panel of researchers, physicians and other parents. Together, they developed a two-part working definition that was adopted by the board and incorporated into NHF policy documents: A cure, it reads, constitutes “restoration of good health by restoring one’s ability to maintain hemostasis without ­significant, ongoing medical intervention.” The second part of the definition notes, “Until a cure is available, there is continuous improvement in the quality of life both physically and mentally for all those afflicted with bleeding/coagulation disorders.”

Beyond Biology

“It would be nice if we could wipe hemophilia off the face of the Earth, but right now we have good enough treatments so that people who have it can function normally,” says pediatrician and hematologist-oncologist Jan van Eys, PhD, MD, professor emeritus at Vanderbilt University School of Medicine in Nashville, Tennessee.

After more than 45 years of treating children with hemophilia, van Eys is convinced that a cure is defined by how well a person functions in his or her life, a concept that is not unique to hemophilia. A cure is part biological, part psychological and part social, he believes. “The idea of a biological cure is what people get hung up on,” van Eys says. “But there is enough factor in the world such that people with hemophilia will be able to function well if they have access and are able to use it. So the biological is the least important of the ‘cures’ in that respect.”

Two factors are necessary for functioning well, van Eys believes. “First, you have to be at ease with having or having had the disease, and not consider yourself stigmatized or nonfunctioning,” he says. “Second, society has to accept you as having or having had the disease—others expect and allow you to function as well as anyone else.”

A psychological and social cure may be more easily achieved by today’s newest patients. “The conversation [physicians have] with parents has changed a lot,” van Eys notes. “Prophylaxis can start at a very early age, and a child may survive without any real joint damage in his life. So I don’t have to warn them about all the crippling that may happen. Hemophilia has changed from a doomsday diagnosis to the potential of a very normal lifestyle.”

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While a normal lifestyle is now possible for children with hemophilia, Metz notes that achieving a cure in this sense is a deeply personal journey. He says it is affected by a person’s experiences of and with the disease. For some, he says, the damage is already done. “A person who’s been affected will have the psychological scars and issues of growing up with a disease from early childhood,” Metz says. “Even if we had a therapy where a person no longer had to infuse, it won’t immediately ‘cure’ people who have other problems, like joint disease or HIV infection.” In his opinion, effective gene therapy would also not have an impact on existing problems. “Even if my son never has another bleed, he can pass the defective gene for hemophilia on to his daughters,” says Bostwick. “He has to live with that.”

For these reasons, van Eys advocates expanded mental health research and support for the bleeding disorders community. “When we talk about research, it is always a temptation to accentuate the biological cure,” says van Eys. “But I believe that it’s just as important to tell parents, ‘We can make your son a happy, healthy, functioning child, with just one problem: He needs an infusion.’”

Small Steps Forward

Today’s newly diagnosed children with inherited bleeding disorders can look forward to a life unimaginable 20 to 30 years ago—relatively unrestricted and with fewer worries about life-threatening bleeds and even joint damage. But parents of these newborns will naturally have higher expectations for their child’s future—including a day when the disease will be eliminated entirely from his or her body. They are as invested as any generation of parents in the medical advances, such as new drug and genetic therapies, that will bring the prospect of a cure even closer.

“The original treatment goal for hemophilia was to save lives, then it was to control bleeding episodes and then it was to prevent long-term joint disease,” says Pipe. “In this way, we are inching toward a cure. Most of what we have seen recently have been continued life improvements, particularly with more convenient therapies like room-temperature stable factor and variations in vial sizes. Longer-acting products are now on the horizon.”

Current clinical trials are recruiting people with hemophilia, inhibitors or von Willebrand disease (VWD) to test new regimens and formulas of factor replacement products, new delivery systems and gene therapy methods.

Patients with VWD are participating in studies testing interleukin-11 (IL-11), a protein that has been used in cancer patients to stimulate bone marrow production of platelets. It is given subcutaneously (under the skin). In patients with VWD, it increases the levels of von Willebrand factor (VWF) and fibrinogen, both of which are needed for clot formation. IL-11 is being evaluated in women with menorrhagia, severe menstrual bleeding; adults who have been unresponsive to DDAVP, one of the standard treatments; and in adults undergoing surgery or major dental procedures. Other studies are testing combination factor VIII/VWF concentrates in patients with VWD under general conditions and in those having surgery.

Although the promise of gene therapy in treating patients with bleeding disorders has not yet been realized, several studies of other novel technologies are underway in 2010. Researchers at NHF’s “Novel Technologies and Gene Transfer for Hemophilia” workshop, held in February at the University of North Carolina at Chapel Hill, reported encouraging results from clinical trials of longer-lasting, faster-acting recombinant factor VIIa, a bypassing agent, in patients with inhibitors. Three products are now in advanced stages of testing.

Another experimental treatment for patients with severe hemophilia A who have developed inhibitors is rituximab, a monoclonal antibody. It has successfully been used in patients with leukemia and rheumatoid arthritis, and is being evaluated to see if it can block or minimize the body’s production of inhibitors.

Some researchers are using gene therapy techniques to insert normal genes into patients with bleeding disorders. The adeno-associated virus, which does not cause disease in humans, is the vehicle by which several research teams are placing the normal factor IX gene into the bodies of patients with severe hemophilia B to see if it provides sustained clotting factor production. (See “Cautious Steps Forward” in “Power to the People,” HemAware January/February, 2009). Other researchers are experimenting with nonviral gene therapy techniques.

An oral delivery system is being tested in patients with hemophilia A or B who have a nonsense mutation, which causes their body to prematurely stop clotting factor production. The drug, Ataluren, was previously used in patients with cystic fibrosis and Duchenne muscular dystrophy. (See “The Allure of Ataluren,” sidebar to the story, “What’s Your Genotype?” HemAware, Spring 2010). It is simply stirred into a liquid beverage and swallowed.

According to Pipe, the trials that have been completed involving gene transfer for hemophilia all showed a very good safety record. Importantly, these first trials in humans provided important observations that have led to additional basic research with hopes of coming back to the clinic with even more safe and effective strategies. “That’s what makes progress seem so slow. Since these trials have been aimed primarily at the safety of gene therapy—rather than a cure—it’s always been back to the drawing board.” He gives the example of using bone marrow transplantation to cure some cancers, but at the risk of triggering other chronic, life-threatening diseases. “We need to be very careful, as we move forward with genetic research, that we don’t adopt it so quickly that we introduce another set of complications for patients.”

Finding research subjects in the developed world, where there are effective treatments, could pose a challenge, Metz predicts. “Eventually, in a few decades, if we are able to really alter the gene in a safe way with fewer risks, how would you convince people with hemophilia who are leading essentially a normal life to undergo a medical procedure that would carry some risk?” he asks. In developing countries, where people with hemophilia have fewer treatment options and face joint disease and even death, it may be easier to find subjects. However, this creates an ethical problem when researchers disproportionately recruit from populations that lack treatments that are readily available in the US, Metz believes.

Pipe expects clinical gene therapy research on other diseases—muscular dystrophy, immune deficiencies and Parkinson's disease—to yield valuable results for bleeding disorders research. “I don’t think people should be so disappointed that they don’t see a lot going on in hemophilia trials now,” Pipe says. “We need to take the time to concentrate on basic science and animal trials and look also at clinical successes elsewhere.”

An additional concern is cost. “This type of research is very, very expensive, and there is no rapid discovery,” says Bostwick. “The bleeding disorders community is unlikely to ever raise enough money ourselves, so we historically have relied heavily on pharmaceutical companies.” 

Advocates shouldn’t be discouraged or concerned that funders will bypass bleeding disorders to concentrate on other, more life-threatening diseases, van Eys says. “Hemophilia A is a unique disease because it resides within a specific gene, which has always made it attractive to genetic researchers,” he says. “I don’t worry about the genetic aspects being ignored.”

“Another thing working to our advantage is increased awareness of clotting disorders in general, like deep vein thrombosis and pulmonary embolism,” says Bostwick. “These disorders are part of the same picture as they are also caused by problems within the clotting cascade.” Since they affect a larger number of people, greater resources are being focused on the basic science that can benefit hemophilia research as well.

People with hemophilia, and those yet to be born with the disease, can look forward to continued incremental advances toward safer, more effective treatments to prevent bleeding. “The ultimate cure would be if the gene were eradicated so that for some generation down the road, no one would ever have to worry about it again,” says Metz. “Mapping the human genome was science fiction 20 to 30 years ago. I believe it’s possible, but it remains the very long-term vision of what a cure could be.”