The Breakthrough Drugs Transforming Hemophilia Care

When two of Sara Pavao’s sons were diagnosed with hemophilia soon after birth, she feared the blood-clotting disorder would limit their lives—or leave them disfigured. As young children, Kapono, now 18, and Duke, 13, bruised frequently. “They’d be black and blue down their shins, on their forearms, and even on their faces after bumping into things,” Pavao recalls.

Today, the brothers surf six-foot waves near their home on Kauai, Hawaii, ride dirt bikes on the island’s trails, and practice jujitsu. Kapono also kickboxes and previously played baseball and skateboarded—activities that would have been unthinkable for many children with hemophilia just a few decades ago.

Their freedom reflects a dramatic transformation in hemophilia care. The first major advance came with emicizumab, followed by several newer medicines introduced over the past two years. Known as nonfactor therapies, the drugs can prevent most dangerous bleeding without replacing the clotting protein patients lack. Some can be given to infants and require only a shot every few weeks, rather than intravenous infusions every few days. At the same time, gene therapy is allowing a limited number of adults to produce their own clotting factor after a single treatment, although the results vary and it remains unclear how long the benefits will last.

“This is one of the biggest success stories in medicine,” says Leslie Raffini, who treats children with hemophilia at Children’s Hospital of Philadelphia. The new medicines are highly effective at preventing bleeding, even in people with severe forms of the disease. Still, she emphasizes, the treatments do not eliminate the risk of bleeding entirely.

For families like Pavao’s, the transformation can be measured in more than bleeding episodes. “We always wanted them to live a full life, and they are,” says Pavao. Even traveling is easier. “We used to take a whole suitcase full of medicines. Now their drugs fit in a small box.”

People with hemophilia lack one of several crucial proteins needed for blood to clot properly. Hemophilia A, which accounts for roughly four out of five cases, is caused by insufficient clotting factor VIII; insufficient factor IX causes hemophilia B. The genetic condition affects roughly 30,000 Americans, the vast majority of whom are male because it is transmitted on the X chromosome. Women and girls can also have the condition, although their symptoms are often milder because many have a working copy of the gene on their second X chromosome.

Severe cases are generally diagnosed in the first weeks of life, when a newborn bleeds excessively after a circumcision or even after being gently held. Nearly all children, including those with milder deficits, are diagnosed by age two when they become mobile and bang into things, according to the U.S. Centers for Disease Control and Prevention.

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Without effective treatment, the prognosis can be grim, leaving many people disabled and at risk of early death. “The classic picture is of a child in a wheelchair because they’ve had numerous bleeds into their joints,” Raffini says. In countries where access to medication remains limited, preventable bleeding and permanent joint damage are still common.

For decades, hemophilia treatment has centered on replacing the missing clotting factor. Beginning in the 1960s and 1970s, scientists produced concentrated factor from pooled human plasma. These products greatly improved patients’ lives but became the source of a devastating health crisis during the 1980s, when HIV and hepatitis viruses spread through contaminated blood products. An estimated 4,000 Americans with hemophilia ultimately died of AIDS.

In the 1990s, scientists developed synthetic versions of the missing factors, which did not rely on donated plasma and made treatment much safer. Initially, doctors prescribed the drugs after bleeding began, but they eventually realized prophylactically elevating factor levels could prevent some bleeds from happening. People taking nonfactor medicines may also receive replacement factor as needed, such as before certain medical or dental procedures.

Factor replacement still has limitations. Protection rises after each infusion and then wanes before the next dose. With nonfactor medicines, “We don't have peaks and troughs, no sawtooth pattern of protection. We have a flat level basically across the board,” says Guy Young, who directs the blood disorders program at Children’s Hospital of Los Angeles. Young has conducted clinical trials of the drugs and consults for several manufacturers.

For some patients, factor replacement creates a more serious problem. About a third of people with severe hemophilia A develop neutralizing antibodies, known as inhibitors, that prevent the medicines from working. That initially happened to both of Pavao’s sons, significantly threatening their health. They overcame the problems with immune tolerance therapy, which studies show is successful about 60 percent of the time.

Nonfactor therapies offer a workaround because they help the blood clot without replacing the missing factor. Depending on the drug, they either fuse other proteins to produce the enzymes needed for clots or they inhibit other proteins that prevent clots, restoring balance to the clotting system. Bleeding events drop dramatically—up to 96 percent lower compared with no preventive treatment. “I can count on one or two fingers the number of patients we have in our program with joint disease from frequent bleeds. This is completely changing how these kids move into adulthood,” Raffini says.

The other major advance in hemophilia treatment is gene therapy, although it remains available to only a small number of patients. Hemgenix, currently the only hemophilia gene therapy on the U.S. market, is approved for certain adults with hemophilia B, the less common form of the disease. The therapy delivers a working copy of the factor IX gene to liver cells, allowing them to produce the missing protein and potentially reducing the need for regular treatment.

The results, however, vary widely. Five years after receiving Hemgenix in a clinical trial, patients produced an average of about 36 percent of the normal level of factor IX—enough to move many from severe to mild hemophilia. “But that’s an average. Not everyone gets there, and where they end up determines how much protection they get from bleeding,” says Radek Kaczmarek, a longtime hemophilia gene therapy researcher at Indiana University School of Medicine, who himself has the disease.

Among the 54 men enrolled in the trial, bleeding rates were nearly two-thirds lower during the five years after treatment than during the period when they received conventional preventive therapy. Nearly all were also able to stop regular factor IX infusions. The findings offer some of the strongest evidence yet that a single gene therapy treatment can provide benefits for years.

Researchers are also working to make gene therapy more potent and predictable. At the same time, other efforts aim to fix the mutation itself with gene-editing technologies, says Roland Herzog, another longtime researcher at the university, who, along with Kaczmarek, published a review of the history and progress of hemophilia gene research last year in the journal Molecular Therapy. Other efforts aim to fix the problematic mutation with gene editing technologies.

“Patients are very interested in the idea of a one-and-done treatment, which only gene therapy can provide,” Herzog says. “This could basically rid them of the disease without needing any more injections, hopefully permanently.”

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Even the best medicines available have potentially dangerous side effects. Gene therapy patients require regular monitoring because the treatment can inflame the liver and reduce production of the new clotting factor. Some nonfactor medicines can also tip the clotting system too far in the other direction, causing rare but potentially dangerous blood clots.

Although the treatments prevent most bleeding, none eliminates the risk. Doctors therefore still generally advise people with hemophilia to avoid the roughest contact sports. “Activities like football and ice hockey are still not good ideas,” Raffini says.

But children with hemophilia have many more options than they once did. Eight-year-old Carson Cusimano, who has hemophilia A, competes in go-kart races. His mother, a nurse, gives him a weekly intravenous infusion of recombinant factor. His four-year-old brother Bryson, with the same condition, actively bikes around their Charlotte, North Carolina, neighborhood. The family doesn’t think twice about taking the boys boating on the lake or jumping waves in the ocean. “I don’t think they notice that they’re different,” their mother, Kaitlin Bartholomew, says. “They get their infusions, and they don’t bleed.”

Pavao says her sons’ doctor appreciates her desire to let her boys pursue activities that bring them joy. “I’m very honest with her about what they’re doing, and she never gives me a hard time,” she says.

Still, Pavao eagerly anticipates the treatment advances yet to come. “I think one day it'll get to where their disease is not even a blip on their radar, that there will be no cautions or restrictions at all. That’s certainly what I hope for.”