FIX inhibitors pose hurdles for kids with hemophilia B: UK study

Children with severe hemophilia B who develop antibodies, also known as inhibitors, against coagulation factor IX (FIX) replacement therapies continue to face major treatment challenges, according to a small study in the U.K.

The study found that attempts to eliminate these inhibitors using an approach called immune tolerance induction (ITI) succeeded in only half of the children who underwent treatment, highlighting both the difficulty of eradicating inhibitors and the ongoing need for alternative treatment options for these patients.

The study, “UK Experience of Children With Inhibitors in Severe Haemophilia B: A Report by the UKHCDO Paediatric Working Party,” was published as a letter to the editor in Haemophilia.

Hemophilia B is caused by mutations in the F9 gene that result in a deficiency of FIX, a protein needed for blood clotting. As a result, people with the condition may experience prolonged or excessive bleeding episodes.

FIX replacement therapy, the standard treatment for hemophilia B, involves supplying the missing clotting factor through infusions into the bloodstream. It may be given regularly as preventive (prophylactic) treatment to reduce the risk of bleeding episodes, or on demand to control bleeds when they occur.

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Immune system at work

In some patients, the immune system recognizes the infused FIX as foreign and produces inhibitors that block its activity. These inhibitors are considered the most serious treatment complication in severe hemophilia B, because they can make FIX replacement therapies ineffective and leave patients with fewer options to prevent or control bleeding.

Inhibitors may also trigger severe allergic reactions and, in some cases, nephrotic syndrome, a kidney disorder characterized by excess protein loss in the urine.

“The current absence of any commissioned non-factor alternative treatments for [severe hemophilia B] inhibitor patients in the UK means that this small group of children continues to have an unmet need, even though there are some promising therapies awaiting licensure and/or commissioning,” the researchers wrote.

One strategy to eliminate inhibitors is ITI, which involves repeated exposure to FIX while dampening immune responses to train the immune system to accept the clotting factor rather than attack it. However, because inhibitors develop in only about 5% to 10% of people with severe hemophilia B, there is limited evidence to guide their management, and reported ITI success rates vary widely.

Drawing on data from the UK National Haemophilia Database through 2024, researchers from the pediatric group of the United Kingdom Haemophilia Centre Doctors’ Organisation reported on the clinical experience of 12 boys with severe hemophilia B who developed FIX inhibitors.

The children had a median age of 18.5 months at the time inhibitors were first detected. Eight boys were receiving standard half-life FIX replacement therapy at the time, and four were being treated with extended half-life therapies, which remain in the bloodstream longer. On average, inhibitors were identified after a median of 10 days of exposure to treatment.

Nine of the 12 boys (75%) experienced allergic or anaphylactic reactions when their inhibitors were first detected. Another developed a fever-related reaction.

Eight children underwent ITI. Five initially received a modified Malmö regimen, which combines FIX replacement therapy with immunosuppressive medications to help the body tolerate the clotting factor.

Three of those children ultimately achieved tolerance and were able to continue receiving preventive FIX treatment. However, two failed treatments despite additional ITI attempts, including immunosuppressive therapies.

Three other boys underwent a different ITI approach known as the Beutel regimen, which pairs high-dose FIX replacement therapy with immunosuppressive medications.

One achieved tolerance and remained on FIX prophylaxis, one relapsed after initially responding and was undergoing a second ITI attempt at the time of reporting, and the third stopped treatment early after developing proteinuria, an excess of protein in the urine that can signal kidney problems.

The remaining four children did not undergo ITI. According to the researchers, decisions not to pursue the approach were driven by concerns about the risks associated with immune suppression, logistical challenges, or family preference. These patients received alternative therapies to help prevent or manage bleeding episodes.

Overall, tolerance was achieved in four of the eight boys who underwent ITI.

“This small national cohort of boys with [severe hemophilia B] complicated by inhibitor development demonstrates again the relatively low likelihood of achieving immune tolerance following ITI,” the researchers wrote.

New, non-factor therapies expected to become available in the UK could provide an important alternative for this small but particularly difficult-to-treat group of patients, they said.