Discovery of Hemophilia A Subgroups May Help Predict FVIII Inhibitor Development

Researchers have identified four distinct subgroups of hemophilia A patients according to their profile of factor VIII-targeting antibodies. This may help predict those at risk for developing inhibitors that halt the efficacy of FVIII replacement therapy.

The results were presented in a poster titled “Data Coming out of the Human Inhibitor PUP Study (HIPS) Reveal 4 Subgroups of Patients with Distinct Antibody Signatures” at the 60^thAmerican Society of Hematology Annual Meeting in December 2018 in San Diego, California.

Hemophilia A is a bleeding disorder caused by deficiency of FVIII, a protein involved in blood clotting. Patients can receive replacement therapy using FVIII, but about 30 percent of them develop antibodies, also called inhibitors, against it.

Why some patients develop these neutralizing antibodies is not fully understood; nonetheless, it is critical to discover biomarkers that predict the development of these inhibitors so that a potential immune intervention strategy is initiated before any major complications arise.

The HIPS study (NCT01652027), an ongoing multicenter observational study, enrolled 25 patients who had not yet received treatment with FVIII. Researchers use blood samples to test for FVIII inhibitors, specific antibodies and mutations, as well as circulating immune cells.

The study aims to identify early immune biomarkers that may help predict the risk for previously untreated patients with severe hemophilia A to develop FVIII inhibitors.

Researchers tested the samples before and after initial treatment with Advate, a third-generation recombinant FVIII; 7-9 days after the first treatment, and 5-7 days after the fifth, 10th, 20th, 30th, 40th, and 50th days of treatment with FVIII.

The analysis revealed the existence of four subgroups of patients, each showing a particular signature of FVIII-specific antibodies.

In the first subgroup, the seven patients developed FVIII inhibition detected after two measurements on consecutive days. In these patients, researchers observed that antibodies targeting FVIII with high affinity were diverse (three different types) and were seen before the first detection of inhibitor activity. All patients in this subgroup had high-risk mutations in the FVIII gene.

A second subgroup of two patients had low levels of FVIII inhibitors and only one type of high- affinity antibody, without the detection of any other antibody classes.

A third subgroup of seven patients had antibodies that did not neutralize the therapeutic activity of FVIII. Six of these patients developed a single type of antibody with low affinity for FVIII; the seventh patient developed a high-affinity antibody.

The fourth subgroup included seven patients who never developed any antibodies/inhibitors against FVIII.

The researchers did not state what happened to the other two participants.

Researchers detected no correlation between the levels of circulating regulatory immune cells, namely FoxP3 positive T cells, and the development of FVIII inhibitors or FVIII-specific antibodies. Immune tolerance to the replacement therapy is linked with induction of regulatory T cells, like FoxP3-T cells.

Overall, “data obtained from the HIPS study identify four distinct patient subgroups based on their specific antibody signatures,” researchers said.

“Most importantly, high-affinity class-switched antibodies preceded clinical inhibitor detection, substantiating their potential role as suitable predictive biomarkers for inhibitor development,” they concluded.