Emicizumab as a Potential Treatment Pathway for Select Hemophilia B Cases

New research highlights the potential of emicizumab, traditionally used to treat hemophilia A (HA), as a promising alternative therapy for certain hemophilia B (HB) genotypes, according to a study published in Blood.

HA and HB are X-linked bleeding disorders caused by reduced activity in clotting factors VIII (FVIII) and IX (FIX), respectively, and are traditionally managed by intravenous factor replacement. Emicizumab, a bispecific antibody that facilitates clotting without requiring FVIII, has transformed HA management by providing an effective, subcutaneously administered treatment. In contrast, HB continues to rely on intravenous FIX infusions, as subcutaneous non-factor therapies (NFTs) have faced challenges due to thrombotic complications.

“Although described as an FVIII mimetic, the emicizumab-FIXa complex is biochemically distinct from FVIIIa-FIXa,” explained Kyumin Lee, Division of Hematology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, and coauthors. “We hypothesized that these differences can be leveraged to repurpose emicizumab as a potential treatment for certain HB F9 genotypes.”

Researchers screened 105 HB-causing FIX variants and identified 41 that showed improved clotting activity when emicizumab was present. Specifically, they found that HB variants with loss-of-function (LOF) mutations in the FIX gene could benefit from the procoagulant effects of emicizumab, as demonstrated in laboratory tests and select patient samples. For instance, clotting times and thrombin generation significantly improved in patient blood samples with the FIX-I397T variant when emicizumab was added, indicating that emicizumab may support clotting activity in specific HB cases.

“Combined, these data demonstrate the potential of emicizumab and likely other FVIII mimetics to improve the procoagulant activity of selected HB-causing FIX variants,” the study authors concluded.

Although emicizumab doesn’t completely replicate FIX function, it could serve as a viable NFT for individuals with select F9 genotypes, offering an alternative to intravenous therapies. This research represents a promising step toward expanding treatment options for HB and underscores the need for further clinical trials to confirm the safety and efficacy of FVIII mimetics in this novel application.

Reference

Lee K, Chau JQ, Suber YB, et al. Enhanced procoagulant activity of select hemophilia B causing factor IX variants with emicizumab. Blood. 2024;144(11):1230-1235. doi:10.1182/blood.2023021944