Preventing factor VIII (FVIII) inhibitors following replacement therapies with FVIII products in patients with hemophilia A remains an unmet medical need. Better understanding of the early events of evolving FVIII inhibitors is essential for risk identification and the design of novel strategies to prevent inhibitor development. The Hemophilia Inhibitor Previously Untreated Patients (PUPs) Study (HIPS; www.clinicaltrials.gov #NCT01652027) is the first prospective cohort study to evaluate comprehensive changes in the immune system during the first 50 exposure days (EDs) to FVIII in patients with severe hemophilia A. HIPS participants were enrolled prior to their first exposure to FVIII or blood products ("true PUPs") and were evaluated for different immunological and clinical parameters at specified time points during their first 50 EDs to a single source of recombinant FVIII. Longitudinal antibody data resulting from this study indicate that there are 4 subgroups of patients expressing distinct signatures of FVIII-binding antibodies. Subgroup 1 did not develop any detectable FVIII-binding immunoglobulin G (IgG) antibodies. Subgroup 2 developed nonneutralizing, FVIII-binding IgG1 antibodies, but other FVIII-binding IgG subclasses were not observed. Subgroup 3 developed transient FVIII inhibitors associated with FVIII-binding IgG1 antibodies, similar to subgroup 2. Subgroup 4 developed persistent FVIII inhibitors associated with an initial development of high-affinity, FVIII-binding IgG1 antibodies, followed by IgG3 and IgG4 antibodies. Appearance of FVIII-binding IgG3 was always associated with persistent FVIII inhibitors and the subsequent development of FVIII-binding IgG4. Some of the antibody signatures identified in HIPS could serve as candidates for early biomarkers of FVIII inhibitor development.

Aflac Cancer and Blood Disorders Center Emory University Children's Healthcare of Atlanta Atlanta GA

Carver College of Medicine Stead Family Department of Pediatrics University of Iowa Iowa City IA

Clinical Coagulation Research Unit Department of Translational Medicine Lund University Malmö Sweden

Comprehensive Center for Hemophilia and Coagulation Disorders Weill Cornell Medicine New York NY

Department of Paediatric Haematology University Hospital Brno Masaryk University Brno Czech Republic

Department of Pediatrics Medical University of Vienna Vienna Austria

Division Hematology Oncology Department of Medicine University of Pittsburgh Medical Center Pittsburgh PA

Division of Hematology Cancer and Blood Diseases Institute Cincinnati Children's Hospital Medical Center University of Cincinnati Cincinnati OH

Drug Discovery Austria Baxalta Innovations GmbH a member of the Takeda group of companies Vienna Austria

Hemophilia Center Oregon Health and Science University Portland OR

Hemophilia Treatment Center University of Kentucky Lexington KY

Indiana Hemophilia and Thrombosis Center Indianapolis IN

Institute Krems Bioanalytics IMC University of Applied Sciences Krems Krems Austria

IRCCS Ca' Granda Foundation Maggiore Hospital Policlinico University of Milan Milan Italy; and

Pediatric Hematology Amsterdam UMC University of Amsterdam Emma Children's Hospital Department of Molecular Cellular Hemostasis Sanquin Research Amsterdam The Netherlands

University of Texas Health Science Center Houston TX

University of Utah School of Medicine Salt Lake City UT

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Prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures during FVIII inhibitor eradication

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ClinicalTrials.gov
NCT01652027