Observational Study of Recombinant Factor-VIII-Fc, Eloctate, in Hemophilia Patients with and without Inhibitors

Background: Inhibitor formation is a serious complication of hemophilia A, occurring in up to 30% with severe disease. It is associated with a T-cell response to infused factor VIII which neutralizes and renders it ineffective. Bypass therapy (rVIIa, FEIBA) is less effective, resulting in high morbidity and mortality. While immune tolerance (ITI) with high-dose FVIII neutralizes the inhibitor, it is costly, invasive, and unsuccessful in 30%. Basic studies suggest rFVIIIFc, Eloctate, is less immunogenic than standard recombinant FVIII, rFVIII, as the Fc portion contains regulatory T cells that promote tolerance. In the hemophilia mouse model, rFVIIIFc reduces inhibitor frequency, lowers titer, and shortens ITI, but little is known of its impact on inhibitor patients, as they were excluded from clinical trials. Methods: We, therefore, reviewed outpatient medical records on 60 patients with hemophilia A with and without inhibitors, cared for at the Hemophilia Center of Western Pennsylvania between January 1, 2006 and June 1, 2017, who were treated with rFVIIIFc and on whom anti-FVIII inhibitor assay results were available. This study was approved by the University of Pittsburgh IRB as an expedited study, PRO17020097. Means, medians, and standard deviations or frequencies (percentages) were determined for clinical variables, including age, race, proportion developing inhibitors, peak titer, proportion achieving tolerance, and time to tolerance on ITI. Comparisons between patients with high-titer, low-titer, and no inhibitors were by student9s t test for continuous data, or chi-square or Fisher9s exact test for discrete data. A p-value of Results: The 60 patients whose charts were reviewed for this study included 18 (30.0%) with hemophilia A with an inhibitor (HA-I), of whom 9 had high-responding inhibitors (≥5 BU) and 9 had low-responding inhibitors ( 0.5, and in disease severity, 83.3% vs. 64.2% Discussion: These findings indicate that PTPs without inhibitors or with tolerized inhibitors do not develop inhibitors after switching to rFVIIIFc. By contrast, most PTPs with high-responding inhibitors who failed or never underwent ITI, develop inhibitor recurrence after switching to rFVIIIFc, but these are rapidly tolerized while continuing rFVIIIFc. In PTPs with low-responding inhibitors, rFVIIIFc may reduce but does not eliminate fluctuating low-level titers. Finally, in PUPs at risk for inhibitor formation, rFVIIIFc may induce low-responding low-titer inhibitors which are rapidly tolerized while continuing rFVIIIFc. Disclosures Ragni: SPARK: Research Funding; NovoNordisk: Honoraria; Alnylam: Consultancy, Honoraria, Research Funding; Sangamo: Research Funding; Genentech/Roche: Research Funding; Bioverativ: Consultancy, Honoraria, Research Funding; MOGAM: Consultancy, Honoraria; Bayer: Consultancy, Honoraria, Research Funding; Biomarin: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria, Research Funding. Malec: Bioverativ: Consultancy, Research Funding.