Recombinant Factor VIII Fc Fusion Protein for First-time Immune Tolerance Induction: Final Results of the verITI-8 Study.

Inhibitor development remains a major challenge in factor VIII (FVIII) replacement therapy. verITI-8 is the first prospective study of a recombinant factor VIII Fc fusion protein (efmoroctocog alfa; rFVIIIFc) for first-time immune tolerance induction (ITI) in males with severe hemophilia A and high-titer inhibitors (historical peak ≥5 Bethesda units [BU]/mL). In this single-arm, open-label, multicenter study, screening was followed by ITI (rFVIIIFc 200 IU/kg/day until tolerization or maximum of 48 weeks). Those who achieved ITI success entered a tapering period, returning to standard prophylaxis, and then entered follow-up. Primary endpoint was time to tolerization with rFVIIIFc defined by inhibitor titer <0.6 BU/mL, incremental recovery (IR) ≥66% of expected IR (IR ≥1.32 IU/dL per IU/kg), and half-life ≥7 hours within 48 weeks. Sixteen subjects received ≥1 rFVIIIFc dose. Twelve (75%), 11 (69%), and 10 subjects (63%), respectively, achieved negative inhibitor titers, an IR ≥66%, and a half-life ≥7 hours (ie, tolerance) within 48 weeks. Median (IQR) times in weeks to achieve these markers of success were 7.4 (2.2-17.8), 6.8 (5.4-22.4), and 11.7 (9.8-26.2), respectively. All subjects experienced ≥1 TEAE (treatment-emergent adverse event [AE]), and 1 reported ≥1 related TEAE (injection site pain). Nine subjects experienced ≥1 treatment-emergent serious AE (TESAE). No thrombotic events, discontinuations due to AEs, or deaths were reported during the study. As the first extended half-life rFVIII with prospective data in ITI, rFVIIIFc offered short time to tolerization with durable responses in almost two-thirds of subjects and was well tolerated. Trial registered at www.clinicaltrials.gov (NCT03093480).