Rescue immune tolerance induction with a recombinant factor Fc-fused VIII: prospective ReITIrate study of clinical, humoral and cellular immune responses.

Background: Immune tolerance induction (ITI) is the gold standard for inhibitor eradication to restore the clinical efficacy of factor replacement therapy in haemophilia. However, as ITI often requires frequent administration over extended periods, it can be considered burdensome for patients and healthcare resources. Therefore, there is a need to optimise ITI treatment, particularly in patients who failed previous ITI attempts. Objectives: The ReITIrate study aimed to prospectively evaluate rescue ITI with efmoroctocog alfa, an extended half-life recombinant FVIII Fc fusion protein (herein rFVIIIFc), within a limited 60-week timeframe in patients with severe haemophilia A and inhibitors who failed previous ITI attempts. Design: ReITIrate was a phase IV, open-label, single-arm, interventional, multicentre study. Methods: Primary endpoint was ITI success (negative titre, <0.6 BU/mL; incremental recovery >66%; elimination half-life ⩾7 hours) within 60 weeks. Exploratory immunophenotype analyses were performed to characterise anti-drug antibodies (ADA) and cellular immune responses. Results: Nine of 16 enrolled subjects completed the ITI period during ReITIrate, of which one subject attained all 3 ITI success criteria after 46 weeks with no relapse. Two subjects achieved partial success (one subject met 2/3 success criteria; one met all criteria, but not simultaneously, with inhibitor recurrence). One additional subject (ITI failure) achieved negative inhibitor titre. Across these four subjects, median (range) time to negative titre was 19 (11-60) weeks. No new safety concerns were identified. IgG4 was the major contributor to the ADA IgG response. Subjects with partial/complete ITI success had fewer IgG subclasses involved than those who failed/withdrew. Immunophenotyping indicated an increase in regulatory T-cells (CD4 Conclusion: This study demonstrates that ITI with rFVIIIFc given within a limited timeframe has potential benefit in a difficult-to-treat inhibitor haemophilia population who failed previous ITI attempts. Trial registration: NCT03103542.