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

Christoph Königs; Shannon L Meeks; Beatrice Nolan; Anja Schmidt; Malin Löfqvist; Jennifer Dumont; Lisa Leickt; Sushrusha Nayak; Stefan Lethagen

doi:10.1177/20406207241300809

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

Ther Adv Hematol. 2024 Nov 23:15:20406207241300809. doi: 10.1177/20406207241300809. eCollection 2024.

Authors

Christoph Königs¹, Shannon L Meeks², Beatrice Nolan³, Anja Schmidt¹, Malin Löfqvist⁴, Jennifer Dumont⁵, Lisa Leickt⁴, Sushrusha Nayak⁴, Stefan Lethagen⁶

Affiliations

¹ Department of Pediatrics and Adolescent Medicine, Clinical and Molecular Hemostasis, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany.
² Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA.
³ Children's Health Ireland at Crumlin, Dublin, Ireland.
⁴ Sobi, Stockholm, Sweden.
⁵ Sanofi, Cambridge, MA, USA.
⁶ Sobi, Swedish Orphan Biovitrum AB, SE-112 76, Sweden.

Abstract

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⁺CD25⁺CD127^low), supporting the ability to perform sensitive blood sampling to identify immune tolerance markers.

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.

Keywords: factor VIII; haemophilia A; immune tolerance; recombinant factor VIII Fc fusion protein; recombinant fusion proteins.

Associated data

ClinicalTrials.gov/NCT03103542