Design of the INHIBIT trial: preventing inhibitors by avoiding ‘danger’, prolonging half-life and promoting tolerance

Abstract

Inhibitor formation is among the most serious complications of hemophilia treatment. With the US FDA licensure of the novel long-lasting recombinant factor VIII (FVIII) Fc fusion protein, Eloctate, which prolongs FVIII half-life, we propose an innovative approach to prevent inhibitor formation. In this paper, we describe a multicenter, Phase II, single-arm, 48-week trial, the INHIBIT trial, to determine if Eloctate, begun before a bleed and continued as once weekly prophylaxis, will reduce inhibitor formation in children with hemophilia A. We hypothesize that avoiding ‘danger,’ that is, immune activation by a bleed at first factor exposure and prolonging FVIII half-life will prevent inhibitors and promote FVIII-specific T-cell tolerance. If successful, this approach will suggest a new paradigm in clinical practice.

Keywords::

• coagulation factor VIII
• hemophilia A
• inhibitor formation
• long-lasting factor VIII
• Tregs
• tolerance

Acknowledgements

MV Ragni designed the research and collected the data. MV Ragni and LM Malec reviewed the findings, formulated the conclusions and wrote the manuscript. We acknowledge the statistical expertise of DJ Brambilla, Research Triangle Institute, Rockville, MD and the clinical expertise of the members of the NHLBI State of the Science Hemophilia von Willebrand Disease Subcommittee, including CM Kessler (Georgetown, Washington, DC), PF Fogarty (University of Pennsylvania, Philadelphia, PA), NC Josephson (University of Washington, Seattle, WA), AT Neff (Vanderbilt, Nashville, TN) and L Raffini (Children’s Hospital of Philadelphia, Philadelphia, PA). The study was supported by NHLBI U34 114674 Feasibility of INHIBIT Trial and CTRC/CTSI NIH NCRR/CTSA UL-1 RR024153.

Financial & competing interests disclosure

MV Ragni receives research funding from Baxter Bioscience, Bayer, Biogen Idec, CSL Behring, Merck, Novartis, Novo-Nordisk, SPARK and Vascular Medicine Institute. LM Malec has received research funding from Baxter Bioscience. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Inhibitor formation is among the most serious complications of hemophilia, for which response to treatment is poorer than factor VIII (FVIII) in non-inhibitor patients, and prevention is unknown.

• Anti-FVIII antibody formation is a T-cell response to foreign infused FVIII.

• Increasing evidence suggests that reducing ‘danger,’ that is, avoiding immune system activation by bleeds, trauma, infection or vaccination at the time of first FVIII exposure and prolonging FVIII half-life may be critical to achieving FVIII tolerance.

• CONCEPT 1: Initiating FVIII before a first bleed or trauma may avoid ‘danger’ signals that activate the immune system and prevent inhibitor formation.

• CONCEPT 2: Initiating weekly prophylaxis with the novel, US FDA-approved long-lasting factor, rFVIIIFc or Eloctate, which improves FVIII half-life may reduce inhibitor formation.

• We propose a multicenter, Phase II, single-arm, 48-week trial, the INHIBIT trial, to evaluate whether Eloctate reduces inhibitor formation in previously untreated children when begun before a bleed or surgery or trauma (preemptive) and continued once weekly to prevent bleeds (prophylaxis).

• If successful, this approach will suggest a new paradigm in the management of individuals with hemophilia.