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.

Reduction of Factor VIII Inhibitor Titers During Immune Tolerance Induction With Recombinant Factor VIII-Fc Fusion Protein

“…Whether or not Eloctate indeed promotes tolerogenicity is still not known and will be answered by the INHIBIT trial . Although none of the 165 patients enrolled in the phase 3 clinical trial using Eloctate developed an inhibitor, it is important to point out that these patients were more than 12 years old with no inhibitor history, and studies on previously untreated patients have not yet been published .…”

The national blueprint for future factor VIII inhibitor clinical trials: NHLBI State of the Science (SOS) Workshop on factor VIII inhibitors

“…Given the significant cost and paucity of subjects available to conduct inhibitor prevention and eradication trials, the Working Group developed an estimate of the number of trials that could be supported within the HTC network (Table ). With approximately 1.82 severe haemophilia A PUPs born per year within the 141 US HTCs or approximately 257 per year, it is estimated only about 64 would qualify for a PUP prevention trial, with 75% disqualified for past factor, past bleed, refusal to participate in a trial, travel and time barriers, and competing trials . Thus, it is estimated up to 2‐3 PUP Inhibitor Prevention Trials utilizing novel design or embedded within registries could be supported within the HTC network.…”

“…Thus, it is estimated up to 2‐3 PUP Inhibitor Prevention Trials utilizing novel design or embedded within registries could be supported within the HTC network. Approximately 10% of the severe haemophilia A population, or 1000, have inhibitors refractory to immune tolerance induction . Because they have such a poor response to treatment and are ineligible for gene therapy, it is anticipated such patients would be likely to enroll in an inhibitor eradication protocol.…”

The immunogenicity of platelet-derived FVIII in hemophilia A mice with or without preexisting anti-FVIII immunity

“…It has been reported that injury (bleeds/trauma) could be one of the risk factors for inhibitor development in HA patients. [41][42][43] In our preliminary studies, blood samples were collected from some of the platelet-infused animals (n 5 6) weekly by retro-orbital venous bleeds, which could represent a minor injury model. Notably, no anti-FVIII antibodies were detected in recipients during the entire study course of platelet infusion (data from early time points not shown).…”