A Multi-center, Prospective Study Evaluating the Rate of Inhibitor Recurrence Following Successful ITI in Patients Receiving Ongoing Once Per Weekly Factor VIII Therapy Along With Emicizumab and in Patients Who Discontinue FVIII Therapy and Are on Emicizumab for Prophylaxis

Background & rationale: Hemophilia A is a serious life-long genetic bleeding disorder resulting from a mutation in the Factor VIII (FVIII) gene leading to abnormally low levels of FVIII. Treatment consists of replacing the missing FVIII with FVIII clotting factor concentrates (CFC). While FVIII CFC are very effective at preventing joint bleeding, they are immunogenic such that ~30% of patients develop anti-drug antibodies which neutralize the effect of the medications and are thus called inhibitors. Patients with inhibitors have worse morbidity and mortality as a result of increased and more difficult to treat bleeding episodes. Therefore, the major goal of therapy for patients who develop these antibodies is eradication of the inhibitor. The only approach that has been shown to be effective is called immune tolerance induction (ITI), and as its name implies, the purpose is to induce the patient's immune system to no longer make the inhibitors. Immune tolerance induction involves administering FVIII CFC on a regular and often intensive (daily) schedule for many months if not years. It can be effective, however, with successful ITI ranging from 40-90% in numerous previous studies. there exists a sizable minority of patients (~20-25% of all hemophilia A patients) who are ITI successes. For these patients, ongoing FVIII therapy has been the standard of treatment although once tolerization has been achieved, the treatment modality reverts to prophylaxis, however the continued regular exposure to prophylaxis is felt to also serve the purpose of maintaining tolerance.there is little to no data on whether ongoing FVIII exposure is required to maintain tolerance, and it is entirely possible that patients can discontinue routine factor therapy and not have a recurrence of their inhibitor. Only one study has even addressed this issue, and it found that inhibitor recurrence rates were the same among a group of tolerized patients who were subsequently adherent to a prophylaxis regimen and another group who were not adherent and therefore not receiving regular FVIII exposure.

While historically, this was a moot issue since the only appropriate therapy for severe hemophilia patients following successful ITI was to be prescribed FVIII prophylaxis, the recent licensure of a new medication has now made this question and knowledge gap very important. Emicizumab (Hemlibra, Roche, Basel, Switzerland) is a novel, bispecific, monoclonal antibody which can substitute for the function of activated FVIII by bringing activated factor IX and factor X into proper alignment and induce the formation of activated factor X.

Despite the high degree of efficacy of emicizumab for bleed prevention in inhibitor patients, the hemophilia community has still largely taken the stance that inhibitor eradication is a vital goal for any child who develops an inhibitor. The issue that the advent of emicizumab has raised, however, is what to do following successful ITI. As stated, traditionally, patients would continue FVIII therapy in the form of prophylaxis and the question of loss of tolerance and inhibitor recurrence was moot, however given the advantages of emicizumab, it is likely that many patients/parents will not accept continuing with the need for repeated intravenous infusions (and central venous catheters in many children) when an alternative agent with excellent efficacy and a much lower treatment burden exists. Thus, objective of this study is to determine whether ongoing factor VIII therapy is required for maintenance of tolerance.

Study population: patients who have undergone successful ITI and are currently on emicizumab or willing to be on emicizumab.

Study methodology: This will be a prospective, randomized trial of weekly FVIII CFC therapy versus no routine FVIII therapy for patients who have undergone successful ITI and are currently on emicizumab or willing to be on emicizumab.