Emicizumab and Immune Tolerance Induction in People with Hemophilia A and Factor VIII Inhibitors: 96-Week Interim Analysis of the AKATSUKI Study

Introduction: Immune tolerance induction (ITI) therapy is indicated for people with hemophilia A (PwHA) to eradicate factor (F)VIII inhibitors. The safety of emicizumab treatment in combination with ITI requires further exploration. This study aims to evaluate the safety of emicizumab during and immediately after ITI. Methods: AKATSUKI (jRCTs041200037) is a Phase IV, open-label, non-randomized, interventional, multicenter study in Japan. PwHA were included if they had a positive FVIII inhibitor titer (≥0.6 BU/mL) and were starting ITI following enrollment, or had undergone ITI, but had not achieved partial ITI success. PwHA who had previously received emicizumab alone or in addition to ITI before study enrollment were also eligible for inclusion. PwHA with FVIII inhibitors received an approved dosing regimen of emicizumab and ITI. An ITI dosing regimen of 50 IU/kg standard half-life (SHL) or extended half-life (EHL) FVIII concentrate three times a week or twice a week, respectively, was permitted. Additional methods, including the dosing regimen of factor concentrate used for post-ITI maintenance therapy and the definitions for the different ITI criteria, have been previously reported (Matsushita et al. BMJ Open 2022). The primary endpoint was evaluation of adverse events (AEs), including thrombotic events (TEs), and abnormal laboratory values during and immediately after ITI. The secondary endpoints included number of treated bleeds; the number of participants who started ITI after study entry who met ITI success criteria; and changes in FVIII inhibitor titer during ITI and after meeting ITI success criteria. Partial success was achieved on the day that a negative FVIII inhibitor status was observed and the participant's blood sample showed normal FVIII recovery. Results: Twelve male participants (median [range] age at study entry: 2.5 [1-54] years) were enrolled. Participants had received emicizumab (n=11), ITI (n=9), or both (n=7) before study entry, and the median (range) duration of ITI and ITI in combination with emicizumab was 536 (12-1,734) days and 203 (7-1,002) days, respectively. This interim analysis was performed 96 weeks after the first study dose of emicizumab in the last enrolled participant (evaluation period, median [range]: 773.5 [224-1,062] days. Data cut-off: November 30, 2023). Overall, 67 AEs were described: one event of Grade 1 swelling was considered emicizumab-related. Two participants each experienced one serious AE from which they recovered: one case of pneumonia and one wound hemorrhage. No TEs were reported. Eighteen treated bleeds were reported in six participants: 17 were traumatic. Of all treated bleeds, 16 were managed with recombinant activated FVII, and two were treated with EHL FVIII. One participant achieved partial ITI success by data cut-off; no treated bleeds were reported or FVIII inhibitors detected since achievement of partial success in this participant. By data cut-off, an additional five participants with a history of ITI before study entry had reached a negative FVIII inhibitor status (median [range] duration of ITI treatment at study entry: 536 [203-1,734] days; median [range] Week 1 FVIII inhibitor titer: 3.9 [0.9-36.0] BU/mL). SHL and EHL products were used in one and four of the participants who reached a negative FVIII inhibitor status, respectively, for ITI treatment. A negative inhibitor status was not achieved in any participants (n=3) who began ITI after study entry (median [range] Week 1 FVIII inhibitor titer: 143.6 [8.2-148.5] BU/mL). One of these participants used a SHL product and two used an EHL product for ITI treatment. One of these participants withdrew from the study before data cut-off. For the three participants with a history of ITI treatment at study entry who did not reach a negative FVIII inhibitor status (median [range] Week 1 FVIII inhibitor titer: 6.9 [0.9-13.3] BU/mL), a SHL product was used for ITI treatment in one participant and an EHL product was used in two participants. Two of these participants withdrew from the study before the 24-week interim analysis. Conclusions: No new safety concerns or TEs were reported in this 96-week interim analysis. Of the 12 participants enrolled, one achieved partial ITI success. A negative inhibitor status was reported in five participants; all had experienced a relatively long period of ITI. The AKATSUKI study continues to evaluate the safety of emicizumab during and after ITI in PwHA.