AKATSUKI third interim analysis: Safety of emicizumab during and after immune tolerance induction implementation

Abstract Background: Immune tolerance induction (ITI) therapy is recommended to eradicate factor (F)VIII inhibitors in people with hemophilia A (PwHA). There are limited safety data available on emicizumab in combination with ITI, particularly concerning thrombotic events (TEs), with ITI efficacy also a subject of interest. This study presents the safety of emicizumab during and directly following ITI. Methods: AKATSUKI (jRCTs041200037) is a Phase IV, prospective, open-label, multicenter study. Eligible PwHA had a positive FVIII inhibitor titer (≥0.6 BU/mL) and would begin ITI therapy after study enrollment, or were undergoing ITI therapy but had not met the criteria for partial ITI success. PwHA with FVIII inhibitors received an approved emicizumab dosing regimen and ITI therapy. ITI dosing regimens included 50 IU/kg standard half-life (SHL) or extended half-life (EHL) FVIII concentrate administered three times a week; for EHL FVIII, a dosing frequency of twice per week was permitted. Further details, including post-ITI maintenance dosing regimens, have been published (Matsushita, BMJ Open 2022). The primary endpoint was evaluation of adverse events (AEs), including TEs, and abnormal clinical laboratory values during and immediately after ITI. Secondary endpoints included number of treated bleeds, number of participants who started ITI after study entry who achieved ITI partial success, and changes in FVIII inhibitor titer during ITI and after achieving partial success. Partial success was defined as a negative FVIII inhibitor test result combined with a normal FVIII recovery value in the participant's blood sample. Results: Twelve male participants (median [range] age at entry: 2.5 [1–54] years) enrolled. Participants received emicizumab (n=11), ITI (n=9), or both (n=7) before enrollment; one participant received emicizumab and ITI separately, with no treatment overlap. The median (range) duration of ITI before enrollment was 536 (12–1,734) days. Three participants began ITI after enrollment, all aged <2 years. This interim analysis was performed 144 weeks after the first study dose of emicizumab in the last enrolled participant (evaluation period, median [range]: 1079.5 [224–1,342] days; data cut-off: October 31, 2024). Three participants used SHL FVIII and nine participants used EHL FVIII for ITI therapy. Overall, 90 AEs were reported and there were no TEs. One Grade 1 event of swelling was considered emicizumab-related, but this resolved the same day it occurred. Three participants experienced a serious AE (SAE), all of which resolved and were considered unrelated to emicizumab or FVIII concentrate. There was one abnormal laboratory value: a Grade 1 prolonged activated partial thromboplastin time influenced by heparin administration. In total, 22 treated bleeds were reported in seven participants: one spontaneous, two surgical and 19 traumatic. Of these, 16 were managed with recombinant activated FVII, six were managed with EHL FVIII and none treated with activated prothrombin complex concentrate. Median annualized bleeding rate during the study period was 0.44 (range: 0.00–2.09). By data cut-off, six participants, all with a history of ITI before study entry, achieved negative FVIII inhibitor status. Median (range) duration of ITI at study entry for these participants was 381 (12–1,734) days and median (range) duration of ITI during the study, up to the point at which a negative FVIII inhibitor status was achieved, was 93 (5–137) weeks. Of these six participants, three maintained continuous FVIII inhibitor negativity during the observation period. Three participants had achieved partial ITI success by data cut-off, though recurrence of FVIII inhibitors occurred in two participants. Of these, one participant experienced FVIII inhibitor recurrence 12 days after partial ITI success was achieved (FVIII inhibitor level = 0.97 BU/mL), the other experienced recurrence 16 days after partial ITI success was achieved (FVIII inhibitor level = 1.82 BU/mL). Conclusions: At this 144-week interim analysis, no new safety concerns or TEs were reported. Effective bleed control was confirmed with a combination of emicizumab and ITI. Of the 12 participants enrolled, three achieved partial ITI success, though two participants had recurrence of FVIII inhibitors. Negative inhibitor status was reported in six participants. AKATSUKI continues to evaluate the safety of emicizumab during, and following, ITI therapy in PwHA with FVIII inhibitors.