AOZORA Study: Interim Analysis of Joint Health in Children with Hemophilia A, without FVIII Inhibitors, 3 Years after Initiating Emicizumab

Background: Progressive joint damage is a common complication of hemophilia A (HA), a condition characterized by excessive bleeding due to missing or inactive coagulation factor (F) VIII. The risk of joint damage in people with HA (PwHA) can be mitigated by prophylaxis. Emicizumab, a bispecific monoclonal antibody that bridges activated FIX and FX to substitute for activated FVIII, is a prophylactic treatment for PwHA, with proven efficacy and a favorable safety profile. However, data on long-term joint health in PwHA receiving emicizumab are sparse.

Methods: AOZORA is an ongoing multicenter, open-label, Phase IV study designed to evaluate the long-term safety and effects on joint health of emicizumab over 6 years in pediatric PwHA without FVIII inhibitors (JapicCTI-194701). Eligible participants were aged <12 years old, weighing >3 kg, and diagnosed with severe congenital HA. They entered AOZORA as emicizumab-naïve or following the Phase III HOHOEMI study (Shima et al. Haemophilia 2019) and are receiving emicizumab at an approved dosing regimen.

The primary endpoints include evaluation of adverse events (AEs), and joint health and function assessment using magnetic resonance imaging (MRI) and the Hemophilia Joint Health Score (HJHS) version 2.1. MRI evaluation uses the International Prophylaxis Study Group (IPSG) MRI scale; a positive IPSG score indicates pathological changes in the knee and/or ankle joints. Exploratory endpoints include: annualized bleed rates (ABRs) for treated bleeds and treated joint bleeds; activities and activity-related treated bleeds. Full details are in the protocol manuscript (Shima et al. BMJ Open 2022).

The AOZORA study has been approved by the Institutional Review Boards of Nara Medical University and the St Marianna University Group. Written informed consent from the legal representative and, where possible, assent from participants ≥3 years old has been obtained.

Results: A total of 30 participants have enrolled in AOZORA. This pre-defined interim analysis presents 3-year joint evaluation results of the 10 participants who continued from HOHOEMI. Data cut-off was the last day of Week 145 for each participant. The participants were a median (range) of 5.9 (1.5-10.7) years old and included two under 2 years of age at enrollment (Table 1). No participant had FVIII inhibitors upon entry into HOHOEMI. All participants were previously treated with FVIII prophylaxis. One participant had a target joint.

All participants had ≥1 AE during the 3 years of observation (HOHOEMI and AOZORA), including four serious AEs in three participants: post-traumatic pain; soft tissue hemorrhage; and skull fracture and epidural hematoma in the same participant. Only one AE, an injection-site reaction, was related to emicizumab. No thrombotic events or thrombotic microangiopathies were observed.

There were no osteochondral changes seen at this interim analysis. Five participants (50%) had no MRI findings at Week 1, which was maintained through Week 145. Five participants (50%) had positive IPSG scores in 13 joints at Week 1: six knee joints and six ankle joints, all with mild effusion/hemarthrosis, and one ankle joint with both mild synovial hypertrophy and mild hemosiderin (Table 2). At Week 145, three (30%) of these five participants' joint health showed improvement as they had no MRI findings in any joint, including the ankle joint with synovial hypertrophy and hemosiderin at Week 1. Two participants (20%) still had positive IPSG scores in three joints: one knee joint and two ankle joints, all with mild effusion/hemarthrosis.

In five participants (50%), HJHS was zero between Week 1 and Week 145. Of the four participants with an HJHS of ≥1 at Week 1, three had a score of zero from Week 97 onwards. The participant with synovial hypertrophy and hemosiderin of the ankle joint had an HJHS of zero throughout.

Calculated mean ABRs for treated bleeds and treated joint bleeds while receiving emicizumab were 0.6 (95% confidence interval [CI]: 0.0-4.8) and 0.1 (0.0-4.0), respectively. Data on activities will be provided in future analyses.

Conclusions: This interim analysis is limited by the small number of participants and relatively short observation period. Nonetheless, these results demonstrate 3-year safety and maintenance or improvement of joint health in 10 children with HA who enrolled in AOZORA following HOHOEMI. Data on all participants will be reported in due course.

Shima:Takeda: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Nara Medical University: Current Employment; Fujimoto Seiyaku: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd.: Speakers Bureau; Ono Yakuhin: Speakers Bureau; CSL Behring: Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Honoraria, Speakers Bureau; UniQure: Consultancy; Bayer Yakuhin: Honoraria. Takedani:Bayer, Chugai, CSL Behring, KMB, Novo Nordisk, Pfizer, Sanofi: Speakers Bureau; Chugai, Nipro: Research Funding; Chugai, Novo Nordisk: Consultancy. Kitsukawa:CSL Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Consultancy; St.Marianna University School of Medicine: Ended employment in the past 24 months; Chiba University Hospital: Current Employment. Taki:Bayer Yakuhin: Honoraria; CSL Behring: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; Fujimoto: Honoraria; KM biologics Co.: Honoraria; Pfizer Japan: Honoraria. Ishiguro:National Centerfor Child Health and Development: Current Employment; Chugai Pharmaceutical Co., Ltd., Pfizer Inc.: Research Funding. Nagao:Pfizer Japan: Honoraria; Japan Blood Products Organization: Honoraria; Novo Nordisk Pharma: Honoraria; KM biologics Co.: Honoraria; Fujimoto Pharmaceutical Corp: Honoraria; Chugai Pharmaceutical Co.: Honoraria; CSL Behring: Honoraria; Sanofi: Honoraria; Bayer Yakuhin: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Nosaka:Chugai Pharmaceutical Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Kyogoku:Chugai Pharmaceutical Co., Ltd: Current Employment. Iwasaki:Chugai PharmaceuticalCo.,Ltd.: Current Employment. Nogami:Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Speakers Bureau; Chugai, Sanofi, Takeda, Bayer, Novo Nordisk, CSL Behring, KMBio, Fujimoto Seiyaku, Sekisu Medical, Sysmex,: Honoraria; Chugai, Sanofi, Takeda, Bayer, Novo Nordisk, KMBio, CSL Behring, Fujimoto Seiyaku, Sekisui Medical, Sysmex, AsahiKasei: Research Funding.