Introduction: AHA is a serious autoimmune bleeding disorder caused by neutralizing antibodies against coagulation factor VIII (FVIII). Standard of care involves immunosuppressive therapy (IST) to suppress formation of anti-FVIII autoantibodies. Recently, prophylaxis with emicizumab (EMI) has been used instead of IST to manage patients with AHA.

Aim: This analysis aimed to compare outcomes of treatment with EMI or IST in patients with AHA. It was prospectively planned as an exploratory analysis of the GTH-AHA-EMI trial (NCT04188639, registered at www.clinicaltrials.gov).

Methods: Individual patient data were retrieved from the GTH-AHA-EMI (n=47, treatment with EMI) and the GTH-AH 01/2010 (n=101, treatment with IST). Propensity score (PS) matching was used accounting for covariates that were previously established to influence bleeding risk and overall survival. Standardized mean differences were used to compare baseline characteristics before and after matching.

Results: Baseline characteristics of the study populations were very similar and further improved by PS matching. IST treated patients had a high risk of bleeding in the first 3 weeks (0.25 to 0.30 clinically relevant new bleeds [CRNB] per patient-week), whereas EMI treated patients were largely protected from bleeding throughout the entire observation period (<0.1 CRNB per patient-week). For the first 12 weeks of observation, the negative-binomial model-based mean bleeding rate of EMI treated patients was 68% lower as compared to IST treated patients (incident rate ratio 0.325, 95% confidence interval [CI] 0.182-0.581, p<0.001). During the first 12 weeks, infections occurred with similar frequency but were less often fatal (IST: 36 events in 29 patients [29% of patients], 11 fatal events; EMI: 11 events in 10 patients [21%], no fatal events). Thromboembolic events were less frequent with EMI (1 event (2%], no fatal event) as compared with IST (7 events in 7 patients [7%], 4 fatal events). Overall survival after 24 weeks was 91% and 76% (hazard ratio 0.44, 95% CI 0.24-0.81, p=0.008, figure).

Conclusions: This PS-matched individual patient data analysis showed better bleed protection and improved survival in patients treated with EMI as compared to patients treated with IST. These observations suggest a change of clinical practice. Patients with newly diagnosed AHA should be offered prophylaxis with EMI to reduce the risk bleeding, and provided sufficient time to allow for clinical stabilization and improvement of their general health status before IST is considered.

Klamroth:Sobi: Honoraria, Other: Advisory board; Pfizer: Honoraria, Other: Advisory board; Octapharma: Honoraria, Other: Advisory board; Sanofi: Honoraria, Other: Advisory board; Roche/Chugai: Honoraria, Other: Advisory board; Novo Nordisk: Honoraria, Other: Advisory board; Grifols: Honoraria, Other: Advisory board; CSL Behring: Honoraria, Other: Advisory board; Biotest: Honoraria, Other: Advisory board; BioMarin: Honoraria, Other: Advisory board; Bayer: Honoraria, Other: Advisory board; Takeda: Honoraria, Other: Advisory board. Greil:Roche: Honoraria, Research Funding. Knoebl:CSL Behring: Honoraria; Biotest: Honoraria; Alexion: Honoraria; Technoclone: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Roche: Honoraria, Research Funding; NovoNordisc: Honoraria, Research Funding; Ablynx/SOBI: Honoraria, Research Funding. Oldenburg:Sparks: Honoraria; Chugai: Honoraria; BioMarin: Honoraria; Biogen Idec: Honoraria; Takeda: Honoraria, Research Funding; SOBI: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Freeline: Honoraria; Grifols: Honoraria; Novo Nordisk: Honoraria; Roche: Honoraria. Miesbach:LFB: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Octapharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Chugai: Consultancy, Speakers Bureau; uniQure: Consultancy; Takeda/Shire: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; BioMarin: Consultancy, Speakers Bureau; Freeline: Consultancy; Regeneron: Consultancy; Roche: Consultancy, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Biotest: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy. Pfrepper:Chugai/Roche: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Zacros: Research Funding; LeoPharma: Research Funding; Bayer: Honoraria; Biomarin: Honoraria; CSL Behring: Honoraria; NovoNordisc: Honoraria; Pfizer: Honoraria; BMS: Honoraria; SOBI: Honoraria. Trautmann-Grill:Roche: Honoraria; Takeda: Honoraria. Pekrul:Roche: Honoraria; Pfizer: Honoraria; CSL Behring: Honoraria; SOBI: Honoraria; Takeda: Honoraria, Research Funding; BMS: Honoraria; NovoNordisc: Honoraria. Holstein:Bayer: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; NovoNordisc: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; SOBI: Honoraria, Research Funding; Biotest: Honoraria; Chugai: Honoraria; LFB: Honoraria; Roche: Honoraria; Takeda: Honoraria. Eichler:Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioMarin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Werwitzke:Sago: Honoraria; Octapharma: Research Funding; Biotest: Honoraria, Research Funding. Tiede:Bayer: Honoraria, Research Funding; Biomain: Honoraria; Biotest: Honoraria, Research Funding; Chugai/Roche: Honoraria, Research Funding; CSL Behring: Honoraria; Novo Nordisk: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; SOBI: Honoraria, Research Funding; Takeda: Honoraria, Research Funding.

Emicizumab is a bispecific, monoclonal antibody capable of binding to factor IXa and X, resulting in spatial approximation and activation of factor X, thereby mimicking the actions of factor VIII. Emicizumab is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients ages newborn and older with hemophilia A with or without factor VIII inhibitors.

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2023
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