Real-World Outcomes of Emicizumab in Hemophilia A with or without FVIII Inhibitors from the Canadian Hemophilia Bleeding Disorder Registry

Background: Hemophilia A is a bleeding disorder characterized by deficiency or absence of blood coagulation factor (F)VIII, which leads to lifelong bleeding tendency. The Canadian Bleeding Disorders Registry (CBDR) is a clinical database designed to assist clinicians in Canadian hemophilia treatment centers with the management of people with bleeding disorders and gain a better understanding of their incidence and prevalence, their treatment patterns, outcomes, and safety. Emicizumab is a bispecific monoclonal antibody that bridges activated FIX and FX to substitute for missing activated FVIII in people with hemophilia A (PwHA), thereby restoring hemostasis. Emicizumab was approved by Health Canada for the treatment of PwHA with FVIII inhibitors in 2018, and for PwHA without FVIII inhibitors in 2019.

In this non-interventional, secondary data use cohort study, we use data routinely collected by the CBDR to evaluate the effectiveness, safety, and treatment patterns of emicizumab in Canada. The study includes patients treated according to routine clinical practice; therefore, it reflects patterns of care and outcomes in the real world, outside of the experimental setting.

Methods: We retrieved de-identified data from the CBDR database of all registered PwHA who had received emicizumab at least once prior to December 31, 2021. Baseline demographic characteristics, including sex, body mass index, FVIII inhibitor status, emicizumab regimen, and immune tolerance induction (ITI) while receiving emicizumab were stratified by disease severity (defined by the level of endogenous FVIII activity) and age. Real-world efficacy outcomes were measured by the proportion of patients with zero traumatic, spontaneous, or joint bleeds as well as annualized bleeding rates (ABR) for any treated bleed. ABRs were calculated as (total number of bleeds/duration of follow-up [days])*365.25. Efficacy outcomes also included patients’ Hemophilia Joint Health Score (HJHS), Patient Reported Outcomes Burdens and Experiences (PROBE), and EQ-5D index and visual analog scale (VAS) scores. We performed a complete data analysis, without imputation. Intra-patient comparisons of bleeding were performed for all patients This study was approved by the research ethics board of McMaster University and other participating centers, and abides by the guiding principles of the Declaration of Helsinki.

Results: In total, 146 PwHA received emicizumab at least once up to December 2021 in the CBDR database. The median (Q1, Q3) age at initiation of emicizumab was 13.9 (6.7, 28.7) years; 58.9% (n=86) of PwHA were ≤18 years (Table 1). Overall, 132 PwHA had severe disease, 10 had moderate disease, and 4 had mild disease. In total, 40.4% (n=59) of PwHA had current FVIII inhibitors, 15.1% (n=22) had a history of FVIII inhibitors, and 44.5% (n=65) had no history of inhibitors; 4.1% (n=6, all with severe HA) received ITI while on emicizumab. Three adverse events were reported during 2021, including two allergic reactions and one case of large hematoma at the operative site following removal of a port-a-cath. No thromboembolisms or thrombotic microangiopathies were reported.

Over a median follow-up of 389.0 days, 76.7% (n=112) of PwHA had no recorded bleeds (Table 2). For the 34 patients with recorded bleeds on emicizumab, median (Q1, Q3) ABR was 1.0 (0.5, 2.0); 13 of the 34 had joint bleeds, 18 had traumatic bleeds, and 19 had spontaneous bleeds.

An intra-patient comparison in all PwHA (n=146) showed a decrease in mean (95% confidence interval [CI]) ABR from 2.38 (1.77-3.22) pre-emicizumab (2018, prior to first dose) to 0.36 (0.24-0.53) post-emicizumab (rate ratio [RR] 0.15, p<0.0001). In PwHA with bleeds before or after initiation of emicizumab (n=97), mean (95% CI) ABR decreased from 5.31 (3.79-7.45) pre-emicizumab to 0.87 (0.58-1.32) post-emicizumab (RR 0.16, p<0.0001).

Conclusions: This analysis describes the baseline characteristics, bleed outcomes, and safety of Canadian PwHA treated with emicizumab before December 31, 2021. The majority had severe disease and current or historical FVIII inhibitors. The data show 76.7% had no recorded bleeds and there was a substantial decrease in bleeds post-emicizumab. The CBDR allows for a longitudinal follow-up of the Canadian hemophilia A population, which can inform healthcare practitioners and regulatory authorities of the real-world safety and effectiveness outcomes of treatments.

Poon:Bayer, CSL-Behring: Research Funding; Bayer, Bioverativ/Sanofi, CSL-Behring, KVR Pharmaceutical, Novo Nordisk, Pfizer, Roche, Sobi, Takeda: Honoraria. Lee:Pfizer: Membership on an entity's Board of Directors or advisory committees. Germini:BioMarin: Research Funding; Pfizer: Research Funding; Bayer: Research Funding; Takeda: Research Funding; Roche: Research Funding; NovoNordisk: Research Funding; McMaster University: Current Employment. Nissen:F. Hoffmann-La Roche Ltd: Current Employment, Current holder of stock options in a privately-held company. Moreno:F. Hoffmann La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company, Honoraria. Santos:F. Hoffmann La Roche, Ltd.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company; Takeda: Current equity holder in private company, Current holder of stock options in a privately-held company; Baxter: Current equity holder in private company, Current holder of stock options in a privately-held company. Matino:McMaster University: Current Employment; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sobi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.