Real-World Safety of Emicizumab: Interim Analysis of the European Haemophilia Safety Surveillance (EUHASS) Database

Background: European Haemophilia Safety Surveillance (EUHASS) is an investigator-led pharmacovigilance program collecting real-world safety data on treatments for inherited bleeding disorders from >90 centers in >25 countries. Emicizumab (HEMLIBRA®) is a bispecific monoclonal antibody approved in Europe for treatment of congenital hemophilia A (HA) of all severities with factor VIII (FVIII) inhibitors and severe HA without FVIII inhibitors. Adverse events (AEs) of interest for emicizumab that impact morbidity, mortality, and treatment options include: FVIII inhibitor occurrence/recurrence, which has been assessed by modelling but is lacking real-world evidence; thrombotic events (TEs); and thrombotic microangiopathies (TMAs). There is a known risk of TMAs when using emicizumab concomitantly with activated prothrombin complex concentrate (aPCC, FEIBA®) at a dose of >100 U/kg/24 hours for ≥24 hours. This analysis will share EUHASS data from 2020 and a 2017-2020 overview in people receiving emicizumab.

Methods: AE data were collected from participating centers from people who received emicizumab alone or in addition to other hemophilia treatments. EUHASS data are not collected according to Medical Dictionary for Regulatory Affairs (MedDRA) classifications; however, AEs were aligned to MedDRA preferred terms for this analysis.

Most people receiving emicizumab in 2017 (n=25), 2018 (n=181), and 2019 (n=414) will be included in the 2020 data, as most people continue emicizumab treatment over time (Khairnar et al. Haemophilia 2022). The number who received emicizumab between Jan 1, 2017−Dec 31, 2020 is unknown, as records are not matched across the years.

Results: From Jan 1, 2020−Dec 31, 2020, data from 985 people who received emicizumab were reported to EUHASS: emicizumab alone (n=832); emicizumab and FVIII products indicated for HA (n=96); emicizumab and activated recombinant FVII (rFVIIa, NovoSeven®; n=56); emicizumab and aPCC (n=1) (Table). A further 22 people received emicizumab and tranexamic acid, but AE data are unavailable. In 2020, a 26-year-old male with severe HA who received emicizumab alone had FVIII inhibitor recurrence after >50 emicizumab exposures (the date of the last FVIII inhibitor test prior to this positive test is unknown). No TEs or TMAs occurred. Two males with HA (40 years and 55 years of age) who received emicizumab alone had an allergic or other acute reaction (rash) 1 hour and 12 hours after dosing, respectively, which were considered definitely/probably related to emicizumab. Both events resolved.

Across ≥985 people spanning 4 years from 2017-2020, four TEs occurred within 30 days of emicizumab dosing (relatedness to emicizumab unknown). Two occurred in 78-year-old males with HA who received emicizumab and another hemophilia treatment: one received emicizumab, rFVIIa, and a FVIII product and had a thrombosis in his port-a-cath 1 day after emicizumab dosing; the other received emicizumab and aPCC and had a myocardial infarction (MI) 10 hours after emicizumab dosing (Shang et al. Blood 2020). Two TEs occurred in males with HA (32 years and 53 years of age) who received emicizumab alone: an MI 24 hours after dosing and a superior mesenteric artery thrombus 6 days after dosing, respectively. Other AEs (both allergic or other acute reactions) reported in 2017-2020 not previously mentioned include a rash (Shang et al. Blood 2020) and headache, visual impairment, and dizziness 24 hours after emicizumab dosing in a 22-year-old male, which were reported as probably related to emicizumab.

This analysis has some limitations. Firstly, off-label use of emicizumab in people with other inherited blood disorders may be recorded, although it has been confirmed that the AEs reported here occurred in people with HA. Secondly, people receiving emicizumab may not be routinely tested for FVIII inhibitors. Finally, comorbidities or other risk factors, AE severity, and whether hemophilia treatments were received concurrently or sequentially or were discontinued, are unknown.

Conclusions: Across 2017-2020 in ≥985 people receiving emicizumab, one FVIII inhibitor recurrence, four TEs, and four allergic or other acute reactions were reported to EUHASS. Based on the EUHASS data to date, the safety profile of emicizumab in people with HA is favorable and consistent with clinical trial data. Roche will continue to monitor real-world safety of emicizumab and share data with the community.

Nissen:F. Hoffmann-La Roche Ltd: Current Employment, Current holder of stock options in a privately-held company. Jiang:Roche Products Ltd: Current Employment; Whittington Health NHS Trust: Ended employment in the past 24 months. Hiew:Roche Products Ltd: Current Employment; University Hospital Dorset: Ended employment in the past 24 months. Aizenas:F. Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company. Tobaruela:F. Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Jew:Genentech, Inc.: Current Employment; Eversana: Ended employment in the past 24 months; F. Hoffmann-La Roche Ltd.: Current equity holder in publicly-traded company.

In Europe, emicizumab is indicated for routine prophylaxis of bleeding episodes in patients with hemophilia A with factor VIII inhibitors and severe hemophilia A with or without factor VIII inhibitors. It is possible that this analysis may capture some off-label use of emicizumab in people with other rare bleeding disorders, but it has been confirmed that the adverse events reported here occurred in people with congenital hemophilia A.