Surveillance Of Emicizumab-Treated Patients: An Analysis of the EUHASS Pharmacovigilance Registry (Emicizumab Pharmacovigilance: EUHASS registry)

Study type

• Study topic:
  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Safety study (incl. comparative)
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Cohort

  Other
• Non-interventional study design, other:
  Cohort surveillance

Study drug and medical condition

• Medicinal product name:
  HEMLIBRA
• Study drug International non-proprietary name (INN) or common name:
  EMICIZUMAB
• Anatomical Therapeutic Chemical (ATC) code:
  (B02BX06) emicizumab

  emicizumab
• Medical condition to be studied:
  Haemophilia A with anti factor VIII

  Haemophilia A without inhibitors

Population studied

• Short description of the study population:
  The study population will consist of patients with congenital Hemophilia A treated with emicizumab at centers participating in the EUHASS registry. Depending on the local approval/reimbursement decisions in the participating countries, the study population may include patients with any level of disease severity without FVIII inhibitors.
• Age groups:
  • Paediatric Population (< 18 years)

    • Neonate

      • Preterm newborn infants (0 – 27 days)
      • Term newborn infants (0 – 27 days)
    • Infants and toddlers (28 days – 23 months)
    • Children (2 to < 12 years)
    • Adolescents (12 to < 18 years)
  • Adult and elderly population (≥18 years)

    • Adults (18 to < 65 years)

      • Adults (18 to < 46 years)
      • Adults (46 to < 65 years)
    • Elderly (≥ 65 years)

      • Adults (65 to < 75 years)
      • Adults (75 to < 85 years)
      • Adults (85 years and over)
• Special population of interest:
  Hepatic impaired

  Immunocompromised

  Pregnant women

  Renal impaired
• Estimated number of subjects:
  680

Study design details

• Study design:
  Cohort surveillance study based on data provided in the EUHASS emicizumab-specific annual report.
• Main study objective:
  The primary objective for this study is to estimate the incidence of TE, TMA, and anaphylaxis under real-world conditions in patients exposed to emicizumab, with or without coagulation factor products.
• Setting:
  The EUHASS program is an investigator-led initiative. Activities are overseen by an independent Steering Committee. Since its initiation in 2008, EUHASS is used by pharmaceutical companies to conduct post-approval authorization studies. At the time of the EUHASS report in 2024, 94 participating centers in 28 countries reported information on all the patients they treated, thus minimizing selection bias.
• Outcomes:
  • Number of patients exposed to emicizumab (directly from EUHASS report); • Number of patients exposed to emicizumab who experienced TE, TMA, and anaphylaxis (directly from EUHASS report); • Proportion of each AE among patients receiving emicizumab, if applicable (calculated based on information from EUHASS report); • Number of patients exposed to emicizumab and each of the following drugs: aPCC, rFVIIa, and FVIII (directly from EUHASS report)*; • Number of patients who experienced TE and TMA exposed to emicizumab and each of the following drugs: aPCC, rFVIIa, and FVIII (directly from EUHASS report)*; • Proportion of TE and TMA among patients exposed to emicizumab and each of the following drugs: aPCC, rFVIIa, and FVIII, if applicable (calculated based on information from EUHASS report)*; ; * Starting from Interim Report Number 6, to avoid duplicate reporting of patients and events, the centers now report to EUHASS only the total yearly number of patients treated with emicizumab, regardless of any concomitant drug usage. Consequently, the yearly subtotals of patients treated with emicizumab alone or emicizumab in combination with coagulation factor products are no longer provided.
• Data analysis plan:
  Descriptive statistics on endpoints, including number and percentage of patients, will be provided. Continuous variables will be summarized by mean, median, minimum, maximum, and interquartile range (IQR). ; Categorical variables will be summarized by counts, percentages, and corresponding 95% confidence intervals (CIs). Data generated within the first 7 calendar years post-marketing authorization throughout the European Union (2018-2024) will be analyzed annually. ; Proportions of each adverse event, along with corresponding 95% CIs, will be calculated annually for all patients exposed to emicizumab. In addition, proportions of TE and TMA will be calculated annually for patients exposed to emicizumab and each of the following agents: aPCC, rFVII, and FVIII.
• Summary results:
  Cumulatively, from the earliest use of emicizumab in 2017 through the 31 December 2024 cut-off date, the sum of person-years exposed to emicizumab, either alone or with coagulation factor products, is estimated to be 9,909 person-years, with 48 AEs reported. This includes 13 patients under ‘thrombosis’ category (age range: 1−78 years), 15 allergic or acute reactions in 12 patients (age range: 10 months−55 years), 8 first-occurrence of inhibitor development (age range: 1−43 years), and 12 inhibitor recurrences (age range: 6−55 years). No instances of TMA and anaphylaxis were reported cumulatively. The crude incidence rate for TE was calculated as 1.31 per 1,000 person-years, assuming full-year exposure for all patients.; ; Throughout the study duration, the observed safety profile of emicizumab remained consistent with established clinical data, and no new safety signals were identified. Notably, no cases of TMA or anaphylaxis were reported during the overall study duration. Consistent with the findings from pivotal clinical trials, the study data confirm that the positive benefit-risk balance of emicizumab for the treatment of hemophilia A remains unchanged.