Volume 12 (2025): Issue 1

Safety profile of concizumab: A systematic review and meta-analysis of randomised controlled trials

Open Access | | Creative Commons Attribution NonCommercial NoDerivatives
Laiba Masood ORCID iD
Muhammad Bilal Akram ORCID iD
Noor Ashfaq ORCID iD
Arib Shafiq Chaudhry ORCID iD
Abdul Wasay ORCID iD
Ramsha Javed ORCID iD
Muhammad Aoun Abbas Khan ORCID iD
Muhammad Abdullah Masood ORCID iD
Muhammad Abdul Muqtadir Qureshi ORCID iD
Hafiz Shahbaz Zahoor ORCID iD
Adina Arshad ORCID iD
Abdul Ahad Waseem ORCID iD

Abstract

Abstract Introduction

Haemophilia, a genetic bleeding disorder caused by deficiencies in clotting factors VIII (haemophilia A) or IX (haemophilia B), impairs coagulation, requiring frequent intravenous clotting factor infusions. Concizumab, a subcutaneous monoclonal antibody targeting tissue factor pathway inhibitor (TFPI), offers a potential alternative for prophylactic treatment.

Objective

This meta-analysis evaluates the safety of concizumab in people with haemophilia, focusing on adverse events, serious adverse events, upper respiratory tract infections, and joint bleeding episodes.

Methodology

A systematic search of PubMed, Cochrane Library, Scopus, Google Scholar, and ClinicalTrials.gov (up to February 15, 2025) identified randomised controlled trials comparing concizumab with placebo or standard therapy. Risk ratios (RR) with 95% confidence intervals (CI) were calculated, and heterogeneity was assessed using the I2 statistic.

Results

Four studies (137 participants) met inclusion criteria. Concizumab showed a non-significant increase in overall adverse events (RR = 1.17; 95% CI: 0.89–1.54). Serious adverse events were lower in the concizumab group (RR = 0.46; 95% CI: 0.06–3.53) but not statistically significant. Upper respiratory tract infections were similar (RR = 0.75; 95% CI: 0.15–3.85). Joint bleeding was slightly reduced (RR = 0.66; 95% CI: 0.45–0.96).

Conclusion

Concizumab appeared generally well tolerated in short-term randomised trials. The current evidence base is small and lacks long-term or real-world data; therefore, the comparative safety of concizumab relative to standard therapies remains uncertain. Given the challenges of conducting large randomised trials in rare diseases, long-term registry-based follow-up may provide the most feasible and informative data on concizumab's safety and efficacy.

Article

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References

  • 1. Blanchette VS, Key NS, Ljung LR, Manco-Johnson MJ, van den Berg HM, Srivastava A; Subcommittee on Factor VIII, Factor IX and Rare Coagulation Disorders of the Scientific and Standardization Committee of the International Society on Thrombosis and Hemostasis. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2014; 12(11): 1935–9. doi: https://doi.org/10.1111/jth.12672.
  • 2. Kloosterman F, Zwagemaker AF, Abdi A, Gouw S, Castaman G, Fijnvandraat K. Hemophilia management: Huge impact of a tiny difference. Res Pract Thromb Haemost 2020; 4(3): 377–385. doi: https://doi.org/10.1002/rth2.12314.
  • 3. Srivastava A, Santagostino E, Dougall A, et al.; WFH Guidelines for the Management of Hemophilia panelists and co-authors. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia 2020; 26 Suppl 6: 1–158. doi: https://doi.org/10.1111/hae.14046. Erratum in: Haemophilia. 2021 Jul;27(4):699. doi: https://doi.org/10.1111/hae.14308.
  • 4. Thornburg CD, Duncan NA. Treatment adherence in hemophilia. Patient Prefer Adherence 2017; 11: 1677–1686. doi: https://doi.org/10.2147/PPA.S139851.
  • 5. Shapiro AD, Mitchell IS, Nasr S. The future of bypassing agents for hemophilia with inhibitors in the era of novel agents. J Thromb Haemost 2018; 16(12): 2362–2374. doi: https://doi.org/10.1111/jth.14296.
  • 6. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019; 366: 14898. doi: https://doi.org/10.1136/bmj.l4898.
  • 7. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372. doi: https://doi.org/10.1136/BMJ.N71.
  • 8. Review Manager (RevMan) [Computer program]. Version 5.4. The Cochrane Collaboration, 2020.
  • 9. Shapiro AD, Angchaisuksiri P, Astermark J, et al. Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results. Blood 2019; 134(22): 1973–1982. doi: https://doi.org/10.1182/blood.2019001542.
  • 10. Matsushita T, Shapiro A, Abraham A, et al.; explorer7 Investigators. Phase 3 Trial of Concizumab in Hemophilia with Inhibitors. N Engl J Med 2023; 389(9): 783–794. doi: https://doi.org/10.1056/NEJMoa2216455.
  • 11. Chowdary P, Angchaisuksiri P, Apte S, et al. Concizumab prophylaxis in people with haemophilia A or haemophilia B without inhibitors (explorer8): a prospective, multicenter, open-label, randomised, phase 3a trial. Lancet Haematol 2024; 11(12): e891–e904. doi: https://doi.org/10.1016/S2352-3026(24)00307-7.
  • 12. Chowdary P, Lethagen S, Friedrich U, et al. Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomised first human dose trial. J Thromb Haemost 2015; 13(5): 743–54. doi: https://doi.org/10.1111/jth.12864.
  • 13. GRADEpro GDT: GRADEpro Guideline Development Tool [Software]. McMaster University and Evidence Prime, 2024. Available from gradepro.org. n.d.
  • 14. Eichler HJ, Angchaisuksiri P, Kavakli K, et al. Concizumab restores thrombin generation potential in patients with haemophilia: pharmacokinetic/pharmacodynamic modelling results of concizumab phase 1/1b data. Haemophilia 2018; 25(1): 60–66. doi: https://doi.org/10.1111/hae.13627.
  • 15. Franchini M, Mannucci PM. Non-factor replacement therapy for haemophilia: a current update. Blood Transfus 2018; 16(5): 457–461. doi: https://doi.org/10.2450/2018.0272-17.
  • 16. Gualtierotti R, Pasca S, Ciavarella A, et al. Updates on novel non-replacement drugs for hemophilia. Pharmaceuticals (Basel) 2022; 15(10): 1183. doi: https://doi.org/10.3390/ph15101183.
  • 17. Ali MA, Aiman W, Bajwa S, Anwer F. Comparison of drugs used for prophylaxis in hemophilia A or B with Inhibitors: A systematic review and frequentist network meta-analysis of randomised clinical trials. Blood 2024; 144 (Suppl 1): 5488. doi: https://doi.org/10.1182/blood-2024-211537.
  • 18. European Medicines Agency. EPAR – Alhemo (concizumab): Initial Marketing Authorisation Documents. EMA/511415/2024. Published 2024. Available from https://www.ema.europa.eu/en/medicines/human/EPAR/alhemo (accessed November 2025).

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Authors

  • Laiba Masood

    ORCID iD
    Shahida Islam Medical and Dental College, Lodhran, Pakistan

  • Muhammad Bilal Akram

    ORCID iD
    Quaid-e-Azam Medical College Bahawalpur, Pakistan

  • Noor Ashfaq

    ORCID iD
    Quaid-e-Azam Medical College Bahawalpur, Pakistan

  • Arib Shafiq Chaudhry

    ORCID iD
    Quaid-e-Azam Medical College Bahawalpur, Pakistan

  • Abdul Wasay

    ORCID iD
    Quaid-e-Azam Medical College Bahawalpur, Pakistan

  • Ramsha Javed

    ORCID iD
    Quaid-e-Azam Medical College Bahawalpur, Pakistan

  • Muhammad Aoun Abbas Khan

    ORCID iD
    Quaid-e-Azam Medical College Bahawalpur, Pakistan

  • Muhammad Abdullah Masood

    ORCID iD
    abdullah3350539539@gmail.com
    Quaid-e-Azam Medical College Bahawalpur, Pakistan

  • Muhammad Abdul Muqtadir Qureshi

    ORCID iD
    Quaid-e-Azam Medical College Bahawalpur, Pakistan

  • Hafiz Shahbaz Zahoor

    ORCID iD
    Quaid-e-Azam Medical College Bahawalpur, Pakistan

  • Adina Arshad

    ORCID iD
    Quaid-e-Azam Medical College Bahawalpur, Pakistan

  • Abdul Ahad Waseem

    ORCID iD
    Quaid-e-Azam Medical College Bahawalpur, Pakistan