Phase 3 Trial of Concizumab in Hemophilia with Inhibitors
Issued Date
2023-01-01
Resource Type
ISSN
00284793
eISSN
15334406
Scopus ID
2-s2.0-85171633814
Journal Title
New England Journal of Medicine
Volume
389
Issue
9
Start Page
783
End Page
794
Rights Holder(s)
SCOPUS
Bibliographic Citation
New England Journal of Medicine Vol.389 No.9 (2023) , 783-794
Suggested Citation
Matsushita T., Shapiro A., Abraham A., Angchaisuksiri P., Castaman G., Cepo K., d’Oiron R., Frei-Jones M., Goh A.S., Haaning J., Jacobsen S.H., Mahlangu J., Mathias M., Nogami K., Rasmussen J.S., Stasyshyn O., Tran H., Vilchevska K., Martinez L.V., Windyga J., You C.W., Zozulya N., Zulfikar B., Jiménez-Yuste V. Phase 3 Trial of Concizumab in Hemophilia with Inhibitors. New England Journal of Medicine Vol.389 No.9 (2023) , 783-794. 794. doi:10.1056/NEJMoa2216455 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/90264
Title
Phase 3 Trial of Concizumab in Hemophilia with Inhibitors
Author's Affiliation
Ramathibodi Hospital
Hémostase Inflammation Thrombose
Instituto de Investigación Sanitaria del Hospital Universitario La Paz
Hospital Pulau Pinang
Institute of Haematology and Transfusion Medicine, Warsaw
Ministry of Health of Russian Federation
Eulji University, School of Medicine
Istanbul Üniversitesi
Nagoya University Hospital
Azienda Ospedaliera Careggi
Great Ormond Street Hospital for Children NHS Foundation Trust
University of the Witwatersrand, Johannesburg
Nara Medical University
Faculty of Medicine, Nursing and Health Sciences
Novo Nordisk A/S
The University of Texas at San Antonio
Christian Medical College, Vellore
National Children's Specialized Hospital «OKHMATDYT»
Institute of Blood Pathology and Transfusion Medicine
Dr. José Eleuterio González Monterrey University Hospital
Indiana Hemophilia and Thrombosis Center
Hémostase Inflammation Thrombose
Instituto de Investigación Sanitaria del Hospital Universitario La Paz
Hospital Pulau Pinang
Institute of Haematology and Transfusion Medicine, Warsaw
Ministry of Health of Russian Federation
Eulji University, School of Medicine
Istanbul Üniversitesi
Nagoya University Hospital
Azienda Ospedaliera Careggi
Great Ormond Street Hospital for Children NHS Foundation Trust
University of the Witwatersrand, Johannesburg
Nara Medical University
Faculty of Medicine, Nursing and Health Sciences
Novo Nordisk A/S
The University of Texas at San Antonio
Christian Medical College, Vellore
National Children's Specialized Hospital «OKHMATDYT»
Institute of Blood Pathology and Transfusion Medicine
Dr. José Eleuterio González Monterrey University Hospital
Indiana Hemophilia and Thrombosis Center
Other Contributor(s)
Abstract
BACKGROUND Concizumab is an anti–tissue factor pathway inhibitor monoclonal antibody designed to achieve hemostasis in all hemophilia types, with subcutaneous administration. A previous trial of concizumab (explorer4) established proof of concept in patients with hemophilia A or B with inhibitors. METHODS We conducted the explorer7 trial to assess the safety and efficacy of concizumab in patients with hemophilia A or B with inhibitors. Patients were randomly assigned in a 1:2 ratio to receive no prophylaxis for at least 24 weeks (group 1) or concizumab prophylaxis for at least 32 weeks (group 2) or were nonrandomly assigned to receive concizumab prophylaxis for at least 24 weeks (groups 3 and 4). After a treatment pause due to nonfatal thromboembolic events in three patients receiving concizumab, including one from the explorer7 trial, concizumab therapy was restarted with a loading dose of 1.0 mg per kilogram of body weight, followed by 0.2 mg per kilogram daily (potentially adjusted on the basis of concizumab plasma concentration as measured at week 4). The primary end-point analysis compared treated spontaneous and traumatic bleeding episodes in group 1 and group 2. Safety, patient-reported outcomes, and pharmacokinetics and pharmacodynamics were also assessed. RESULTS Of 133 enrolled patients, 19 were randomly assigned to group 1 and 33 to group 2; the remaining 81 were assigned to groups 3 and 4. The estimated mean annualized bleeding rate in group 1 was 11.8 episodes (95% confidence interval [CI], 7.0 to 19.9), as compared with 1.7 episodes (95% CI, 1.0 to 2.9) in group 2 (rate ratio, 0.14 [95% CI, 0.07 to 0.29]; P<0.001). The overall median annualized bleeding rate for patients receiving concizumab (groups 2, 3, and 4) was 0 episodes. No thromboembolic events were reported after concizumab therapy was restarted. The plasma concentrations of concizumab remained stable over time. CONCLUSIONS Among patients with hemophilia A or B with inhibitors, the annualized bleeding rate was lower with concizumab prophylaxis than with no prophylaxis. (Funded by Novo Nordisk; explorer7 ClinicalTrials.gov number, NCT04083781.)