Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A
For benign hematology, this is a good article about gene therapy in Hemophilia A.
Phase 3 Trial of Concizumab in Hemophilia with Inhibitors
Author(s): Tadashi Matsushita, M.D., Ph.D., Amy Shapiro, M.D., Aby Abraham, M.D., D.M., Pantep Angchaisuksiri, M.D., Giancarlo Castaman, M.D., Katarina Cepo, M.D., Roseline d’Oiron, M.D., Melissa Frei-Jones, M.D., Ai-Sim Goh, F.R.C.P., Jesper Haaning, Ph.D., Sanja Hald Jacobsen, M.Sc., Johnny Mahlangu, M.B., B.Ch., Mary Mathias, M.D., Keiji Nogami, M.D., Josephine Skovgaard Rasmussen, D.V.M., Oleksandra Stasyshyn, M.D., Huyen Tran, M.D., M.Clin.Epi., Kateryna Vilchevska, M.D., Laura Villarreal Martinez, M.D., Jerzy Windyga, M.D., Chur Woo You, M.D., Nadezhda Zozulya, M.D., Bulent Zulfikar, M.D., and Victor Jiménez-Yuste, M.D., Ph.D. for the explorer7 Investigators*
Source: N Engl J Med 2023; 389:783-794 DOI: 10.1056/NEJMoa2216455
Dr. Maen Hussein's Thoughts
Prophylactic use reduced annualized bleeding in hemophilia A and B pts with inhibitors. Concizumab is an anti–tissue factor pathway inhibitor monoclonal antibody.
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. opens in new tab.)
Author Affiliations
From the Department of Transfusion Medicine, Nagoya University Hospital, Nagoya (T.M.), and Nara Medical University, Kashiwara (K.N.) — both in Japan; Indiana Hemophilia and Thrombosis Center, Indianapolis (A.S.); the Department of Hematology, Christian Medical College, Vellore, India (A.A.); the Division of Hematology, Department of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand (P.A.); the Center for Bleeding Disorders and Coagulation, Department of Oncology, Careggi University Hospital, Florence, Italy (G.C.); Novo Nordisk, Søborg, Denmark (K.C., J.H., S.H.J., J.S.R.); the Reference Center for Hemophilia and Rare Congenital Bleeding Disorders, Bicêtre Hospital Assistance Publique–Hôpitaux de Paris, University of Paris-Saclay and UMR_S1176 INSERM, Le Kremlin-Bicêtre, France (R.O.); the Department of Pediatrics, University of Texas Health Long School of Medicine, San Antonio (M.F.-J.); the Department of Medicine, Hospital Pulau Pinang, Georgetown, Malaysia (A.-S.G.); the Department of Molecular Medicine and Haematology, University of the Witwatersrand, National Health Laboratory Service, Johannesburg (J.M.); Great Ormond Street Hospital for Children NHS Foundation Trust, London (M.M.); the Institute of Blood Pathology and Transfusion Medicine, Lviv (O.S.), and National Specialized Children’s Hospital Okhmatdyt, Kyiv (K.V.) — both in Ukraine; the Ronald Sawers Haemophilia Centre,Alfred Hospital, and the Australian Centre for Blood Diseases, Monash University — both in Melbourne, VIC, Australia (H.T.); Dr. José Eleuterio González Monterrey University Hospital, Monterrey, México (L.V.M.); the Department of Hemostasis Disorders and Internal Medicine, Laboratory of Hemostasis and Metabolic Diseases, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the Department of Pediatrics, Daejeon Eulji Medical Center, Eulji University School of Medicine, Daejeon, South Korea (C.W.Y.); the National Research Center for Hematology of the Ministry of Health of the Russian Federation, Moscow (N.Z.); the Division of Pediatric Hematology–Oncology, Istanbul University Oncology Institute, Istanbul, Turkey (B.Z.); and the Hematology Department, La Paz University Hospital, Hospital La Paz Institute for Health Research, Universidad Autónoma Madrid, Madrid (V.J.-Y.). Dr. Matsushita can be contacted at tmatsu@med.nagoya-u.ac.jp or at the Department of Transfusion Medicine, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya 466-0065, Japan. A list of the explorer7 investigators is provided in the Supplementary Appendix, available at NEJM.orgRelated Articles
Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B
Another interesting article on benign hematology, this one is about gene therapy in Hemophilia B.
