• Steven W Pipe, LeebeekFrank W GFWGFrom the Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor (S.W.P.); the Department of Hematology, Erasmus University Medical Center, University Medical Center Rotterdam, Rotterdam (F.W.G.L.), Van Creveldkliniek, Michael Recht, Nigel S Key, Giancarlo Castaman, Wolfgang Miesbach, Susan Lattimore, Kathelijne Peerlinck, Paul Van der Valk, Michiel Coppens, Peter Kampmann, Karina Meijer, Niamh O'Connell, K John Pasi, Daniel P Hart, Rashid Kazmi, Jan Astermark, Cedric R J R Hermans, Robert Klamroth, Richard Lemons, Nathan Visweshwar, Annette von Drygalski, Guy Young, Shelley E Crary, Miguel Escobar, Esteban Gomez, Rebecca Kruse-Jarres, Doris V Quon, Emily Symington, Michael Wang, Allison P Wheeler, Robert Gut, Ying P Liu, Ricardo E Dolmetsch, David L Cooper, Yanyan Li, Brahm Goldstein, and Paul E Monahan.
• From the Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor (S.W.P.); the Department of Hematology, Erasmus University Medical Center, University Medical Center Rotterdam, Rotterdam (F.W.G.L.), Van Creveldkliniek, University Medical Center Utrecht, University Utrecht, Utrecht (P.V.V.), Vascular Medicine, Amsterdam University Medical Center, University of Amsterdam (M.C.), Amsterdam Cardiovascular Sciences, Pulmonary Hypertension and Thrombosis (M.C.), and uniQure Biopharma (Y.P.L.), Amsterdam, and University Medical Center Groningen, Groningen (K.M.) - all in the Netherlands; Yale University School of Medicine, New Haven, CT (M.R., S.L.); American Thrombosis and Hemostasis Network, Rochester, NY (M.R.); the Department of Medicine and UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill (N.S.K.); the Center for Bleeding Disorders and Coagulation, Department of Oncology, Careggi University Hospital, Florence, Italy (G.C.); the Department of Hemostaseology and Hemophilia Center, Medical Clinic 2, Institute of Transfusion Medicine and Immunohematology, University Hospital Frankfurt, Frankfurt (W.M.), the Comprehensive Care Hemophilia Treatment Center, Vivantes Klinikum im Friedrichshain, Berlin, and the Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Medical Faculty, University of Bonn, Bonn (R. Klamroth) - all in Germany; the Department of Vascular Medicine and Hemostasis, Hemophilia Center, University Hospitals Leuven, Leuven (K.P.), the Division of Hematology, Cliniques Universitaires Saint-Luc, Brussels (C.R.J.R.H.), and Université Catholique de Louvain, Louvain-la-Neuve (C.R.J.R.H.) - all in Belgium; the Department of Hematology, Rigshopitalet Copenhagen, Copenhagen (P.K.); National Coagulation Centre, St. James's Hospital, Dublin (N.O.); Barts and the London School of Medicine and Dentistry, Queen Mary University of London (K.J.P., D.P.H.), and the Royal London Hospital Haemophilia Centre, Barts Health NHS Trust (D.P.H.), London, University Hospital Southampton and National Institute for Health and Care Research Clinical Research Facility, Southampton (R. Kazmi), and Cambridge University NHS Foundation Trust, Addenbrooks Hospital, Cambridge (E.S.) - all in the United Kingdom; the Department of Translational Medicine, Lund University, and the Department of Hematology Oncology and Radiation Physics, Skåne University Hospital - both in Malmö, Sweden (J.A.); the Department of Pediatrics, University of Utah, and Primary Children's Hospital, Salt Lake City (R.L.); University of South Florida, Tampa (N.V.); the Department of Medicine, Hemophilia and Thrombosis Treatment Center, San Diego (A.D.), the Cancer and Blood Disorders Institute, Children's Hospital Los Angeles (G.Y.), the Orthopaedic Hemophilia Treatment Center, the Luskin Orthopaedic Institute for Children (D.V.Q.), and the University of Southern California Keck School of Medicine (G.Y.), Los Angeles, and the Center for Inherited Blood Disorders, Orange (E.G.) - all in California; Arkansas Children's Hospital, Pulaski, and University of Arkansas for Medical Sciences, Little Rock (S.E.C.); University of Texas Health Science Center, McGovern Medical School, and Gulf States Hemophilia and Thrombophilia Center - both in Houston (M.E.); Washington Center for Bleeding Disorders and University of Washington, Seattle (R.K.-J.); Hemophilia and Thrombosis Center, University of Colorado Anschutz Medical Campus, Aurora (M.W.); the Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville (A.P.W.); uniQure, Lexington, MA (R.G., R.E.D., D.L.C.); and CSL Behring, King of Prussia, PA (Y.L., B.G., P.E.M.).
• N. Engl. J. Med. 2023 Feb 23; 388 (8): 706718706-718.

BackgroundModerate-to-severe hemophilia B is treated with lifelong, continuous coagulation factor IX replacement to prevent bleeding. Gene therapy for hemophilia B aims to establish sustained factor IX activity, thereby protecting against bleeding without burdensome factor IX replacement.MethodsIn this open-label, phase 3 study, after a lead-in period (≥6 months) of factor IX prophylaxis, we administered one infusion of adeno-associated virus 5 (AAV5) vector expressing the Padua factor IX variant (etranacogene dezaparvovec; 2×1013 genome copies per kilogram of body weight) to 54 men with hemophilia B (factor IX activity ≤2% of the normal value) regardless of preexisting AAV5 neutralizing antibodies. The primary end point was the annualized bleeding rate, evaluated in a noninferiority analysis comparing the rate during months 7 through 18 after etranacogene dezaparvovec treatment with the rate during the lead-in period. Noninferiority of etranacogene dezaparvovec was defined as an upper limit of the two-sided 95% Wald confidence interval of the annualized bleeding rate ratio that was less than the noninferiority margin of 1.8. Superiority, additional efficacy measures, and safety were also assessed.ResultsThe annualized bleeding rate decreased from 4.19 (95% confidence interval [CI], 3.22 to 5.45) during the lead-in period to 1.51 (95% CI, 0.81 to 2.82) during months 7 through 18 after treatment, for a rate ratio of 0.36 (95% Wald CI, 0.20 to 0.64; P<0.001), demonstrating noninferiority and superiority of etranacogene dezaparvovec as compared with factor IX prophylaxis. Factor IX activity had increased from baseline by a least-squares mean of 36.2 percentage points (95% CI, 31.4 to 41.0) at 6 months and 34.3 percentage points (95% CI, 29.5 to 39.1) at 18 months after treatment, and usage of factor IX concentrate decreased by a mean of 248,825 IU per year per participant in the post-treatment period (P<0.001 for all three comparisons). Benefits and safety were observed in participants with predose AAV5 neutralizing antibody titers of less than 700. No treatment-related serious adverse events occurred.ConclusionsEtranacogene dezaparvovec gene therapy was superior to prophylactic factor IX with respect to the annualized bleeding rate, and it had a favorable safety profile. (Funded by uniQure and CSL Behring; HOPE-B ClinicalTrials.gov number, NCT03569891.).Copyright © 2023 Massachusetts Medical Society.

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