Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B

Steven W. Pipe, Frank W. G. Leebeek, 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 LemonsNathan 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, Paul E. Monahan

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52 Citations (Scopus)

Abstract

Background: Moderate-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. Methods: In 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. Results: The 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. Conclusions: Etranacogene dezaparvovec gene therapy was superior to prophylactic factor IX with respect to the annualized bleeding rate, and it had a favorable safety profile.

Original languageEnglish
Pages (from-to)706-718
Number of pages13
JournalNew England journal of medicine
Volume388
Issue number8
DOIs
Publication statusPublished - 2023

Keywords

  • Childhood Diseases
  • Coagulation
  • Genetics
  • Genetics General
  • Hematology/Oncology
  • Pediatrics

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