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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

110 Citations (Scopus)


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
Issue number8
Publication statusPublished - 23 Feb 2023

Bibliographical note

Funding Information:
HOPE-B is a phase 3, open-label, single-dose, multicenter study conducted at 33 sites (17 in the United States, 13 in the European Union, and 3 in the United Kingdom). The study is conducted in accordance with International Council for Harmonisation Good Clinical Practice guidelines and ethical principles originating in the Declaration of Helsinki. The study began on June 27, 2018, and the 18-month registrational analysis includes data up to October 18, 2021; additional safety and efficacy data collection is ongoing for 5 years. The , available with the full text of this article at, was approved by institutional review boards and independent ethics committees at each study site. All the participants provided written informed consent. The data were collected and analyzed by CSL Behring; the academic authors had full access to the data. Medical writers (funded by CSL Behring) wrote the manuscript that was submitted, with input from the authors, and the authors provided approval of the manuscript before submission. The authors vouch for the accuracy and completeness of the data and for the fidelity of the study to the protocol.

Publisher Copyright:
© 2023 Massachusetts Medical Society.


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