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 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; Paul E. Monahan

doi:10.1056/NEJMoa2211644

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 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, Paul E. Monahan

^*Corresponding author for this work

University of Michigan, Ann Arbor
Erasmus MC
Yale University
American Thrombosis and Hemostasis Network
University of North Carolina at Chapel Hill
Azienda Ospedaliera Careggi
Goethe University Frankfurt
KU Leuven
Utrecht University
Amsterdam UMC
University of Copenhagen
University of Groningen, University Medical Center Groningen
Department of Surgery, Dublin, Ireland
Queen Mary University of London
Department of Gastroenterology, The Royal London Hospital, Barts Health NHS Trust, London, UK
University Hospital Southampton NHS Foundation Trust
Lund University
Université catholique de Louvain
Vivantes Netzwerk für Gesundheit GmbH
University of Bonn
University of Utah
University of South Florida
Hemophilia and Thrombosis Treatment Center
University of Southern California
University of Arkansas for Medical Sciences, Little Rock, USA
University of Texas Health Science Center at Houston
Center for Inherited Blood Disorders, Orange, CA, USA
University of Washington
The Luskin Orthopaedic Institute for Children
Cambridge University Hospitals NHS Foundation Trust
University of Colorado Anschutz Medical Campus
Vanderbilt University
uniQure
CSL Behring, Marburg, King of Prussia, Pennsylvania, USA

Research output: Contribution to journal › Article › Academic › peer-review

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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 language	English
Pages (from-to)	706-718
Number of pages	13
Journal	New England journal of medicine
Volume	388
Issue number	8
DOIs	https://doi.org/10.1056/NEJMoa2211644
Publication status	Published - 2023

Keywords

Childhood Diseases
Coagulation
Genetics
Genetics General
Hematology/Oncology
Pediatrics

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Pipe, S. W., Leebeek, F. W. G., Recht, M., Key, N. S., Castaman, G., Miesbach, W., Lattimore, S., Peerlinck, K., van der Valk, P., Coppens, M., Kampmann, P., Meijer, K., O'connell, N., Pasi, K. J., Hart, D. P., Kazmi, R., Astermark, J., Hermans, C. R. J. R., Klamroth, R., ... Monahan, P. E. (2023). Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B. New England journal of medicine, 388(8), 706-718. https://doi.org/10.1056/NEJMoa2211644

@article{fc90859d49b34449b3ef5e49d680d988,

title = "Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B",

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{\texttimes}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.",

keywords = "Childhood Diseases, Coagulation, Genetics, Genetics General, Hematology/Oncology, Pediatrics",

author = "Pipe, \{Steven W.\} and Leebeek, \{Frank W. G.\} and Michael Recht and Key, \{Nigel S.\} and Giancarlo Castaman and Wolfgang Miesbach and Susan Lattimore and Kathelijne Peerlinck and \{van der Valk\}, Paul and Michiel Coppens and Peter Kampmann and Karina Meijer and Niamh O'connell and Pasi, \{K. John\} and Hart, \{Daniel P.\} and Rashid Kazmi and Jan Astermark and Hermans, \{Cedric R. J. R.\} and Robert Klamroth and Richard Lemons and Nathan Visweshwar and \{von Drygalski\}, Annette and Guy Young and Crary, \{Shelley E.\} and Miguel Escobar and Esteban Gomez and Rebecca Kruse-Jarres and Quon, \{Doris V.\} and Emily Symington and Michael Wang and Wheeler, \{Allison P.\} and Robert Gut and Liu, \{Ying P.\} and Dolmetsch, \{Ricardo E.\} and Cooper, \{David L.\} and Yanyan Li and Brahm Goldstein and Monahan, \{Paul E.\}",

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 NEJM.org, 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: {\textcopyright} 2023 Massachusetts Medical Society.",

year = "2023",

doi = "10.1056/NEJMoa2211644",

language = "English",

volume = "388",

pages = "706--718",

journal = "New England journal of medicine",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

number = "8",

}

Pipe, SW, Leebeek, FWG, Recht, M, Key, NS, Castaman, G, Miesbach, W, Lattimore, S, Peerlinck, K, van der Valk, P, Coppens, M, Kampmann, P, Meijer, K, O'connell, N, Pasi, KJ, Hart, DP, Kazmi, R, Astermark, J, Hermans, CRJR, Klamroth, R, Lemons, R, Visweshwar, N, von Drygalski, A, Young, G, Crary, SE, Escobar, M, Gomez, E, Kruse-Jarres, R, Quon, DV, Symington, E, Wang, M, Wheeler, AP, Gut, R, Liu, YP, Dolmetsch, RE, Cooper, DL, Li, Y, Goldstein, B & Monahan, PE 2023, 'Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B', New England journal of medicine, vol. 388, no. 8, pp. 706-718. https://doi.org/10.1056/NEJMoa2211644

TY - JOUR

T1 - Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B

AU - Pipe, Steven W.

AU - Leebeek, Frank W. G.

AU - Recht, Michael

AU - Key, Nigel S.

AU - Castaman, Giancarlo

AU - Miesbach, Wolfgang

AU - Lattimore, Susan

AU - Peerlinck, Kathelijne

AU - van der Valk, Paul

AU - Coppens, Michiel

AU - Kampmann, Peter

AU - Meijer, Karina

AU - O'connell, Niamh

AU - Pasi, K. John

AU - Hart, Daniel P.

AU - Kazmi, Rashid

AU - Astermark, Jan

AU - Hermans, Cedric R. J. R.

AU - Klamroth, Robert

AU - Lemons, Richard

AU - Visweshwar, Nathan

AU - von Drygalski, Annette

AU - Young, Guy

AU - Crary, Shelley E.

AU - Escobar, Miguel

AU - Gomez, Esteban

AU - Kruse-Jarres, Rebecca

AU - Quon, Doris V.

AU - Symington, Emily

AU - Wang, Michael

AU - Wheeler, Allison P.

AU - Gut, Robert

AU - Liu, Ying P.

AU - Dolmetsch, Ricardo E.

AU - Cooper, David L.

AU - Li, Yanyan

AU - Goldstein, Brahm

AU - Monahan, Paul E.

N1 - 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 NEJM.org, 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.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - Childhood Diseases

KW - Coagulation

KW - Genetics

KW - Genetics General

KW - Hematology/Oncology

KW - Pediatrics

UR - https://www.scopus.com/pages/publications/85149659290

U2 - 10.1056/NEJMoa2211644

DO - 10.1056/NEJMoa2211644

M3 - Article

C2 - 36812434

SN - 0028-4793

VL - 388

SP - 706

EP - 718

JO - New England journal of medicine

JF - New England journal of medicine

IS - 8

ER -

Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B

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