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 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

Hematology/Van Creveldclinic

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

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	The New England journal of medicine
Volume	388
Issue number	8
DOIs	https://doi.org/10.1056/NEJMoa2211644
Publication status	Published - 23 Feb 2023

Keywords

Factor IX/genetics
Genetic Therapy/methods
Genetic Vectors/administration & dosage
Hemophilia B/complications
Hemorrhage/etiology
Humans
Male
Pediatrics
Hematology/Oncology
Childhood Diseases
Coagulation
Genetics General
Genetics

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10.1056/NEJMoa2211644

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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. The New England journal of medicine, 388(8), 706-718. https://doi.org/10.1056/NEJMoa2211644

@article{8d9eb2942be54afa81ae9e17055e9b4b,

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; 2×1013 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 = "Factor IX/genetics, Genetic Therapy/methods, Genetic Vectors/administration \& dosage, Hemophilia B/complications, Hemorrhage/etiology, Humans, Male, Pediatrics, Hematology/Oncology, Childhood Diseases, Coagulation, Genetics General, Genetics",

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 = "Publisher Copyright: {\textcopyright} 2023 Massachusetts Medical Society.",

year = "2023",

month = feb,

day = "23",

doi = "10.1056/NEJMoa2211644",

language = "English",

volume = "388",

pages = "706--718",

journal = "The 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', The 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

PY - 2023/2/23

Y1 - 2023/2/23

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 - Factor IX/genetics

KW - Genetic Therapy/methods

KW - Genetic Vectors/administration & dosage

KW - Hemophilia B/complications

KW - Hemorrhage/etiology

KW - Humans

KW - Male

KW - Pediatrics

KW - Hematology/Oncology

KW - Childhood Diseases

KW - Coagulation

KW - Genetics General

KW - Genetics

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 - The New England journal of medicine

JF - The New England journal of medicine

IS - 8

ER -

Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B

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