Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B
(2023) In New England Journal of Medicine 388(8). p.706-718- 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... (More)
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.
(Less)
- author
- organization
- publishing date
- 2023
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Childhood Diseases, Coagulation, Genetics, Genetics General, Hematology/Oncology, Pediatrics
- in
- New England Journal of Medicine
- volume
- 388
- issue
- 8
- pages
- 13 pages
- publisher
- Massachusetts Medical Society
- external identifiers
-
- pmid:36812434
- scopus:85149659290
- ISSN
- 0028-4793
- DOI
- 10.1056/NEJMoa2211644
- language
- English
- LU publication?
- yes
- id
- 9523cf94-85cb-478e-b63b-08992dc1c4aa
- date added to LUP
- 2023-04-03 11:43:22
- date last changed
- 2024-06-14 16:47:08
@article{9523cf94-85cb-478e-b63b-08992dc1c4aa,
abstract = {{<p>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.</p>}},
author = {{Pipe, Steven W. and Leebeek, Frank W.G. and Recht, Michael and Key, Nigel S. and Castaman, Giancarlo and Miesbach, Wolfgang and Lattimore, Susan and Peerlinck, Kathelijne and Van Der Valk, Paul and Coppens, Michiel and Kampmann, Peter and Meijer, Karina and O'connell, Niamh and Pasi, K. John and Hart, Daniel P. and Kazmi, Rashid and Astermark, Jan and Hermans, Cedric R.J.R. and Klamroth, Robert and Lemons, Richard and Visweshwar, Nathan and Von Drygalski, Annette and Young, Guy and Crary, Shelley E. and Escobar, Miguel and Gomez, Esteban and Kruse-Jarres, Rebecca and Quon, Doris V. and Symington, Emily and Wang, Michael and Wheeler, Allison P. and Gut, Robert and Liu, Ying P. and Dolmetsch, Ricardo E. and Cooper, David L. and Li, Yanyan and Goldstein, Brahm and Monahan, Paul E.}},
issn = {{0028-4793}},
keywords = {{Childhood Diseases; Coagulation; Genetics; Genetics General; Hematology/Oncology; Pediatrics}},
language = {{eng}},
number = {{8}},
pages = {{706--718}},
publisher = {{Massachusetts Medical Society}},
series = {{New England Journal of Medicine}},
title = {{Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B}},
url = {{http://dx.doi.org/10.1056/NEJMoa2211644}},
doi = {{10.1056/NEJMoa2211644}},
volume = {{388}},
year = {{2023}},
}