Gene Therapy with Fidanacogene Elaparvovec in Adults with Hemophilia B.
(2024) In New England Journal of Medicine 391(12). p.1108-1118- Abstract
Background Fidanacogene elaparvovec, an adeno-associated virus (AAV) gene-therapy vector for hemophilia B containing a high-activity human factor IX variant (FIX-R338L/FIX-Padua), was associated with sustained factor IX activity in a phase 1-2a study. Methods We conducted a phase 3 open-label study of fidanacogene elaparvovec at a dose of 5×1011 vector genome copies per kilogram of body weight. Men 18 to 65 years of age with hemophilia B and a factor IX level of 2% or less were eligible for screening if they had received at least 6 months of therapy with prophylactic factor IX concentrate. The primary end point, tested for noninferiority, was the annualized bleeding rate (treated and untreated bleeding episodes) from week 12... (More)
Background Fidanacogene elaparvovec, an adeno-associated virus (AAV) gene-therapy vector for hemophilia B containing a high-activity human factor IX variant (FIX-R338L/FIX-Padua), was associated with sustained factor IX activity in a phase 1-2a study. Methods We conducted a phase 3 open-label study of fidanacogene elaparvovec at a dose of 5×1011 vector genome copies per kilogram of body weight. Men 18 to 65 years of age with hemophilia B and a factor IX level of 2% or less were eligible for screening if they had received at least 6 months of therapy with prophylactic factor IX concentrate. The primary end point, tested for noninferiority, was the annualized bleeding rate (treated and untreated bleeding episodes) from week 12 to month 15 after treatment with fidanacogene elaparvovec as compared with the prophylaxis lead-in period. Superiority, additional efficacy end points, and safety were also assessed. Results Of 316 men who underwent screening for the lead-in study, 204 (64.6%) were not eligible; 188 (59.5%) of those were ineligible owing to the presence of anti-AAV neutralizing antibodies. Of the 45 participants who received fidanacogene elaparvovec, 44 completed at least 15 months of follow-up. The annualized rate of bleeding for all bleeding episodes decreased by 71%, from 4.42 (95% confidence interval [CI], 1.80 to 7.05) at baseline to 1.28 (95% CI, 0.57 to 1.98) after gene therapy, a treatment difference of -3.15 episodes (95% CI, -5.46 to -0.83; P=0.008). This result shows the noninferiority and superiority of fidanacogene elaparvovec to prophylaxis. At 15 months, the mean factor IX activity was 26.9% (median, 22.9%; range, 1.9 to 119.0) by one-stage SynthASil assay. A total of 28 participants (62%) received glucocorticoids for increased aminotransferase levels or decreased factor IX levels (or both) starting between 11 and 123 days. No infusion-related serious adverse events, thrombotic events, development of factor IX inhibitors, or malignant conditions were observed. Conclusions Fidanacogene elaparvovec was superior to prophylaxis for the treatment of participants with hemophilia B, leading to reduced bleeding and stable factor IX expression. (Funded by Pfizer; BENEGENE-2 ClinicalTrials.gov number, NCT03861273.).
(Less)
- author
- organization
- publishing date
- 2024-09-26
- 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
- 391
- issue
- 12
- pages
- 11 pages
- publisher
- Massachussetts Medical Society
- external identifiers
-
- pmid:39321362
- scopus:85205685004
- ISSN
- 0028-4793
- DOI
- 10.1056/NEJMoa2302982
- language
- English
- LU publication?
- yes
- id
- fa33668e-aa68-4926-bc83-2b5a3e3cf3f4
- date added to LUP
- 2024-12-11 11:22:23
- date last changed
- 2025-07-10 17:23:41
@article{fa33668e-aa68-4926-bc83-2b5a3e3cf3f4,
abstract = {{<p>Background Fidanacogene elaparvovec, an adeno-associated virus (AAV) gene-therapy vector for hemophilia B containing a high-activity human factor IX variant (FIX-R338L/FIX-Padua), was associated with sustained factor IX activity in a phase 1-2a study. Methods We conducted a phase 3 open-label study of fidanacogene elaparvovec at a dose of 5×10<sup>11</sup> vector genome copies per kilogram of body weight. Men 18 to 65 years of age with hemophilia B and a factor IX level of 2% or less were eligible for screening if they had received at least 6 months of therapy with prophylactic factor IX concentrate. The primary end point, tested for noninferiority, was the annualized bleeding rate (treated and untreated bleeding episodes) from week 12 to month 15 after treatment with fidanacogene elaparvovec as compared with the prophylaxis lead-in period. Superiority, additional efficacy end points, and safety were also assessed. Results Of 316 men who underwent screening for the lead-in study, 204 (64.6%) were not eligible; 188 (59.5%) of those were ineligible owing to the presence of anti-AAV neutralizing antibodies. Of the 45 participants who received fidanacogene elaparvovec, 44 completed at least 15 months of follow-up. The annualized rate of bleeding for all bleeding episodes decreased by 71%, from 4.42 (95% confidence interval [CI], 1.80 to 7.05) at baseline to 1.28 (95% CI, 0.57 to 1.98) after gene therapy, a treatment difference of -3.15 episodes (95% CI, -5.46 to -0.83; P=0.008). This result shows the noninferiority and superiority of fidanacogene elaparvovec to prophylaxis. At 15 months, the mean factor IX activity was 26.9% (median, 22.9%; range, 1.9 to 119.0) by one-stage SynthASil assay. A total of 28 participants (62%) received glucocorticoids for increased aminotransferase levels or decreased factor IX levels (or both) starting between 11 and 123 days. No infusion-related serious adverse events, thrombotic events, development of factor IX inhibitors, or malignant conditions were observed. Conclusions Fidanacogene elaparvovec was superior to prophylaxis for the treatment of participants with hemophilia B, leading to reduced bleeding and stable factor IX expression. (Funded by Pfizer; BENEGENE-2 ClinicalTrials.gov number, NCT03861273.).</p>}},
author = {{Cuker, Adam and Kavakli, Kaan and Frenzel, Laurent and Wang, Jiaan Der and Astermark, Jan and Cerqueira, Monica H. and Iorio, Alfonso and Katsarou-Fasouli, Olga and Klamroth, Robert and Shapiro, Amy D. and Hermans, Cédric and Ishiguro, Akira and Leavitt, Andrew D. and Oldenburg, Johannes B. and Ozelo, Margareth C. and Teitel, Jerome and Biondo, Francesca and Fang, Annie and Fuiman, Joanne and Mckay, John and Sun, Pengling and Rasko, John E.J. and Rupon, Jeremy}},
issn = {{0028-4793}},
keywords = {{Childhood Diseases; Coagulation; Genetics; Genetics General; Hematology/Oncology; Pediatrics}},
language = {{eng}},
month = {{09}},
number = {{12}},
pages = {{1108--1118}},
publisher = {{Massachussetts Medical Society}},
series = {{New England Journal of Medicine}},
title = {{Gene Therapy with Fidanacogene Elaparvovec in Adults with Hemophilia B.}},
url = {{http://dx.doi.org/10.1056/NEJMoa2302982}},
doi = {{10.1056/NEJMoa2302982}},
volume = {{391}},
year = {{2024}},
}