Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B

被引：127

作者：

Pipe, S. W. ^{[1
,2
]}

Leebeek, F. W. G. ^{[3
]}

Recht, M. ^{[7
,8
]}

Key, N. S. ^{[9
,10
]}

Castaman, G. ^{[11
]}

Miesbach, W. ^{[12
,13
]}

Lattimore, S. ^{[7
]}

Peerlinck, K. ^{[16
]}

Van der Valk, P. ^{[4
]}

Coppens, M. ^{[5
,6
]}

Kampmann, P. ^{[19
]}

Meijer, K.

O'Connell, N. ^{[20
]}

Pasi, K. J. ^{[21
]}

Hart, D. P. ^{[21
,22
]}

Kazmi, R. ^{[23
,24
]}

Astermark, J. ^{[25
,26
]}

Hermans, C. R. J. R. ^{[17
,18
]}

Klamroth, R. ^{[14
,15
]}

Lemons, R. ^{[27
,28
]}

Visweshwar, N. ^{[29
]}

von Drygalski, A. ^{[30
]}

Young, G. ^{[31
,33
]}

Crary, S. E. ^{[35
,36
]}

Escobar, M. ^{[37
,38
]}

Gomez, E. ^{[34
]}

Kruse-Jarres, R. ^{[39
,40
]}

Quon, D. V. ^{[32
]}

Symington, E.

Wang, M. ^{[41
]}

Wheeler, A. P. ^{[42
]}

Gut, R. ^{[43
]}

Liu, Y. P.

Dolmetsch, R. E. ^{[43
]}

Cooper, D. L. ^{[43
]}

Li, Y. ^{[44
]}

Goldstein, B. ^{[44
]}

Monahan, P. E. ^{[44
]}

机构：

[1] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA

[3] Erasmus Univ, Univ Med Ctr Rotterdam, Med Ctr, Dept Hematol, Rotterdam, Netherlands

[4] Univ Utrecht, Univ Med Ctr Utrecht, Van Creveldklin, Utrecht, Netherlands

[5] Univ Amsterdam, Vasc Med, Med Ctr, Amsterdam, Netherlands

[6] Amsterdam Cardiovasc Sci Pulm Hypertens & Thrombo, Amsterdam, Netherlands

[7] Yale Univ, Sch Med, New Haven, CT USA

[8] Amer Thrombosis & Hemostasis Network, Rochester, NY USA

[9] Univ N Carolina, Dept Med, Chapel Hill, NC USA

[10] Univ N Carolina, UNC Blood Res Ctr, Chapel Hill, NC USA

[11] Careggi Univ Hosp, Dept Oncol, Ctr Bleeding Disorders & Coagulat, Florence, Italy

[12] Univ Hosp Frankfurt, Dept Hemostaseol, Frankfurt, Germany

[13] Univ Hosp Frankfurt, Hemophilia Ctr, Med Clin 2, Inst Transfus Med & Immunohematol, Frankfurt, Germany

[14] Vivantes Klinikum Friedrichshain, Comprehens Care Hemophilia Treatment Ctr, Berlin, Germany

[15] Univ Bonn, Univ Hosp Bonn, Inst Expt Hematol & Transfus Med, Fac Med, Bonn, Germany

[16] Univ Hosp Leuven, Dept Vasc Med & Hemostasis, Hemophilia Ctr, Leuven, Belgium

[17] Clin Univ St Luc, Div Hematol, Brussels, Belgium

[18] Catholic Univ Louvain, Louvain La Neuve, Belgium

[19] Rigshop Copenhagen, Dept Hematol, Copenhagen, Denmark

[20] St James Hosp, Natl Coagulat Ctr, Dublin, Ireland

[21] Queen Mary Univ London, Barts & London Sch Med & Dent, London, England

[22] Barts Hlth NHS Trust, Royal London Hosp, Haemophilia Ctr, London, England

[23] Univ Hosp Southampton, Southampton, Hants, England

[24] Natl Inst Hlth & Care Res, Clin Res Facil, Southampton, Hants, England

[25] Lund Univ, Dept Translat Med, Lund, Sweden

[26] Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Malmo, Sweden

[27] Univ Utah, Dept Pediat, Salt Lake City, UT USA

[28] Primary Childrens Med Ctr, Salt Lake City, UT USA

[29] Univ S Florida, Tampa, FL USA

[30] Hemophilia & Thrombosis Treatment Ctr, Dept Med, San Diego, CA USA

[31] Childrens Hosp Los Angeles, Canc & Blood Disorders Inst, Los Angeles, CA USA

[32] Luskin Orthopaed Inst Children, Orthopaed Hemophilia Treatment Ctr, Los Angeles, CA USA

[33] Univ Southern Calif, Keck Sch Med, Los Angeles, CA USA

[34] Ctr Inherited Blood Disorders, Orange, CA USA

[35] Arkansas Childrens Hosp, Pulaski, AR USA

[36] Univ Arkansas Med Sci, Little Rock, AR USA

[37] Univ Texas Hlth Sci Ctr Houston, McGovern Med Sch, Houston, TX USA

[38] Gulf States Hemophilia & Thrombophilia Ctr, Houston, TX USA

[39] Washington Ctr Bleeding Disorders, Washington, DC USA

[40] Univ Washington, Seattle, WA USA

[41] Univ Colorado, Hemophilia & Thrombosis Ctr, Anschutz Med Campus, Aurora, CO USA

[42] Vanderbilt Univ, Dept Pathol Microbiol & Immunol, Med Ctr, Nashville, TN USA

[43] UniQure, Lexington, MA USA

[44] CSL Behring, King Of Prussia, PA USA

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2023年 / 388卷 / 08期

关键词：

FACTOR-IX; PREEXISTING IMMUNITY; LIMITATIONS; EXPRESSION; ANTIBODIES; LIVER;

D O I：

10.1056/NEJMoa2211644

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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; 2x10(13) 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 pre-dose 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.

引用

页码：706 / 718

页数：13

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