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Multicenter Study
. 2023 Oct 10;7(19):5671-5679.
doi: 10.1182/bloodadvances.2022008886.

Stable and durable factor IX levels in patients with hemophilia B over 3 years after etranacogene dezaparvovec gene therapy

Annette von Drygalski  1 , Esteban Gomez  2 , Adam Giermasz  3 , Giancarlo Castaman  4 , Nigel S Key  5 , Susan U Lattimore  6 , Frank W G Leebeek  7 , Wolfgang A Miesbach  8 , Michael Recht  9   10 , Robert Gut  11 , Ricardo Dolmetsch  11 , Paul E Monahan  12 , Sandra Le Quellec  13 , Steven W Pipe  14
Affiliations
Multicenter Study

Stable and durable factor IX levels in patients with hemophilia B over 3 years after etranacogene dezaparvovec gene therapy

Annette von Drygalski et al. Blood Adv. .

Abstract

Etranacogene dezaparvovec (AMT-061) is a recombinant adeno-associated virus serotype 5 (AAV5) vector containing a codon-optimized Padua variant human factor IX (FIX) transgene with a liver-specific promoter. Here, we report 3-year outcomes from a phase 2b, open-label, single-dose, single-arm, multicenter trial conducted among adults with severe or moderately severe hemophilia B (FIX ≤2%). All participants (n = 3) received a single intravenous dose (2 × 1013 gene copies per kg) and will be followed up for 5 years. The primary end point of FIX activity ≥5% at 6 weeks was met. Secondary end points included bleed frequency, FIX concentrate use, joint health, and adverse events (AEs). All participants required routine FIX prophylaxis and had neutralizing antibodies to AAV5 before etranacogene dezaparvovec treatment. After administration, FIX activity rose to a mean of 40.8% in year 1 and was sustained in year 3 at 36.9%. All participants discontinued FIX prophylaxis. Bleeding was completely eliminated in 2 out of 3 participants. One participant required on-demand FIX replacement therapy per protocol because of elective surgical procedures, for 2 reported bleeding episodes, and twice for a single self-administered infusion because of an unreported reason. One participant experienced 2 mild, self-limiting AEs shortly after dosing. During the 3-year study period, there were no clinically significant elevations in liver enzymes, no requirement for steroids, no FIX inhibitor development, and no late-emergent safety events in any participant. Etranacogene dezaparvovec was safe and effective in adults with hemophilia B over 3 years after administration. This trial was registered at www.clinicaltrials.gov as #NCT03489291.

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Conflict of interest statement

Conflict-of-interest disclosure: A.v.D. is a consultant for BioMarin, Sanofi Genzyme, Novo Nordisk, Pfizer, uniQure, and Hematherix. A.G. is a consultant for Bioverativ, Genentech/Roche, BioMarin, and uniQure and serves as a speaker bureau of Bioverativ and Genentech/Roche. G.C. received grants/research support from CSL Behring, Pfizer, and Sobi and serves as a speaker bureau of Bayer, BioMarin, Roche, Sobi, Grifols, LFB, Novo Nordisk, Werfen, Kedrion, and uniQure. N.S.K. received grants/research support from Grifols and Takeda and is a consultant for uniQure, BioMarin, and Novo Nordisk. S.U.L is a consultant for uniQure. F.W.G.L. received grants/research support from CSL Behring, Shire/Takeda, Roche, and Sobi and is a consultant for uniQure, Takeda, Novo Nordisk, and BioMarin. W.A.M. received grants/research support from Bayer, Biotest, Takeda, LFB, Octapharma, Novo Nordisk, Pfizer, and uniQure and is a consultant for Bayer, BioMarin, Freeline, LFB, Octapharma, Novo Nordisk, Pfizer, and uniQure. M.R. received research funding from Bayer, BioMarin, CSL Behring, Genentech, Grifols, Hema Biologics, LFB, Novo Nordisk, Octapharma, Pfizer, Sanofi, Spark Therapeutics, Takeda, and uniQure; is a consultant for Catalyst Biosciences, CSL Behring, Genentech, Hema Biologics, Kedrion, Novo Nordisk, Pfizer, Sanofi, Takeda, and uniQure; and is on the board of directors for Foundation for Women and Girls with Blood Disorders, Partners in Bleeding Disorders Education, and Thrombosis and Hemostasis Societies of North America. E.G. serves as a speaker bureau of Global Blood Therapeutics. R.G. is an employee of uniQure. R.D. is an employee of uniQure. S.L.Q. is an employee of CSL Behring. P.E.M. is an employee of CSL Behring. S.W.P. received a grant/research support from Bayer, BioMarin, Freeline, Novo Nordisk, and Roche/Genentech and is a consultant for ApcinteX, ASC Therapeutics, Bayer, BioMarin, CSL Behring, GeneVentiv, HEMA Biologics, Freeline Therapeutics, Novo Nordisk, Pfizer, Regeneron/Intellia, Roche/Genentech, Sanofi, Spark Therapeutics, Takeda, and uniQure.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Study design. (A) Recording of bleeds and FIX replacement before and after etranacogene dezaparvovec treatment. Assessment of bleeds and FIX replacement before screening were based on medical records. (B) No e-diary recording during long-term follow-up. Figure adapted from Von Drygalski A et al.
Figure 2.
Figure 2.
Sustained increases in FIX activity after etranacogene dezaparvovec administration. Uncontaminated FIX activity measured by using a 1-stage aPTT assay. ∗Samples at baseline and Week 1 may have included activity from exogenous FIX replacement. aPTT, activated partial thromboplastin time.
See this image and copyright information in PMC

References

    1. Srivastava A, Santagostino E, Dougall A, et al. WFH guidelines for the management of hemophilia, 3rd edition. Haemophilia. 2020;26(suppl 6):1–158. - PubMed
    1. Young G, Collins PW, Colberg T, et al. Nonacog beta pegol (N9-GP) in haemophilia B: a multinational phase III safety and efficacy extension trial (paradigm™4) Thromb Res. 2016;141:69–76. - PubMed
    1. Santagostino E, Martinowitz U, Lissitchkov T, et al. Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood. 2016;127(14):1761–1769. - PMC - PubMed
    1. Melchiorre D, Manetti M, Matucci-Cerinic M. Pathophysiology of hemophilic arthropathy. J Clin Med. 2017;6(7):63. - PMC - PubMed
    1. White GC, Rosendaal F, Aledort LM, et al. Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost. 2001;85(3):560. - PubMed

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