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Review
. 2024 Apr 9;8(7):1796-1803.
doi: 10.1182/bloodadvances.2023010511.

Hemophilia B and gene therapy: a new chapter with etranacogene dezaparvovec

Xavier M Anguela  1 , Katherine A High  2   3
Affiliations
Review

Hemophilia B and gene therapy: a new chapter with etranacogene dezaparvovec

Xavier M Anguela et al. Blood Adv. .

Abstract

The US Food and Drug Administration (FDA)'s authorization of etranacogene dezaparvovec (Hemgenix) is a significant milestone, constituting not only the first FDA approval of a gene therapy for hemophilia but also the first approval of a liver-targeted adeno-associated virus vector gene therapy. This review summarizes the nonclinical studies and clinical development that supported regulatory clearance. Similar to other gene therapies for single gene disorders, both the short-term safety and the phenotypic improvement were unequivocal, justifying the modest-sized safety and efficacy database, which included 57 participants across the phase 2b (3 participants) and phase 3 (54 participants) studies. The most common adverse reactions included liver enzyme elevation, headache, flu-like symptoms, infusion-related reactions, creatine kinase elevation, malaise, and fatigue; these were mostly transient. One participant had hepatocellular carcinoma on a study-mandated liver ultrasound conducted 1 year after vector infusion; molecular analysis of the resected tumor showed no evidence of vector-related insertional mutagenesis as the etiology. A remarkable 96% of participants in the phase 3 trial were able to stop factor IX (FIX) prophylaxis, with the study demonstrating noninferiority to FIX prophylaxis in terms of the primary end point, annualized bleeding rate. Key secondary end points such as the annualized infusion rate, which declined by 97%, and the plasma FIX activity level at 18 months after infusion, with least squares mean increase of 34.3 percentage points compared with baseline, were both clinically and statistically significant. The FDA's landmark approval of Hemgenix as a pioneering treatment for hemophilia stands on the shoulders of >20 years of gene therapy clinical research and heralds a promising future for genomic medicines.

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Conflict of interest statement

Conflict-of-interest disclosure: K.A.H. and X.M.A. are former employees of Spark Therapeutics, where they worked on a similar investigational product for hemophilia B, fidanacogene elaparvovec.

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References

    1. Manno CS, Pierce GF, Arruda VR, et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med. 2006;12(3):342–347. - PubMed
    1. Davidoff AM, Gray JT, Ng CY, et al. Comparison of the ability of adeno-associated viral vectors pseudotyped with serotype 2, 5, and 8 capsid proteins to mediate efficient transduction of the liver in murine and nonhuman primate models. Mol Ther. 2005;11(6):875–888. - PubMed
    1. Nathwani AC, Gray JT, Ng CYC, et al. Self-complementary adeno-associated virus vectors containing a novel liver-specific human factor IX expression cassette enable highly efficient transduction of murine and nonhuman primate liver. Blood. 2006;107(7):2653–2661. - PMC - PubMed
    1. Nathwani AC, Rosales C, McIntosh J, et al. Long-term safety and efficacy following systemic administration of a self-complementary AAV vector encoding human FIX pseudotyped with serotype 5 and 8 capsid proteins. Mol Ther. 2011;19(5):876–885. - PMC - PubMed
    1. Simioni P, Tormene D, Tognin G, et al. X-linked thrombophilia with a mutant factor IX (factor IX Padua) N Engl J Med. 2009;361(17):1671–1675. - PubMed