Gene therapy is an innovative approach to treatment that either introduces a functional gene or inactivates or edits the gene causing a disease. For hemophilia B, this means that an effective gene therapy could transfer a working F9 gene into hepatocytes and allow patients to achieve long-term endogenous factor IX expression.1-4
Mutation of the F9 gene in patients with hemophilia B prevents them from producing sufficient factor IX1,5
Gene transfer is an approach to gene therapy that delivers a functional gene—an F9 gene, in the case of hemophilia B—either directly to the patient (in vivo gene therapy) or into cells that have been taken from the patient and treated before being returned to the patient (ex vivo gene therapy)4,6
To accomplish this, the functional gene is inserted into an inactivated viral shell (the vector), which carries the gene to specific target cells2,7,8
In clinical trials, gene therapies for hemophilia B have utilized a type of vector called an adeno-associated virus, or AAV, which can target specific areas of the body—including the liver, where factor IX is produced2,7
Serotypes AAV2, AAV5, AAV6, AAV8, and AAV9 have been shown to exhibit liver tropism and are thus well suited to liver-directed AAV gene therapy. AAV5 is the most phylogenetically distinct of the serotypes commonly used in gene therapy and may have more exclusive tropism for the liver than other AAV serotypes9,10
Further, the F9 gene is small enough to fit inside a standard AAV vector2,11
Average number of spontaneous bleeds in the previous 6 months12
Having joint damage12
Experiencing joint pain at least a few times per month12
*Short‐term prophylaxis is prolonged treatment following a bleed until full recovery and prophylaxis prior to physical activity. Long‐term prophylaxis is regular preventative injections. Of the 110 people surveyed, 29 were being treated with short‐term prophylaxis only, 74 were being treated with long‐term prophylaxis only, and 7 were being treated with both short‐term and long‐term prophylaxis.
Reducing or eliminating the need for routine factor IX prophylaxis13
Providing the long-term benefits of sustained factor IX activity levels13
References: 1. What is Hemophilia? Centers for Disease Control and Prevention. Last reviewed July 25, 2018. Accessed October 13, 2022. https://www.cdc.gov/ncbddd/hemophilia/facts.html 2. Perrin GQ, Herzog RW, Markusic DM. Update on clinical gene therapy for hemophilia. Blood. 2019;133(5):407-414.doi:10.1182/blood-2018-07-820720 3. Pipe SW, Recht M, Key NS, et al. First data from the Phase 3 HOPE-B gene therapy trial: efficacy and safety of etranacogene dezaparvovec (AAV5-Padua hFIX variant; AMT-061) in adults with severe or moderate-severe hemophilia B treated irrespective of pre-existing anti-capsid neutralizing antibodies. Presented at: 62nd ASH Annual Meeting and Exposition; December 5-8, 2020; Virtual. 4. What is Gene Therapy? US Food & Drug Administration. Last reviewed August 1, 2022. Accessed October 13, 2022. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/what-gene-therapy 5. Arruda VR, Doshi BS. Gene therapy for hemophilia: facts and quandaries in the 21st century. Mediterr J Hematol Infect Dis. 2020;12(1):e2020069. doi:10.4084/MJHID.2020.069 6. Rodríguez-Merchán EC, De Pablo-Moreno JA, Liras A. Gene therapy in hemophilia: recent advances. Int J Mol Sci. 2021;22(14):7647. doi:10.3390/ijms22147647 7. Dhungel BP, Bailey CG, Rasko JEJ. Journey to the center of the cell: tracing the path of AAV transduction. Trends Mol Med. 2021;27(2):172-184. Accessed October 13, 2022. doi:10.1016/j.molmed.2020.09.010 8. Miesbach W, O'Mahony B, Key NS, Makris M. How to discuss gene therapy for haemophilia? A patient and physician perspective. Haemophilia. 2019;25(4):545-557. doi:10.1111/hae.13769 9. Pipe S, Leebeek FWG, Ferreira V, Sawyer EK, Pasi J. Clinical considerations for capsid choice in the development of liver-targeted AAV-based gene transfer. Mol Ther Methods Clin Dev. 2019;15:170-178. doi:10.1016/j.omtm.2019.08.015 10. Zincarelli C, Soltys S, Rengo G, Rabinowitz JE. Analysis of AAV serotypes 1-9 mediated gene expression and tropism in mice after systemic injection. Mol Ther. 2008;16(6):1073-1080. doi:10.1038/mt.2008.76 11. Batty P, Lillicrap D. Hemophilia gene therapy: approaching the first licensed product. Hemasphere. 2021;5(3):e540. doi:10.1097/HS9.0000000000000540 12. Data on file. Available from CSL Behring as DOF HGX-001. 13. Pipe SW. Delivering on the promise of gene therapy for haemophilia. Haemophilia. 2021;27(suppl 3):114-121. doi:10.1111/hae.14027
Warning and Precautions
Infusion reactions, including hypersensitivity reactions and anaphylaxis, may occur. Monitor during administration and for at least 3 hours after end of infusion. If symptoms occur, slow or interrupt administration. Re-start administration at a slower infusion once resolved.
Post-dose, monitor for elevated transaminase levels. Consider corticosteroid treatment should elevations occur. The integration of liver-targeting AAV vector DNA into the genome may carry the theoretical risk of hepatocellular carcinoma development. For patients with preexisting risk factors for hepatocellular carcinogenicity, perform regular (eg, annual) abdominal ultrasound and alpha-fetoprotein testing following administration.
Immune-mediated neutralization of the AAV5 vector capsid
Preexisting neutralizing anti-AAV antibodies may impede transgene expression at desired levels.
Monitoring Laboratory Tests
In addition to monitoring liver function, monitor for Factor IX activity and Factor IX inhibitors after administration.
The most common adverse reactions (incidence ≥5%) were elevated ALT, headache, blood creatine kinase elevations, flu-like symptoms, infusion-related reactions, fatigue, nausea, malaise, and elevated AST.
HEMGENIX®, etranacogene dezaparvovec-drlb, is an adeno-associated virus vector-based gene therapy indicated for the treatment of adults with Hemophilia B (congenital Factor IX deficiency) who:
HEMGENIX is for single use intravenous infusion only.
Please see full prescribing information for HEMGENIX.