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HEMGENIX AAV5 GENE THERAPY
Specifically designed to target hemophilia B
HEMGENIX is a gene therapy that uses an in vivo method of gene transfer, introducing a functional copy of the F9 gene to compensate for the F9 mutation. See how it works:
What does HEMGENIX consist of?
Liver-directed AAV5 vector
This nonreplicating, nonpathogenic AAV5 (adeno-associated viral vector serotype 5)
was chosen because there is a lower prevalence of preexisting immunity (neutralizing
antibodies or NAbs) to it in the general population.
AAV5 targets liver cells,* and also has a serotype-specific tropism for hepatocytes,
which are an ideal target for transduction since they are where factor IX is normally
produced.1-6 Please note that there is no exclusion for patients with positive neutralizing antibodies to AAV5 with HEMGENIX.
*Based on animal studies.
Highly active factor IX-Padua gene variant
Factor IX-Padua has been shown to generate 5 to 8 times higher mean endogenous factor IX activity than the more common wild-type gene. The factor IX-Padua gene is under the control of a liver-specific promoter.7,8
With HEMGENIX, the factor IX-Padua gene is contained within an AAV5 vector to introduce a functional copy of the F9 gene into a patient’s hepatocytes.
References: 1. 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 2. 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 3. Louis Jeune V, Joergensen JA, Hajjar RJ, Weber T. Pre-existing anti–adeno-associated virus antibodies as a challenge in AAV gene therapy. Hum Gene Ther Methods. 2013;24(2):59-67. doi:10.1089/hgtb.2012.243 4. Vance MA, Mitchell A, Samulski RJ. AAV biology, infectivity and therapeutic use from bench to clinic. In: Hashad D, ed. Gene Therapy: Principles and Challenges [Internet]. IntechOpen; 2015. Accessed October 13, 2022. doi:10.5772/61988 5. Ronzitti G, Gross DA, Mingozzi F. Human immune responses to adeno-associated virus (AAV) vectors. Front Immunol. 2020;11:670. Published April 17, 2020. doi:10.3389/fimmu.2020.00670 6. 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 7. 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. doi:10.1056/NEJMoa0904377 8. Nathwani AC. Gene therapy for hemophilia. Hematology Am Soc Hematol Educ Program. 2019;2019(1):1-8. doi:10.1182/hematology.2019000007
Patient Selection
Perform baseline testing to select patients, including titer testing for Factor IX (FIX) inhibitor presence. Do not administer HEMGENIX®, etranacogene dezaparvovec-drlb, to patients with FIX inhibitors or a history of FIX inhibitors. Perform liver health assessments, consulting with a hepatologist if needed. Also perform laboratory tests to evaluate hepatitis B and C, and postpone treatment if patient has active infection, as this may reduce the efficacy of HEMGENIX and/or increase the risk of adverse reactions.
Warnings and Precautions
Hypersensitivity and Infusion Reactions
Infusion reactions, including hypersensitivity reactions and anaphylaxis, have occurred. Monitor during administration and for at least 3 hours after end of infusion. If symptoms occur, slow or interrupt administration. When symptoms have resolved, restart administration at a slower infusion rate.
Hepatotoxicity/Hepatocellular Carcinogenicity
Hepatotoxicity with elevated liver transaminase has occurred after HEMGENIX treatment. Monitor ALT levels once per week for 3 months and thereafter monthly up to 1 year after administration. Consider corticosteroid treatment should elevations occur and as clinically indicated.
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, consider liver ultrasound and alpha-fetoprotein testing following administration, and monitor for hepatocellular carcinomas for five years following administration of HEMGENIX.
Immune-Mediated Neutralization of the AAV5 vector capsid
Preexisting neutralizing anti-AAV antibodies may impede transgene expression at desired therapeutic levels. Following treatment with HEMGENIX, all patients developed neutralizing anti-AAV5 antibodies to AAV5 vector capsid.
Monitoring Laboratory Tests
Monitor patients regularly for FIX activity (eg, weekly for 3 months), especially when exogenous FIX is administered, as it may take several weeks following HEMGENIX administration before hemostatic control becomes apparent. Hemostatic support may be needed for some patients. Monitor patients through appropriate clinical observations and laboratory tests for the development of inhibitors to FIX.
Adverse Reactions
The most common adverse reactions (incidence ≥5% in clinical trials) are elevated ALT, headache, blood creatine kinase elevations, flu-like symptoms, infusion-related reactions, fatigue, nausea, malaise, and elevated AST.
Indication
HEMGENIX is 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.
To report SUSPECTED ADVERSE REACTIONS, contact the CSL Behring Pharmacovigilance Department at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
