Description
Entranacogene dezaparvovec (Hemgenix^®) is a one-time gene replacement therapy indicated for the prevention of bleeding episodes in adult individuals with moderate-severe to severe hemophilia B. Hemophilia B is an X-linked genetic disorder characterized by a deficiency in clotting factor IX (FIX) resulting in impaired clotting. Severity of hemophilia B is determined based off the amount of FIX in the blood plasma.

Entranacogene dezaparvovec (Hemgenix) is an adeno-associated virus (AAV) gene therapy composed of a recombinant AAV5 (rAAV5) vector with the FIX Padua transgene. Expression of this transgene in liver cells yields functional human clotting FIX-Padua which is then secreted into circulation.

Policy

Hemgenix is considered MEDICALLY NECESSARY when the following criteria is met:

1. Diagnosis of Hemophilia B (congenital Factor IX deficiency)
2. Submission of medical records (e.g., chart notes) documenting one of the following:
   1.  Both of the following:
      1. Diagnosis of severe hemophilia B
      2. Documentation of endogenous Factor IX levels less than 1% of normal Factor IX (< 0.01 IU/mL)

OR

2. 2. All of the following:
      1. Diagnosis of moderately severe hemophilia B
      2. Documentation of endogenous Factor IX levels greater than or equal to 1% to less than or equal to 2% (greater than or equal to 0.01 IU/mL to less than or equal to 0.02 IU/mL)
      3. Patient has current or historical life-threatening hemorrhage or repeated, serious spontaneous bleeding episodes
3. Paid claims or submission of medical records (e.g., chart notes) confirming that the patient is currently using Factor IX prophylaxis therapy (e.g., BeneFIX, Ixinity, Rixubis, etc.) and will discontinue treatment after stable on Hemgenix therapy
4. Patient has greater than 150 previous exposure days of treatment with a Factor IX agent
5. Patient is 18 years of age or older
6. Submission of medical records (e.g., chart notes) documenting that the patient does not have any of the following:
   1. Positive human immunodeficiency virus (HIV) test at screening that is not controlled with anti-viral therapy
   2. Active infection with hepatitis B or C virus
   3. Currently on antiviral treatment for hepatitis B or C
   4. Positive Factor IX inhibitor titer test prior to therapy
   5. History of Factor IX inhibitor
   6. Anti-AAV antibody (e.g., AAV-5) titers exceeding 1:678
7. Submission of medical records (e.g., chart notes) documenting that the following laboratory values have been checked prior to therapy and are less than two times the upper limit of normal:
   1. Alanine aminotransferase (ALT)
   2. Alkaline phosphatase (ALP)
   3. Aspartate aminotransferase (AST)
   4. Total bilirubin
8. Submission of medical records (e.g., chart notes) documenting that hepatic ultrasound and elastography have been completed prior to therapy
9. Prescribed by a hematologist at a Hemophilia Treatment Center (HTC)
10. Patient has never received Hemgenix treatment in their lifetime

Notes: Per prescribing information, Hemgenix can be administered only once.

All other uses of Hemgenix are considered NOT MEDICALLY NECESSARY.

Background
Hemophilia B is a genetic bleeding disorder resulting from missing or insufficient levels of blood clotting Factor IX. Most individuals who have Hemophilia B and experience symptoms are men. The prevalence of Hemophilia B in the population is about 1 in 40,000; Hemophilia B represents about 15% of patients with hemophilia.² Treatment typically involves replacing the missing or deficient clotting factor to improve the body’s ability to stop bleeding and promote healing. Patients with severe Hemophilia B typically require a routine treatment regimen of intravenous (IV) infusions of Factor IX replacement products to maintain sufficient levels of clotting factor to prevent bleeding episodes.

The term “gene therapy” usually has been used to describe an ex vivo or in vivo therapy whereby RNA or DNA are introduced into target cells (ex vivo) or tissues (in vivo) by a delivery vector while “cellular therapy” is a broad term that encompasses both the infusion of a cellular product for the purpose of hematopoietic reconstitution and the infusion of a cellular product intended to have a direct immunologic impact.⁹ There is a general consensus among the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the American Society of Gene and Cell Therapy (ASGCT) defining gene therapy as changes in gene expression, achieved by replacing or correcting a disease-causing gene, inactivating a target gene, or inserting a new or modified gene, using a vector or delivery system of genetic sequence or gene, genetically modified microorganisms, viruses, or cells.^6,7,8 The rapid growth of cellular and gene therapies over the past few years has revealed the need for an accurate and uniform taxonomy. Work is ongoing across a number of industry stakeholders including clinicians, scientists, payers, and coders to standardize nomenclature regarding what constitutes a cellular therapy or a gene therapy.⁹ In the United States, the FDA establishes the regulatory framework for clinical trials and approval of therapeutic agents such as gene and cellular therapy. Specifically, the FDA Center for Biologics Evaluation and Research regulates cellular therapy products and human gene therapy products as biologics, as well as some devices related to cellular and gene therapy.⁷

Hemgenix is a one-time gene therapy product given as a single dose by IV infusion. Hemgenix consists of a viral vector carrying a gene for clotting Factor IX. Specifically, AAV5-hFIXco-Padua (AMT- 061) is a recombinant adeno-associated viral vector of serotype 5 (AAV5) containing the Padua variant of a codon-optimized human FIX complementary deoxyribonucleic acid (cDNA) under the control of a liver-specific promoter.³ The gene is expressed in the liver to produce Factor IX protein, to increase blood
levels of Factor IX and thereby limit bleeding episodes.

References

1. Hemgenix^® [package insert]. Kankakee, IL: CSL Behring LLC, November 2022.
2. FDA. News Release. FDA Approves First Gene Therapy to Treat Adults with Hemophilia B. November 11, 2022.https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treat-adults-hemophilia-b. Accessed December 20, 2022.
3. ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/study/NCT03569891. Accessed December 20, 2022.
4. Von Drygalski A, Giermasz A, Castaman G, et al. Etranacogene dezaparvovec (AMT-061 phase 2b): normal/near normal FIX activity and bleed cessation in hemophilia B [published correction appears in Blood Adv. 2020 Aug 11;4(15):3668]. Blood Adv. 2019;3(21):3241-3247 doi:10.1182/bloodadvances.2019000811.
5. Miesbach W, Meijer K, Coppens M, et al. Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B. Blood. 2018;131(9):1022-1031 doi:10.1182/blood-2017-09-804419.
6. European Medicines Agency. Multidisciplinary: Gene Therapy. Available at: https://www.ema.europa.eu/en/humanregulatory/research-development/scientific-guidelines/multidisciplinary/multidisciplinary-gene-therapy. Accessed December 20, 2022.
7. U.S. Food and Drug Administration : What is gene therapy?. Available at: https://www.fda.gov/vaccines-bloodbiologics/cellular-gene-therapy-products/what-gene-therapy. Accessed December 20, 2022.
8. American Society of Gene and Cell Therapy : Gene Therapy 101: Different Approaches. Available at:https://patienteducation.asgct.org/gene-therapy-101/different-approaches. Accessed December 20, 2022.
9. Sharma A, Farnia S, Otegbeye F, et al. Nomenclature for Cellular and Genetic Therapies: A Need for Standardization. Transplant Cell Ther. 2022;28(12):795-801. doi:10.1016/j.jtct.2022.08.029.
10. Blanchette VS, Key NS, Ljung LR, et al. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost. 2014;12(11):1935-1939. doi:10.1111/jth.12672.

Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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