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Gene Therapy Research in Hemophilia B

HEMGENIX	HEMGENIX Preparation and Administration	Gene Therapy Information	Educational Materials	Conferences and Events	Key Publications	Additional Resources	Disease States

Gene Therapy Information

History of Hemophilia Treatment

What Is Gene Therapy?

Gene Therapy Approaches in Hemophilia A and B

Gene Therapy Approaches Are Being Investigated for Both Hemophilia A and B

Gene therapy approaches are being utilized for both hemophilia A and B

^{AAV, adeno-associated virus; FIX, factor IX; FVIII, factor VIII.}^{1. Arruda VR, Doshi BS. Mediterr J Hematol Infect Dis 2020; 12:e2020069. 2. ClinicalTrials.gov search results. Accessed August 2021. 3. ClinicalTrials.gov search results. Accessed August 2021.}

Gene Therapy in Hemophilia B

What Is the "Padua" Variant?

The Padua variant is widely being studied in gene therapy for Hemophilia B

This hyper functional variant is caused by a natural gain of function mutation leading to increased FIX activity

Padua Variant Graph

Single gain-of-function mutation (leucine for arginine at amino acid 338) in the FIX gene that yields 8-fold increase in specific activity (FIX activity per molecule)

^{Simioni P, et al. NEJM 2009;361:1671-1675.}

Goals for Gene Therapy

Transgene/Vectors

How Gene Therapy Is Delivered

How Gene Therapy is delivered

Adeno-associated virus (AAV) vectors carry DNA
The DNA resides in the host cell nucleus, but usually does not integrate into the genome
AAV vectors are administered in vivo, by direct injection either systemically or into an organ

^{AAV=adeno-associated virus.

1. Carter BJ. Mol Ther. 2004;10(6):981–989; 2. Mitchell AM, et al. Curr Gene Ther. 2010;10(5):319–340; 3. Bulcha JT, et al. Signal Transduct Target Ther. 2021;6(1):53.}

AAV Serotypes

Choosing the Right Vector Serotypes

Choosing the right Vector Serotypes

AAV vector delivers target transgene to specific cells
Each serotype has different specificity to organs within the body
Factors are synthesized in the liver, want a vector specific to liver
AAV5 and AAV8 target liver based on large animal model study

^{Adapted from Vance, et al. 2015.}

AAV Vectors

AAV Vectors Are Derived From Wild-type AAV

AAV Vectors are derived from Wild-type AAV

Does not shed DNA
Can package transgene with sequences up to 5 kb
Majority of vector genomes do not integrate into host genomes
Wild-type AAV is non-pathogenic, weakly immunogenic, replication-deficient

^{High KA, Roncarolo MG. N Engl J Med. 2019;381(5):455-464; https://uniqure.com/patients/Gene-Therapy-Information.pdf; Miesbach, W et al. Blood. 2018; 131(9);1022-10ç31.}

Safety Considerations

Neutralizing Antibodies Neutralizing Anti-bodies

Many people have pre-existing antibodies against AAV capsid proteins

Binding antibodies, or

Neutralizing antibodies

Making gene therapy ineffective or inefficient

Immune Response to Transfected Cells

The immune system can limit the efficacy of AAV-based gene therapy at 2 critical points:^1,2
- Points of administration
- Post administration
Associated with evidence of liver toxicity in ~60% of patients
Ongoing immune reactions can lead to loss of factor expression
Often precludes re-administration of gene therapy

Immune Response Trans Cells

^{Batty P and Lillicrap D. HemaSphere 2021;5:3(e540); Nathwani AC. Am Soc Hematol Educ Program. 2019;1-8.}

Important Safety Information for HEMGENIX

Warning and Precautions

Infusion Reactions

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.

Hepatotoxicity/Hepatocellular Carcinoma

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.

Adverse Reactions

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.

Indication for HEMGENIX

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:

Currently use Factor IX prophylaxis therapy, or
Have current or historical life-threatening hemorrhage, or
Have repeated, serious spontaneous bleeding episodes.

HEMGENIX is for single use intravenous infusion only.

Contraindications: None.

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.