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Hemophilia B Information	Plasma Academy	Gene Therapy Information in Hemophilia B	Educational Materials	Key Publications

Gene Therapy Information in Hemophilia B

Factor Replacement Therapy

what is gene therapy

Gene therapy is a transformative treatment that addresses underlying genetic mutations to treat a disease, with several agents already approved for use1,2

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 Vectors Are Derived From Wild-type AAV

AAV Vectors

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

Many people have pre-existing antibodies against AAV capsid proteins. These antibodies can be binding antibodies, or neutralizing antibodies.
Neutralizing antibodies will usually inhibit the ability of the AAV vector to deliver the therapeutic gene to its target cell (hepatocyte)
- Making gene therapy ineffective or inefficient
Many people (30-80%) have neutralizing antibodies to AAV

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

Safety Considerations

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

Key Similarities and Differences of Hemophilia A and Hemophilia B

CLINICAL SYMPTOMS AND SEVERITY

Clinical symptoms are similar in PWHA and PWHB (bleeding into joints, muscle and soft tissue)
Studies have shown differences in disease severity, with PWHB displaying a milder phenotype than PWHA

MOLECULAR BASIS OF DISEASE

Hemophilia A is mostly caused by intron 22 inversions, while hemophilia B is mostly caused by missense mutations
FVIII is much larger and more structurally complex than FIX
FVIII cDNA is much larger than FIX cDNA and candidate therapies have been truncated for use with gene therapy vectors
FVIII protein is much larger than FIX and is not native to the hepatocytes

GENE THERAPY VECTOR DESIGN

Vector designs are similar in hemophilia A and B - both use AAV-based vectors with codon-optimization and a liver-specific promoter
A B-domain-deleted FVIII is used in gene therapy to allow for insertion into critical applicable vectors; full-length FIX gene can be used

AAV=adeno-associated virus; cDNA=complementary DNA; FI= factor IX; FVIII=factor VIII; PWHA=people with hemophilia A; PWHB=people with hemophilia B.

1. Castaman G, Matino D.Haematologica 2019; 104:1702–1709 2. Batty P, Lillicrap D.HemaSphere 2021; 5:3(e540)

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.