Introduction

Etranacogene dezaparvovec-drlb is a recombinant adeno-associated virus serotype 5 (AAV5) vector-based gene therapy containing a codon-optimized DNA sequence of the gain-of-function Padua variant of human coagulation Factor IX.

Uses for Etranacogene Dezaparvovec

Etranacogene dezaparvovec-drlb has the following uses:

Etranacogene dezaparvovec-drlb is 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. Designated an orphan drug by FDA for this use.

Efficacy of etranacogene dezaparvovec-drlb was evaluated in an open-label, single-dose, single-arm, multinational study in 54 adult male subjects 19–75 years of age with severe or moderately severe hemophilia B. Patients completed a lead-in period of at least 6 months during which they received an individualized prophylactic factor IX regimen, and then were treated with a single IV dose of etranacogene dezaparvovec-drlb 2 × 10¹³ genome copies/kg body weight. The estimated mean annualized bleeding rate (ABR) during months 7 to 18 after treatment was 1.9 bleeds/year compared with an estimated mean ABR of 4.1 during the lead-in period. Further study is needed to evaluate long-term safety.

The National Hemophilia Society's Medical and Scientific Advisory Council (MASAC) has published guidance for hemophilia treatment centers on delivering gene therapy for hemophilia. For additional information, consult the guidelines at https://www.hemophilia.org/healthcare-professionals/guidelines-on-care/masac-documents/masac-document-277-masac-recommendations-on-hemophilia-treatment-center-preparedness-for-delivering-gene-therapy-for-hemophilia.

Etranacogene Dezaparvovec Dosage and Administration

General

Etranacogene dezaparvovec-drlb is available in the following dosage form(s) and strength(s):

Etranacogene dezaparvovec-drlb is a suspension for IV infusion.

Etranacogene dezaparvovec-drlb is provided in kits containing 10 to 48 single-use vials, each kit constituting a dosage unit based on the patient's body weight.

Etranacogene dezaparvovec-drlb has a nominal concentration of 1 × 10¹³ genome copies/mL, and each vial contains an extractable volume of not less than 10 mL.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

For single-use IV infusion only. Administer as an IV infusion through a peripheral venous catheter; do not administer as an IV push or bolus.

• Perform baseline testing to select patients, including testing for Factor IX inhibitor presence and liver health tests.

• The recommended dose of etranacogene dezaparvovec-drlb is 2 × 10¹³ genome copies (gc) per kg of body weight (or 2 mL/kg body weight). See Full Prescribing Information for instructions on calculating dose and number of vials required.

• Administer etranacogene dezaparvovec-drlb as an IV infusion after dilution with 0.9% sodium chloride (normal saline) at a constant infusion rate of 500 mL/hour (8 mL/minute).

• If an infusion-related reaction occurs during administration, decrease the infusion rate or stop the infusion. Administer treatment as needed to manage infusion reaction. If the infusion is stopped, restart the infusion at a slower rate when the infusion reaction is resolved. If the infusion rate needs to be reduced, or stopped and restarted, etranacogene dezaparvovec-drlb should be infused within 24 hours after the dose is prepared.

• See Full Prescribing Information for additional instructions on preparation and administration of etranacogene dezaparvovec-drlb, and for monitoring recommendations.

Contraindications

• None.

Warnings/Precautions

Infusion Reactions

Infusion reactions, including hypersensitivity reactions and anaphylaxis, may occur. Symptoms may include chest tightness, headaches, abdominal pain, lightheadedness, flu-like symptoms, shivering, flushing, rash, and hypertension. Closely monitor patients for signs or symptoms of an infusion reaction throughout the infusion period and for at least 3 hours after end of infusion. Do not infuse the product faster than 500 mL/hour.

In the event of an infusion reaction during administration, the infusion may be slowed or stopped. If the infusion is stopped, restart at a slower rate when the infusion reaction has resolved. Consider treatment with a corticosteroid or antihistamine for management of an infusion reaction.

Hepatotoxicity

IV administration of a liver-directed AAV vector could potentially lead to liver transaminase elevations (transaminitis). Transaminitis, particularly when observed in the first 3 months after etranacogene dezaparvovec administration, is presumed to occur due to immune-mediated injury of transduced hepatocytes and may reduce the therapeutic efficacy of the AAV-vector based gene therapy.

In clinical studies with etranacogene dezaparvovec-drlb, most subjects had asymptomatic, and predominantly mild elevations in transaminases. Elevated ALT levels occurred most often in the first 4 months after etranacogene dezaparvovec-drlb administration. There were some subjects who had a late onset of elevated ALT levels between months 6–24 (range = 42 IU/L-193 IU/L); however, all of these ALT values were <2× ULN with the exception of one subject. Three additional subjects had AST elevations with onset and resolution between months 6 and 12 (range = 41 IU/L – 96 IU/L).

In one subject, an ALT elevation >5× ULN occurred 24 days after etranacogene dezaparvovec-drlb administration and resolved by 51 days post-administration. There was one subject who had an AST elevation > 5× ULN that occurred 11 months post-etranacogene dezaparvovec-drlb administration and resolved to <2× ULN 8 days later.

The majority of the elevated ALT values returned to baseline, however in 9 subjects, ALT values never resolved to normal (range at 2-year follow up = 48 IU/L – 193 IU/L).

Closely monitor transaminase levels once per week for 3 months after etranacogene dezaparvovec administration to mitigate the risk of potential hepatotoxicity. Continue to monitor transaminases in all patients who developed liver enzyme elevations until liver enzymes return to baseline.

In case of increased ALT levels above the upper limit of normal or double baseline levels, consider implementing a course of corticosteroid, along with human Factor IX activity monitoring.

Immune-mediated Neutralization of the AA5 Vector Capsid

In AAV-vector based gene therapies, preexisting neutralizing anti-AAV antibodies may impede transgene expression at desired therapeutic levels. Following treatment with etranacogene dezaparvovec-drlb, all subjects developed neutralizing anti-AAV antibodies. Currently, there is no validated neutralizing anti-AAV5 antibody assay.

In the clinical studies with etranacogene dezaparvovec-drlb, an unvalidated clinical trial assay was utilized to assess preexisting neutralizing anti-AAV5 antibodies. The subject sub-group with detectable preexisting neutralizing anti-AAV5 antibodies up to titers of 1:678 showed mean Factor IX activity that was numerically lower compared to that subject sub-group without detectable preexisting neutralizing anti-AAV5 antibodies. Subjects, with and without preexisting neutralizing anti-AAV5 antibodies, demonstrated hemostatic protection. In one subject with a preexisting neutralizing anti-AAV5 antibody titer of 1:3212, no human Factor IX expression was observed, and restart of the exogenous Factor IX prophylaxis was needed for bleeding events.

Patients who intend to receive treatment with etranacogene dezaparvovec-drlb are encouraged to enroll in a study to measure pre-existing anti-AAV5 neutralizing antibodies by calling CSL Behring at 1-800-504-5434. The study evaluates the effect of pre-existing anti-AAV5 neutralizing antibodies on the risk of bleeding.

Hepatocellular Carcinogenicity

The integration of liver-targeting AAV vector DNA into the genome may carry the theoretical risk of hepatocellular carcinoma development.

Etranacogene dezaparvovec-drlb is composed of a non-replicating AAV5 vector whose DNA persists largely in episomal form. Random integration of etranacogene dezaparvovec vector DNA to the human DNA at low frequency is possible. No etranacogene dezaparvovec-associated clonal expansion or carcinogenicity was observed in clinical studies. One subject with preexisting risk factors for developing hepatic cancer developed a hepatocellular carcinoma, which was assessed as not likely related to etranacogene dezaparvovec treatment based on vector integration site analyses and whole genome sequencing.

Patients with preexisting risk factors for hepatocellular carcinoma (e.g., patients with cirrhosis, advanced hepatic fibrosis, hepatitis C or B, non-alcoholic fatty liver disease, chronic alcohol consumption, non-alcoholic steatohepatitis, advanced age) should receive abdominal ultrasound screenings and be monitored regularly (e.g., annually) for alpha-fetoprotein (AFP) elevations in the 5 years following administration.

Monitoring Laboratory Tests

After etranacogene dezaparvovec administration, regularly monitor patient's Factor IX activity levels.

When using an in vitro activated partial thromboplastin time (aPTT)-based one-stage clotting assay (OSA) for determining Factor IX activity, plasma Factor IX activity results can be affected by both the type of aPTT reagent and the reference standard used in the assay. This is important to consider particularly when changing the laboratory and/or reagents used in the assay. Therefore, the same assay and reagents are recommended to be used to monitor Factor IX activity over time.

The results of Factor IX activity tests are lower if measured with chromogenic substrate assay (CSA) compared to OSA.

In the clinical efficacy study with etranacogene dezaparvovec-drlb, the post-dose Factor IX activity measured with CSA returned lower values with the mean CSA to OSA Factor IX activity ratio ranging from 0.41 to 0.55.

Monitor patients through appropriate clinical observations and laboratory tests for the development of inhibitors to Factor IX after etranacogene dezaparvovec administration. Perform an assay that detects Factor IX inhibitors if bleeding is not controlled, or plasma Factor IX activity levels decrease.

Specific Populations

Pregnancy

Etranacogene dezaparvovec is not intended for administration in women. No adverse effects on mating rate and fertility indices or fetal weights were observed in healthy naïve female mice mated with healthy male mice that were IV administered a predecessor of etranacogene dezaparvovec-drlb product 6 days prior to mating. Vector DNA was not detected in the uterus, placenta, or fetus.

In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Lactation

Etranacogene dezaparvovec-drlb is not intended for administration in women.

Females and Males of Reproductive Potential

No clinical studies have been performed to evaluate the effects of etranacogene dezaparvovec-drlb on fertility in humans. Twenty days after IV administration of a predecessor of etranacogene dezaparvovec-drlb product in healthy male mice, vector DNA was detected in all reproductive tissues examined (epididymis, seminal vesicles, testes, and sperm). However, no differences were observed in mating rates and fertility indices in healthy naïve female mice following mating with the dosed males.

Pediatric Use

The safety and efficacy of etranacogene dezaparvovec-drlb in pediatric patients have not been established.

Geriatric Use

The clinical studies included a total of 6 geriatric subjects 68 to 75 years of age with hemophilia B at the time of enrollment. No meaningful differences in the safety and efficacy profile were observed in these subjects compared to subjects 18 to 65 years of age, and no dose adjustment was made.

Hepatic Impairment

Limited clinical data in subjects with liver impairment indicate numerically lower FIX activity as compared to subjects without hepatic impairment. In the clinical studies, no dose adjustment was made in subjects with hepatic pathologies. The safety and efficacy in subjects with advanced hepatic impairment, including cirrhosis, advanced liver fibrosis, or uncontrolled hepatitis B and C, have not been studied.

Renal Impairment

Limited clinical data are available in subjects with mild and moderate renal impairment. In the clinical studies, no dose adjustment was made in these subjects. The safety and efficacy in subjects with severe renal impairment and end-stage renal disease have not been studied.

Common Adverse Effects

The most common adverse reactions (incidence ≥5%) were elevated ALT, headache, blood creatine kinase elevations, flu-like symptoms, infusion-related reactions, fatigue, malaise, and elevated AST.

General

Etranacogene dezaparvovec-drlb is available in the following dosage form(s) and strength(s):

Etranacogene dezaparvovec-drlb is a suspension for IV infusion.

Etranacogene dezaparvovec-drlb is provided in kits containing 10 to 48 single-use vials, each kit constituting a dosage unit based on the patient's body weight.

Etranacogene dezaparvovec-drlb has a nominal concentration of 1 × 10¹³ genome copies/mL, and each vial contains an extractable volume of not less than 10 mL.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

For single-use IV infusion only. Administer as an IV infusion through a peripheral venous catheter; do not administer as an IV push or bolus.

• Perform baseline testing to select patients, including testing for Factor IX inhibitor presence and liver health tests.

• The recommended dose of etranacogene dezaparvovec-drlb is 2 × 10¹³ genome copies (gc) per kg of body weight (or 2 mL/kg body weight). See Full Prescribing Information for instructions on calculating dose and number of vials required.

• Administer etranacogene dezaparvovec-drlb as an IV infusion after dilution with 0.9% sodium chloride (normal saline) at a constant infusion rate of 500 mL/hour (8 mL/minute).

• If an infusion-related reaction occurs during administration, decrease the infusion rate or stop the infusion. Administer treatment as needed to manage infusion reaction. If the infusion is stopped, restart the infusion at a slower rate when the infusion reaction is resolved. If the infusion rate needs to be reduced, or stopped and restarted, etranacogene dezaparvovec-drlb should be infused within 24 hours after the dose is prepared.

• See Full Prescribing Information for additional instructions on preparation and administration of etranacogene dezaparvovec-drlb, and for monitoring recommendations.

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.