etranacogene dezaparvovec (Rx)

>10%

ALT increased (42%)

AST increased (42%)

Blood creatine kinase increased (42%)

Infusion-related reactions (33%)

Headache (18%)

Flu-like symptoms (14%)

Fatigue (12%)

Malaise (12%)

1-10%

Nausea (7%)

Hypersensitivity (4%)

Contraindications

None

Cautions

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 for signs or symptoms throughout infusion period and for at least 3 hr after end of infusion
• Do not exceed infusion rate of 500 mL/hr
• If infusion reaction occurs, slow rate, or stop and restart at slower rate once reaction resolves
• Consider treatment with a corticosteroid or antihistamine for management of an infusion reaction

Hepatotoxicity

• IV administration of a liver-directed adeno-associated virus (AAV) vector may lead to liver transaminase elevations (transaminitis)
• Transaminitis, particularly in the first 3 months after administration, is presumed to occur due to immune-mediated injury of transduced hepatocytes and may reduce therapeutic efficacy of the gene therapy
• Closely monitor transaminase levels weekly for 3 months after administration to mitigate risk of hepatotoxicity
• Continue to monitor transaminases in all patients who developed liver enzyme elevations until enzymes return to baseline
• In case of increased ALT levels >ULN or double baseline levels, consider implementing a course of corticosteroid, along with human Factor IX activity monitoring

Immune-mediated neutralization of the AAV5 vector capsid

• In AAV-vector based gene therapies, preexisting neutralizing antiAAV antibodies may impede transgene expression at desired therapeutic levels
• Following treatment, all subjects developed neutralizing antiAAV antibodies
• Currently, there is no validated neutralizing antiAAV5 antibody assay

• Anti-AAV5 antibody study

  • Encourage patients who intend to receive treatment to enroll in a study to measure preexisting antiAAV5 neutralizing antibodies by calling CSL Behring at 1-800-504-5434
  • Study evaluates effect of pre-existing antiAAV5 neutralizing antibodies on bleeding risk

Hepatocellular carcinogenicity

• Integration of liver-targeting AAV vector DNA into the genome may carry theoretical risk of hepatocellular carcinoma development
• Etranacogene dezaparvovec composed of non-replicating AAV5 vector whose DNA persists largely in episomal form
• Random integration of the 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 treatment based on vector integration site analyses and whole genome sequencing
• Perform abdominal ultrasound screenings in patients with preexisting risk factors for hepatocellular carcinoma (eg, patients with cirrhosis, advanced hepatic fibrosis, Hepatitis C or B, nonalcoholic fatty liver disease [NAFLD], chronic alcohol consumption, nonalcoholic steatohepatitis [NASH], advanced age)
• Monitor regularly (eg, annually) for alpha-fetoprotein (AFP) elevations for 5 yr after administration

Monitoring laboratory tests

• After administration, regularly monitor FIX activity levels (eg, weekly x 3 months)
• When using an in vitro activated partial thromboplastin time (aPTT)-based one-stage clotting assay (OSA) for determining FIX activity, plasma FIX 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 laboratory and/or reagents used in the assay
• Therefore, the same assay and reagents are recommended to be used to monitor FIX activity over time
• Results of FIX activity tests are lower if measured with chromogenic substrate assay (CSA) compared with OSA
• In the clinical efficacy study, post-dose Factor IX activity measured with CSA returned lower values, with the mean CSA-to-OSA FIX activity ratio ranging from 0.41-0.55
• Monitor through appropriate clinical observations and laboratory tests for development of inhibitors to FIX after administration
• Perform an assay that detects Factor IX inhibitors if bleeding is not controlled, or plasma FIX activity levels decrease

Pregnancy

Not intended for administration in females

Factor IX deficiency is an X-linked inherited bleeding disorder, usually manifested in males and transmitted by females who carry the causative mutation on the X chromosome

Animal studies

• No adverse effects on mating rate and fertility indices or fetal weights observed in healthy naïve female mice mated with healthy male mice that were intravenously administered a predecessor of etranacogene dezaparvovec product 6 days before mating
• Vector DNA was not detected in uterus, placenta, or fetus

Lactation

Not intended for administration in females

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Adeno-associated virus-5 (AAV5)-based gene therapy designed to deliver a copy of a gene encoding the Padua variant of human coagulation Factor IX (hFIX598 Padua)

Single IV infusion results in cell transduction and increase in circulating Factor IX activity in patients with Hemophilia B

Elimination

Clearance

• Confirmed by 3 subsequent measurements below limit of detection (LOD), was achieved in all subjects at both dose levels from all the matrices except for semen, where clearance was achieved in 9/10 subjects

Maximum time to clearance of vector DNA

• Urine: 22 weeks
• Saliva and nasal secretions: 26 weeks
• Feces: 40 weeks
• Semen: 52 weeks
• Blood: 159 weeks

IV Incompatibilities

DO NOT infuse in same IV line with any other products

IV Compatibilities

0.9% NaCL

IV Preparation

Follow institutional policies, and use proper aseptic technique and engineering controls (eg, biological safety cabinet or isolator) to prepare drug

DO NOT expose to light from any UV radiation disinfection lamp

Before preparing

• Confirm patient’s identity matches with patient-specific identifier number on outer carton
• Verify required dose based on patient’s body weight (BW)
• Confirm carton contains enough vials to prepare patient-specific infusion bag

Preparing 0.9% NaCl infusion bags

• Before diluting, spike 0.9% NaCl infusion bag(s) with applicable connector
• Connect a luer-lock syringe at mixing adapter site of applicable connector
• Withdraw volume equal to calculated drug volume (in mL) from 500-mL 0.9% NaCl infusion bag(s)

• Amount of 0.9% NaCl withdrawn is dependent on patient’s BW

  • <120 kg BW: Requires 1 bag of 500-mL 0.9% NaCl; withdraw an equal volume of 0.9% NaCl solution to the total drug volume (in mL ) from 1 bag
  • ≥120 kg BW: Requires 2 bags of 500-mL 0.9% NaCl; withdraw an equal volume of 0.9% NaCl solution to the total drug volume (in mL), and remove half of that volume from each of the 2 bags

Dilution

• Dilute with 0.9% NaCl only before administering
• Before diluting, inspect each vial; discard if particulates, cloudiness, or discoloration is visible
• Gently swirl vials 3 times (about 10 seconds) to homogenize suspension
• To avoid foaming, DO NOT shake vial(s)
• Remove cap from vials, and disinfect rubber stopper with sterilizing agent
• Withdraw from each vial using a 20 G needle/vial adapter and syringe
• Use recommended 20-mL luer-lock or larger syringe that is suitable for volume measuring and a needle; DO NOT use filter needles during preparation
• Use new needle/vial adapter and syringe for each vial; discard needles and syringes in an appropriate container
• Slowly add required dose from syringe(s) directly to prepared 0.9% NaCl infusion bag(s) to bring total volume in each infusion bag back to 500 mL
• DO NOT add drug into airspace of bag to avoid foaming during preparation
• Repeat previous steps with additional needles/vial adaptors and syringes to inject total calculated volume to infusion bag(s) required for dose
• Gently invert infusion bag(s) at least 3 times (about 10 seconds) to mix solution and ensure even distribution of diluted product
• To avoid foaming, DO NOT shake the diluted prepared infusion bag(s)
• Label infusion bag(s)
• Connect infusion bag(s) to an infusion tube prefilled with sterile 0.9% NaCl solution to reduce the risk of spillage and/or aerosol formation
• Transport diluted infusion bag(s) in the transport container/bag protected from light to administration site, avoiding any shaking or excessive agitation

IV Administration

Infuse IV through a peripheral venous catheter; DO NOT administer IV push or bolus

Visually inspect diluted infusion before administering; diluted solution should be clear and colorless; discard if particulates, cloudiness, or discoloration are visible

Use an integrated (in-line) 0.2-mcm filter made from PES

Prime IV line and drip chamber with sterile 0.9% NaCl before administering

Connect prefilled IV infusion line/drip chamber to main IV line

Infuse at a constant infusion rate of 500 mL/hr (8 mL/min)

DO NOT infuse in same IV line with any other products

DO NOT use a central line or port

If infusion reaction occurs during administration, may reduce infusion rate or stop infusion and manage reaction

If infusion is stopped, restart at a slower rate once reaction is resolved

If infusion rate needs to be reduced, or stopped and restarted, infuse drug within 24 hr after dose preparation

Once infusion is completed, flush IV infusion line/drip chamber at the same infusion rate with 0.9% NaCl solution to ensure all drug is delivered

Treat drug spills with a virucidal agent with proven activity against nonenveloped viruses; discard unused product and disposable materials that may have come in contact with etranacogene dezaparvovec in accordance with local biosafety guidelines applicable for handling and disposal of the pharmaceutical waste

Monitoring

Post-administration

• Monitor ALT/AST levels weekly for 3 months following administration
• If patient develops elevated liver enzymes, continue to monitor AST/ALT until returned to baseline
• In the event of ALT increase to above normal limits or to twice the patient’s baseline in first 3 months post-dose, consider a course of corticosteroids
• For patients with clinically relevant ALT increases who need corticosteroid treatment, start prednisolone or prednisone at 60 mg/day PO, with a subsequent taper in response to normalizing ALT levels

• Prednisolone treatment applied in clinical studies

  • Medications equivalent to prednisolone may also be used
  • Consider combined immunosuppressant regimen or use of other products in case of prednisolone treatment failure or contraindication
  • Week 1: 60 mg/day
  • Week 2: 40 mg/day
  • Week 3: 30 mg/day
  • Week 4: 30 mg/day
  • Maintenance dose until ALT level returns to baseline level: 20 mg/day
  • Taper dose after ALT reaches baseline: Reduce daily dose by 5 mg/week

Monitor Factor IX activity

• Usually weekly for 3 months
• Monitor regularly for their Factor IX (FIX) activity, especially when exogenous FIX is administered
• May take several weeks before improved hemostatic control becomes apparent; therefore, continued hemostatic support with exogenous human FIX may be needed during first weeks after infusion
• Use the same assay and reagents to monitor patients; using different assays may impact test results
• Use of exogenous Factor IX concentrates before and after administration may impede assessment of endogenous, drug-derived FIX activity
• Perform regular alpha-fetoprotein (AFP) level testing and abdominal ultrasound (eg, annually) in patients with preexisting risk factors for hepatocellular carcinoma (eg, in patients with cirrhosis, advanced hepatic fibrosis, Hepatitis B or C, NAFLD, chronic alcohol consumption, NASH, advanced age)
• Monitor for human FIX inhibitors
• Perform post-dose inhibitor testing if bleeding is not controlled, or plasma Factor IX activity levels decrease

Storage

Shipping

• Shipped at 2-8ºC (36-46ºF)

Unopened vials

• Upon receipt, refrigerate at 2-8ºC (36-46ºF)
• Store in original carton until use
• Protect from light until time of dilution and administration
• DO NOT freeze

Diluted solution

• Once diluted, store in infusion bag at 15-25ºC (59-77ºF)
• Protect from light
• Use within 24 hr after preparing