Version May 2024
Hemophilia B: Note: Prior to etranacogene dezaparvovec administration, perform factor IX inhibitor titer testing. If positive for factor IX inhibitors, retest within ~2 weeks. If both the initial and repeat tests are positive, do not administer etranacogene dezaparvovec. Assess ALT, AST, alkaline phosphatase, and total bilirubin, as well as hepatic ultrasound and elastography. If radiological liver abnormalities and/or sustained liver enzyme elevations are present, consider consultation with a hepatologist to assess eligibility for etranacogene dezaparvovec therapy. Monitor factor IX activity regularly; benefit from etranacogene dezaparvovec administration may not be apparent for several weeks, and exogenous human factor IX may be necessary during the first weeks following infusion.
IV: 2 × 1013 genome copies/kg (which is 2 mL/kg) as a single one-time dose (Ref); refer to the manufacturer’s labeling for further information.
CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling; limited clinical data suggest that no dosage adjustment may be necessary in patients with mild or moderate kidney impairment. In clinical studies, no dosage adjustment was made in patients with mild or moderate kidney impairment.
CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
End-stage kidney disease: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
Hepatic impairment prior to treatment initiation:
There are no dosage adjustments provided in the manufacturer’s labeling. In clinical studies, no dosage adjustment was made in patients with hepatic pathologies. The safety and efficacy of etranacogene dezaparvovec in advanced hepatic impairment, including cirrhosis, advanced liver fibrosis, or uncontrolled hepatitis B and C, have not been studied. If radiological liver abnormalities and/or sustained liver enzyme elevations are present, consider consultation with a hepatologist to assess eligibility for etranacogene dezaparvovec therapy.
Hepatotoxicity following treatment:
If ALT > ULN or double baseline levels in the first 3 months post dose: Consider administration of a course of corticosteroids, followed by a taper when ALT has normalized. In clinical studies, the corticosteroid dosing was as follows:
|
Timeline |
Prednisolone Oral Dose |
|---|---|
|
a Corticosteroids equivalent to prednisolone may also be used. A combined immunosuppressant regimen or other medications can be considered in the event of prednisolone treatment failure or contraindication. | |
|
b In clinical studies, the mean duration of corticosteroid therapy was ~81 days (range: 51 to 130 days). | |
|
Week 1 |
60 mg/day |
|
Week 2 |
40 mg/day |
|
Week 3 |
30 mg/day |
|
Week 4 |
30 mg/day |
|
Maintenance dose until ALT returns to baseline level |
20 mg/day |
|
Taper dose after ALT baseline level achieved |
Reduce daily prednisolone dose by 5 mg/week |
Infusion reactions: May slow or stop the infusion. If the infusion is stopped, restart at a slower rate when the infusion reaction has resolved. Consider corticosteroid or antihistamine administration for infusion reaction management.
Refer to adult dosing.
Increased serum alanine aminotransferase and increased serum aspartate aminotransferase have been reported with etranacogene dezapravovec. In clinical trials, most elevations were asymptomatic and mild, although elevations >3 to 5 times ULN have been reported.
Mechanism: Possibly due to immune-mediated injury of transduced hepatocytes (especially when observed within the first 3 months of therapy).
Onset: Varied; in clinical trials, most elevations occurred within the first 3 to 4 months of therapy, although onset up to 24 months post-infusion has been reported.
Risk factors:
• Preexisting risk factors for elevated transaminases (eg, hepatitis C, HIV)
Infusion-related reactions and hypersensitivity reactions have been reported with etranacogene dezaparvovec. Symptoms may consist of abdominal pain, chest tightness, flu-like symptoms, flushing, headache, hypertension, lightheadedness, shivering, and skin rash.
Onset: Rapid; in clinical trials, reactions occurred during or within minutes after initiation of the infusion.
Risk factors:
• Rapid infusion (>500 mL/hour)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adult males.
>10%:
Cardiovascular: Increased serum creatine kinase
Hepatic: Increased serum alanine aminotransferase, increased serum aspartate aminotransferase
Hypersensitivity: Infusion-related reaction
Immunologic: Antibody development
Nervous system: Fatigue, headache, malaise
Respiratory: Flu-like symptoms
1% to 10%:
Gastrointestinal: Nausea
Hypersensitivity: Hypersensitivity reaction
There are no contraindications listed in the manufacturer's labeling.
Concerns related to adverse effects:
• Hepatocellular carcinogenicity: Liver-targeting adeno-associated (AAV) vector DNA integration into the genome may be associated with the theoretical risk of development of hepatocellular carcinoma. No etranacogene dezaparvovec–associated clonal expansion or carcinogenicity was observed in clinical studies. Risk factors for hepatocellular carcinoma include cirrhosis, advanced hepatic fibrosis, hepatitis B or C, metabolic dysfunction associated steatohepatitis, and advanced age.
Other warnings/precautions:
• Immunogenicity: In AAV vector-based gene therapies, preexisting neutralizing anti-AAV antibodies may inhibit transgene expression at intended therapeutic levels. In studies, subjects with detectable preexisting neutralizing anti-AAV5 antibodies (detected using an unvalidated clinical trial assay) demonstrated mean factor IX activity that was numerically lower compared to subjects without detectable preexisting neutralizing anti-AAV5 antibodies. Subjects demonstrated hemostatic protection, regardless of the presence of neutralizing anti-AAV5 antibodies. One patient with a high preexisting neutralizing anti-AAV5 antibody titer (1:3,212) did not demonstrate human factor IX expression; re-initiation of exogenous factor IX prophylaxis was required for bleeding events.
• Vector distribution/shedding: Vector distribution in blood, and vector shedding in semen and other excreta and secreta may occur following etranacogene dezaparvovec administration. Advise patients to not donate blood, organs, tissues, or cells for transplantation.
Hemgenix is available in customizable kits containing 10 to 48 single-use vials; each vial contains an extractable volume of not less than 10 mL. Each kit constitutes a dosage unit based on the patient’s body weight.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Suspension, Intravenous:
Hemgenix: 1 x 1013 gc/mL (10 mL)
IV: Administer as an IV infusion through a peripheral venous catheter (do not use a central line or port) with an in-line 0.2-micron polyether sulfone (PES) filter; do not administer as an IV push or bolus. Connect the prefilled IV infusion line/drip chamber to the main IV line (which has been primed with NS prior to use). Infuse etranacogene dezaparvovec at a constant infusion rate of 500 mL/hour (or 8 mL/minute). Do not infuse etranacogene dezaparvovec in the same IV line with any other medications. After completion of the etranacogene dezaparvovec infusion, flush the line with NS at 500 mL/hour to ensure all etranacogene dezaparvovec is delivered.
If an infusion reaction occurs during etranacogene dezaparvovec administration, may reduce the rate or stop the infusion; if the infusion is stopped, resume at a slower rate when the infusion reaction has resolved. If infusion rate is reduced or infusion is stopped, complete balance of infusion within 24 hours after the dose is prepared.
Use biosafety precautions for disposal of unused product and/or supplies which came in contact with etranacogene dezaparvovec. If a spill occurs, treat with a virucidal agent with proven activity against nonenveloped viruses.
Hemophilia B: Treatment of hemophilia B (congenital factor IX deficiency) in adults who currently use factor IX prophylaxis therapy, or have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes.
Etranacogene dezaparvovec may be confused with onasemnogene abeparvovec, voretigene neparvovec.
None known.
There are no known significant interactions.
Etranacogene dezaparvovec is not intended for use in patients who could become pregnant.
Etranacogene dezaparvovec is not intended for use in lactating patients.
Factor IX inhibitor titer testing prior to therapy; if positive, retest within ~2 weeks; if both the initial and repeat tests are positive, do not administer etranacogene dezaparvovec. Perform inhibitor titer testing post infusion if bleeding is not controlled, or plasma factor IX activity levels decrease. Post infusion, monitor factor IX activity regularly (eg, weekly for 3 months) and as clinically necessary, particularly when exogenous factor IX is administered (if feasible, use the same assay and reagents over time for monitoring each patient). Assess ALT, AST, alkaline phosphatase, and total bilirubin, as well as hepatic ultrasound and elastography prior to treatment. Monitor ALT and AST weekly for 3 months following etranacogene dezaparvovec administration; continue to monitor transaminases in all patients who develop liver enzyme elevations until return to baseline. Regularly assess alpha-fetoprotein levels and abdominal ultrasound (eg, annually) for 5 years post infusion in patients with preexisting risk factors for hepatocellular carcinoma (eg, cirrhosis, advanced hepatic fibrosis, hepatitis B or C, metabolic dysfunction associated steatotic liver disease, chronic alcohol consumption, metabolic dysfunction associated steatohepatitis, and advanced age). Monitor for signs/symptoms of infusion reactions during infusion and for at least 3 hours following administration.
Etranacogene dezaparvovec is an adeno-associated virus serotype 5 (AAV5) vector-based gene therapy. It is a nonreplicating recombinant AAV5 containing a codon-optimized DNA sequence of the gain-of-function Padua variant of human factor IX (variant R338L), under control of a liver-specific promotor 1 (LP1). Etranacogene dezaparvovec administration results in cell transduction and increases circulating factor IX activity in patients with hemophilia B.
Onset: The mean uncontaminated (eg, excluding measurements within 5 half-lives of factor IX replacement therapy) factor IX activity levels of 39%, 41.5%, 36.9%, and 36.7% of normal, respectively, were achieved at 6, 12, 18, and 24 months. The time to onset of factor IX protein expression post etranacogene dezaparvovec dose was detectable (by first uncontaminated measurement) at week 3 in the clinical study.
Excretion: In a clinical study, 74% of subjects achieved absence of vector DNA from blood and 87% from semen by month 24 post etranacogene dezaparvovec administration.
Altered kidney function: In a clinical study, subjects with CrCl 60 to 89 mL/minute had ~37% higher factor IX activity relative to those with CrCl ≥90 mL/minute following etranacogene dezaparvovec administration.
Hepatic function impairment: A clinical study that included subjects with hepatic steatosis (scored with the Controlled Attenuation Parameter [CAP]) showed the mean uncontaminated factor IX activity for subjects with a CAP score <S2 versus ≥S2 at months 6, 12, 18, and 24 post etranacogene dezaparvovec dose were 40.8 versus 34.5, 46.4 versus 32.6, 41.6 versus 29.2, and 40.2 versus 28.4, respectively.
Older adults: Factor IX activity levels were up to ~2-fold higher in subjects 60 to 75 years of age compared to subjects 18 to <40 years of age (based on limited data).
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