Brand name: Beqvez
Drug class: Gene Therapy

Introduction

Fidanacogene elaparvovec-dzkt is a recombinant adeno-associated virus (AAV) vector-based gene therapy.

Uses for Fidanacogene Elaparvovec-dzkt

Fidanacogene elaparvovec-dzkt has the following uses:

Fidanacogene elaparvovec-dzkt is indicated for the treatment of adults with moderate to severe hemophilia B (congenital factor IX deficiency) who currently use factor IX prophylaxis therapy, or have current or historical life-threatening hemorrhage, or repeated, serious spontaneous bleeding episodes. Fidanacogene elaparvovec-dzkt is only indicated in such patients who do not have neutralizing antibodies to adeno-associated virus serotype Rh74var (AAVRh74var) capsid as detected by an FDA-approved test. Fidanacogene elaparvovec-dzkt has been designated an orphan drug by the FDA for the treatment of hemophilia B.

Efficacy of fidanacogene elaparvovec-dzkt was evaluated in a prospective, open-label, single-arm multinational study in 45 adult male patients with moderately severe to severe hemophilia B who were negative for pre-existing neutralizing antibodies to AAVRh74var capsid. Patients received a single IV infusion of fidanacogene elaparvovec-dzkt 5 x 10¹¹ vg/kg and entered a 6-year follow up period. The main efficacy outcome was a noninferiority test of annualized bleeding rate (ABR) during the efficacy evaluation period compared with the ABR during a baseline period. Mean ABR during the efficacy evaluation period (median follow-up of 2 years) was 2.5 bleeds/year compared to a mean baseline ABR of 4.5 bleeds/year, meeting the noninferiority criteria. Routine factor IX prophylaxis was resumed in 13% of patients; one patient required intermittent factor IX therapy and had a higher ABR post-treatment compared to baseline.

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.

Fidanacogene Elaparvovec-dzkt Dosage and Administration

General

Fidanacogene elaparvovec-dzkt is available in the following dosage form(s) and strength(s):

Fidanacogene elaparvovec-dzkt is a suspension for IV infusion after dilution.

Fidanacogene elaparvovec-dzkt has a nominal concentration of 1 × 10¹³ vg/mL, and each vial contains an extractable volume of 1 mL.

The total number of vials will be customized to meet dosing requirements for individual patients based on their weight.

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 one-time single-dose IV infusion only.

• Initiate and administer fidanacogene elaparvovec-dzk in hospitals and other clinical centers under the supervision of a physician experienced in the treatment of hemophilia.

• Administer fidanacogene elaparvovec-dzk in a setting where personnel and equipment are immediately available to treat infusion-related reactions.

• Perform baseline testing to select patients, including testing for pre-existing antibodies to AAVRh74var, factor IX inhibitor presence, and liver health tests. Information on FDA-approved tests for the detection of AAVRh74var pre-existing neutralizing antibodies is available at http://www.fda.gov/companiondiagnostics.

• The recommended dose of fidanacogene elaparvovec-dzkt is 5 × 10¹¹ vector genomes per kg (vg/kg) of body weight, administered as a single peripheral IV infusion over 60 minutes (approximately 3 mL/min). Dose based on adjusted body weight for those with a BMI >30 kg/m². See Full Prescribing Information for instructions on calculating patient's dose weight and dose volume required.

• Prior to infusion, dilute the appropriate volume of fidanacogene elaparvovec-dzkt suspension in 0.9% sodium chloride with 0.25% human serum albumin (HSA) for a total infusion volume of 200 mL.

• Fidanacogene elaparvovec-dzkt contains genetically modified vectors. Personal protective equipment (including gloves, safety goggles, laboratory coat and sleeves) should be worn while preparing or administering the treatment.

• If an infusion-related reaction occurs during administration, reduce the infusion rate or stop the infusion. Administer treatment as needed to manage infusion reaction. If the infusion is stopped, restart at a lower rate when the infusion reaction has resolved. If the infusion rate needs to be reduced, or stopped and restarted, fidanacogene elaparvovec-dzkt should be infused within 24 hours of dose preparation.

• See Full Prescribing Information for additional instructions on preparation and administration of fidanacogene elaparvovec-dzkt, and for monitoring recommendations.

Cautions for Fidanacogene Elaparvovec-dzkt

Contraindications

None.

Warnings/Precautions

Hepatotoxicity

Intravenous administration of a liver-directed AAV vector could potentially lead to liver transaminase elevations. Transaminase elevations, particularly when observed in the first 4 months after fidanacogene elaparvovec-dzkt 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 fidanacogene elaparvovec-dzkt, transaminase elevations (defined as ≥1.5 x baseline) occurred in 29 of 45 and 7 of 15 patients in study 1 and study 2 respectively. Twenty-eight (62%) patients in clinical study 1 received corticosteroids for transaminase elevation and/or decline in factor IX activity. The mean time to corticosteroid initiation was 45 days. The mean duration of corticosteroid treatment was 113 days (range: 41 to 276 days). Three (20%) patients in clinical study 2 received corticosteroids for transaminase elevation and/or decline in factor IX activity with time to initiation and duration of corticosteroid use within the range seen in clinical study 1.

Monitor ALT, AST, and factor IX activity levels once or twice weekly for at least 4 months and institute corticosteroid treatment in response to transaminase elevation and/or decrease in FIX activity, as required. Monitor for and manage adverse reactions secondary to corticosteroid therapy.

For the first year following administration of fidanacogene elaparvovec-dzkt, advise patients to limit alcohol consumption, as alcohol may impact liver enzyme elevation and potentially reduce factor IX activity over time.

Infusion Reactions

Infusion reactions, including hypersensitivity reactions and anaphylaxis, may occur. Symptoms of hypersensitivity may include but are not limited to hypotension, pyrexia, palpitation, nausea, vomiting, chills, or headache. Closely monitor patients for clinical signs and symptoms of infusion reactions throughout the infusion period and for at least 3 hours after end of infusion. 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 an antihistamine, corticosteroid or other measures for management of an infusion reaction.

Malignancy

The integration of liver-targeting AAV vector DNA into the genome may carry the theoretical risk of hepatocellular carcinoma development. Integration of AAV vector DNA into the host cell DNA in other tissues may also occur.

Monitor patients with risk factors for hepatocellular carcinoma (e.g., hepatitis B or C, non-alcoholic fatty liver disease, chronic alcohol consumption, non-alcoholic steatohepatitis, advanced age) with regular liver ultrasound (e.g., annually) and alpha-fetoprotein testing for 5 years following fidanacogene elaparvovec-dzkt.

In the event that a malignancy occurs, contact Pfizer Inc. at 1-800-438-1985 to obtain instructions on collecting patient samples for testing.

Monitoring Laboratory Tests

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. Higher inter-laboratory and inter-reagent variability in OSA results is observed at the lower factor IX activity levels (0.025 IU/mL). This is important to consider particularly when changing the laboratory and/or reagents used in the assay. It is recommended where possible to use the same laboratory (applicable to both, chromogenic or one-stage assays) for factor IX activity monitoring over time, particularly during the timeframe for corticosteroid treatment decision making, to minimize the impact of inter-laboratory variability.

In clinical study 1 with fidanacogene elaparvovec-dzkt, silica-based OSA returned consistently higher values of factor IX activity compared to ellagic acid-based OSA and chromogenic substrate assay (CSA). Generally, values of the ellagic acid-based OSA aligned with values of CSA.

Based on clinical trials (central laboratory), the approximate conversion factor between a silica-based OSA and ellagic acid-based OSA/CSA is 2. For example, a factor IX activity level of 10 IU/dL using CSA calculates approximately to a level of 20 IU/dL using silica-based OSA. At low factor IX activity levels (0.05 IU/mL), the conversion factor is approximately 2.5.

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

Specific Populations

Pregnancy

Fidanacogene elaparvovec-dzkt is not intended for administration in women. There are no data from the use of fidanacogene elaparvovec-dzkt in pregnant women. No animal reproductive studies have been conducted with fidanacogene elaparvovec-dzkt.

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

Lactation

There is no information regarding the presence of fidanacogene elaparvovec-dzkt in human milk, the effect on the breastfed infant, and the effects on milk production.

Fidanacogene elaparvovec-dzkt is not intended for administration in women.

Females and Males of Reproductive Potential

No studies in animals or clinical studies have been performed to evaluate the potential effects of fidanacogene elaparvovec-dzkt on fertility in humans.

Vector DNA was shed in semen but declined to undetectable levels in semen within a mean of 1 to 4 months after infusion. Male patients should refrain from donating sperm, be abstinent or use a male condom for up to 6 months after receiving fidanacogene elaparvovec-dzkt.

Pediatric Use

The safety and efficacy of fidanacogene elaparvovec-dzkt in pediatric patients have not been established.

Geriatric Use

The clinical study did not have any patient ≥65 years of age. The safety and efficacy of fidanacogene elaparvovec-dzkt have not been established in geriatric patients.

Hepatic Impairment

Fidanacogene elaparvovec-dzkt has not been studied in patients with hepatic impairment.

Renal Impairment

Fidanacogene elaparvovec-dzkt has not been studied in patients with renal impairment.

Human Immunodeficiency Virus (HIV) Positive Patients

Clinical studies of fidanacogene elaparvovec-dzkt included a limited number of HIV patients, which precludes a determination of whether the efficacy and safety data differ when compared to patients without HIV infection.

Factor IX Inhibitors

The safety and effectiveness of fidanacogene elaparvovec-dzkt in patients with prior or active factor IX inhibitors have not been established. Patients with history of or active factor IX inhibitors should not take fidanacogene elaparvovec-dzkt.

After administration of fidanacogene elaparvovec-dzkt, patients should be monitored for the development of factor IX inhibitors by appropriate clinical observations and laboratory tests.

Common Adverse Effects

The most common adverse reaction (incidence ≥5%) was an increase in transaminases.

Drug Interactions

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:

No interaction studies have been performed.

The use of fidanacogene elaparvovec-dzkt in patients receiving hepatotoxic medication or using hepatotoxic substances is limited. Use of hepatotoxic medications or substances may reduce the efficacy of fidanacogene elaparvovec-dzkt, and the risk of serious hepatic reactions may increase following administration.

Prior to fidanacogene elaparvovec-dzkt administration, review the patient’s existing medications to determine if they should be modified to prevent anticipated interactions described in this section.

Monitor concomitant medications after fidanacogene elaparvovec-dzkt administration and evaluate the need to change concomitant medications based on patient’s hepatic status and risk.

Prior to fidanacogene elaparvovec-dzkt infusion, ensure patients are up to date on their vaccinations. If concomitant corticosteroid administration is needed following fidanacogene elaparvovec-dzkt infusion, delay administration of live vaccines until the patient has been weaned off corticosteroids.

Actions

Mechanism of Action

Fidanacogene elaparvovec-dzkt (fidanacogene elaparvovec-dzkt) is a gene therapy designed to introduce in the transduced cells a functional copy of the factor IX gene encoding a high-activity FIX variant (FIX-R338L, hFIX Padua).

The AAVRh74var capsid is able to transduce hepatocytes, the natural site of factor IX synthesis. Single IV infusion of fidanacogene elaparvovec-dzkt results in cell transduction and increase in circulating factor IX activity in patients with hemophilia B.

Advice to Patients

• Inform patients that pre-infusion blood tests will be necessary to look for factor IX inhibitors and detect pre-existing antibodies to AAVRh74var. If these tests are positive, the patient will not be a candidate for fidanacogene elaparvovec-dzkt therapy.

• Inform patients that infusion reactions, including hypersensitivity reactions, may occur. Patients will be monitored during and for at least 3 hours after infusion.

• Educate patients on possible symptoms of infusion reactions during and after infusion and advise them to immediately inform medical staff if they experience such a reaction.

• Advise patients that fidanacogene elaparvovec-dzkt can elevate certain liver enzymes. Baseline and periodic blood tests will be required to assess liver health and bleeding risk. Corticosteroid treatment may be necessary if this occurs, and patients should be encouraged to complete the course as prescribed.

• Advise patients of the importance to maintain or improve hepatic health. Potential hepatotoxic medicinal substances, herbal supplements, and alcohol may reduce the efficacy of fidanacogene elaparvovec-dzkt, and the risk of serious hepatic reactions may increase following fidanacogene elaparvovec-dzkt administration.

• Advise patients that if bleeding occurs following administration of fidanacogene elaparvovec-dzkt, blood tests will be performed for factor IX activity and factor IX inhibitors.

• Advise patients that tapering factor IX concentrates/hemostatic agents may be necessary. Counsel patients on whether and how to continue or restart their use, and on actions in case of invasive procedures, surgery, trauma, or bleeds.

• Advise patients that not all patients may respond to fidanacogene elaparvovec-dzkt and that currently it is not possible to predict who will respond and how long the treatment response will continue. Counsel patients, as necessary, on when they may need to re-instate prophylactic use of factor IX concentrates/hemostatic agents.

• Advise patients that vector distribution in blood (within the body), and vector shedding in semen and other excreta and secreta may occur post-infusion. Patients should not donate blood, organs, tissues, or cells for transplantation.

• Advise male patients to refrain from donating sperm, and to be abstinent or use a male condom for up to 6 months after receiving fidanacogene elaparvovec-dzkt.

• Temporary vector shedding of intravenously administered AAV-based gene therapies occurs primarily through urine and feces, and to some extent saliva, mucus, and semen. Advise patients and/or their caregivers on the proper handling of any materials that have come into contact with patient bodily waste or fluids; recommended procedures include storage of waste material in sealed bags prior to disposal into regular trash. Provide instructions to patients and/or their caregivers regarding proper hand hygiene when coming into direct contact with patient secretions or excretions. These precautions should be followed for 6 months after fidanacogene elaparvovec-dzkt infusion.

• Advise patients that adjustments to their vaccination schedule may be necessary during corticosteroid use. Inform patients where feasible, if corticosteroid use is needed, their vaccination schedule should be adjusted appropriately.

• Inform patients that fidanacogene elaparvovec-dzkt is a liver-directed AAV therapy and may theoretically increase the risk of hepatocellular carcinoma. Patients with risk factors for hepatocellular carcinoma should be monitored for 5 years with regular ultrasound and blood tests. No malignancies were observed to date in the fidanacogene elaparvovec-dzkt clinical studies. Since the vector can insert into DNA of any cell, other malignancies may also occur.

• Advise patients that they should be enrolled in a 15-year registry to evaluate the long-term efficacy and safety of hemophilia treatments.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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