Beqvez Product Monograph

RECENT MAJOR LABEL CHANGES

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TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES ............................................................................................. 2

TABLE OF CONTENTS ............................................................................................................... 2

PART I: HEALTH PROFESSIONAL INFORMATION ....................................................................... 4

1 INDICATIONS ................................................................................................................ 4

1.1 Pediatrics ................................................................................................................. 4

1.2 Geriatrics ................................................................................................................. 4

2 CONTRAINDICATIONS .................................................................................................. 4

4 DOSAGE AND ADMINISTRATION .................................................................................. 4

4.1 Dosing Considerations ............................................................................................. 4

4.2 Recommended Dose and Dosage Adjustment ........................................................ 5

4.4 Administration ......................................................................................................... 7

4.5 Missed Dose .......................................................................................................... 11

5 OVERDOSAGE ............................................................................................................. 11

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................ 11

7 WARNINGS AND PRECAUTIONS ................................................................................. 12

7.1 Special Populations ................................................................................................ 15

7.1.1 Pregnant Women ............................................................................................ 15

7.1.2 Breast-feeding ................................................................................................. 15

7.1.3 Pediatrics ......................................................................................................... 15

7.1.4 Geriatrics ......................................................................................................... 15

8 ADVERSE REACTIONS ................................................................................................. 15

8.1 Adverse Reaction Overview ................................................................................... 15

8.2 Clinical Trial Adverse Reactions ............................................................................. 16

8.3 Less Common Clinical Trial Adverse Reactions ...................................................... 17

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ............................................................................................................ 17

8.5 Post-Market Adverse Reactions ............................................................................ 18

9 DRUG INTERACTIONS ................................................................................................. 18

9.2 Drug Interactions Overview ................................................................................... 18

9.3 Drug-Behavioural Interactions ............................................................................... 18

9.4 Drug-Drug Interactions .......................................................................................... 18

9.5 Drug-Food Interactions .......................................................................................... 18

9.6 Drug-Herb Interactions .......................................................................................... 18

9.7 Drug-Laboratory Test Interactions ......................................................................... 18

10 CLINICAL PHARMACOLOGY ........................................................................................ 19

10.1 Mechanism of Action ....................................................................................... 19

10.2 Pharmacodynamics ......................................................................................... 19

10.3 Pharmacokinetics ............................................................................................ 21

11 STORAGE, STABILITY AND DISPOSAL .......................................................................... 21

12 SPECIAL HANDLING INSTRUCTIONS ............................................................................ 22

PART II: SCIENTIFIC INFORMATION ........................................................................................ 24

13 PHARMACEUTICAL INFORMATION ............................................................................. 24

14 CLINICAL TRIALS ......................................................................................................... 24

14.1 Clinical Trials by Indication .............................................................................. 24

14.3 Immunogenicity ............................................................................................... 26

15 MICROBIOLOGY ......................................................................................................... 26

16 NON-CLINICAL TOXICOLOGY ...................................................................................... 26

PATIENT MEDICATION INFORMATION ................................................................................... 28

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

BEQVEZ (fidanacogene elaparvovec) is an adeno-associated viral (AAV) vector-based gene therapy indicated for the treatment of adults (aged 18 years or older) with moderately severe to severe Hemophilia B (congenital Factor IX deficiency) who are negative for neutralizing antibodies to variant AAV serotype Rh74.

1.1 Pediatrics

Pediatrics (<18 years of age): The safety and efficacy of BEQVEZ in children below 18 years of age have not been studied. No data are available.

1.2 Geriatrics

Geriatrics: The safety and efficacy of BEQVEZ in patients ≥65 years of age have not been established. No data are available.

2 CONTRAINDICATIONS

BEQVEZ is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

Treatment must be prescribed and administered in clinical centres by a health professional who is experienced in treating Hemophilia B.

Before administration of BEQVEZ:

Patient selection

For patient selection, baseline testing is required. This includes examinations of:

• Preexisting neutralizing AAVRh74var antibodies (see 7 WARNINGS AND PRECAUTIONS). It is recommended that testing be done as close as possible to infusion (e.g., within approximately 8 weeks). If a patient is positive for AAVRh74var neutralizing antibodies they will not be eligible for treatment with BEQVEZ (see 1 INDICATIONS and 14 CLINICAL TRIALS).
• Factor IX inhibitor presence. In case of a positive test for alloantibodies against Factor IX, a re-test within approximately 2 weeks should be performed. If both the initial test and re-test results are positive, the patient should not receive BEQVEZ.

• Liver health, including:

  • Enzyme testing (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin) within 4 weeks prior to BEQVEZ infusion. It is

    • establish patient’s ALT baseline.
  • Hepatic ultrasound and fibrosis assessment to confirm no significant liver fibrosis, within 3 months prior to BEQVEZ infusion.

In case of radiological liver abnormalities and/or sustained liver enzyme elevations, consideration of a consultation with a hepatologist is recommended to assess eligibility for BEQVEZ, noting that patients with significant/unstable liver disease were excluded from clinical studies with BEQVEZ (see 7 WARNINGS AND PRECAUTIONS).

• In case of serological evidence of HIV-1 or HIV-2: within 8 weeks prior to infusion, confirm CD4⁺ cell count > 200 mm³ and viral load ≤ 20 copies/mL. In patients who do not meet these criteria, consider retesting. Those who do not meet these criteria are not eligible to receive BEQVEZ.

4.2 Recommended Dose and Dosage Adjustment

The recommended dose of BEQVEZ is 5 × 10¹¹ vector genomes per kg (vg/kg) of body weight administered as a single dose intravenous infusion.

To determine the patient’s dose, the following calculation steps are needed:

1. 1. Calculation of patient’s dose weight

The dose of BEQVEZ is limited by the patient’s body mass index (BMI) kg/m². Calculate the dosing weight based on the BMI as per the following table:

1. 2. Calculation of patient’s dose volume in millilitres (mL)

BEQVEZ dose (in mL) = Patient’s dose weight in kilograms (calculated in step 1) divided by a factor of 20

The division factor 20 is calculated by dividing the concentration of vector genomes per mL of BEQVEZ solution (1 × 10¹³ vg/mL) by the per kilogram dose (5 × 10¹¹ vg/kg).

Examples of dose volume calculation:

BEQVEZ is provided in various pack sizes to accommodate the required number of vials to meet the dosing requirements for each patient based on their calculated dose weight. The number of vials per pack are provided in Table 1 along with the corresponding dosing weight bands.

Special populations

Hepatic impairment

Patients with significant/unstable liver disease were excluded from clinical trials with BEQVEZ including patients with alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) levels greater than twice the upper limit of normal (ULN); bilirubin greater than 1.5 times the ULN, current unstable liver or biliary disease (defined by the presence of ascites, liver-related coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis), active viral hepatitis; and/or pre-existing diagnosis of portal hypertension, splenomegaly, or hepatic encephalopathy. The safety and efficacy of BEQVEZ in these patients have not been established. No dose adjustments are recommended in patients with hepatic impairment should they be considered eligible for treatment with BEQVEZ. See 4.1 Dosing Considerations for guidance on patient selection including the need to evaluate liver health.

Renal impairment

Patients with renal impairment defined as creatinine > 2.0 mg/dL were excluded from clinical studies. The safety and efficacy of BEQVEZ in these patients have not been established.

Geriatrics

Patients ≥ 65 years were excluded from clinical trials with BEQVEZ. The safety and efficacy of BEQVEZ in patients ≥ 65 years of age have not been established.

Pediatrics

The safety and efficacy of BEQVEZ in children and adolescents under 18 years of age have not yet been established. No data are available. Health Canada has not authorized an indication for pediatric use (see 1.1 Pediatrics).

Women

BEQVEZ is not intended for administration in women.

4.4 Administration

Preparation

BEQVEZ is prepared for intravenous infusion by diluting in 0.9% sodium chloride with 0.25% human serum albumin (HSA).

Precautions to be taken before handling or administering BEQVEZ

This medicinal product contains recombinant viral vector product. Personal protective equipment (including gloves, safety goggles, laboratory coat and sleeves) should be worn while preparing or administering BEQVEZ.

For detailed instructions on the handling, accidental exposure to and disposal of this medicinal product, please see 12 SPECIAL HANDLING INSTRUCTIONS.

Preparation of diluent solution (0.9% sodium chloride with 0.25% HSA)

• HSA used for preparation of BEQVEZ must be commercially available in Canada (i.e., have a Drug Identification Number). Either 20% w/v or 25% w/v HSA is recommended.
• Calculate the volume of HSA required to achieve a final concentration of 0.25% w/v HSA in a 200 mL final infusion volume.
• Calculate the volume of medicinal product required based on the patient’s body weight and BMI as described in section 4.2. Recommended Dose and Dosage Adjustment.
• Calculate the volume of 0.9% sodium chloride required to achieve a final infusion volume of 200 mL when combined with the medicinal product and HSA.
• Combine the calculated volume of HSA with the calculated volume of 0.9% sodium chloride in an appropriate intravenous (IV) infusion container. Materials compatible with BEQVEZ are listed below:

• Mix the diluent solution gently. Do not shake. Incubate the diluent solution in the infusion container at room temperature (15°C to 30°C) for at least 10 minutes prior to adding BEQVEZ.

Product vial thawing

• Remove BEQVEZ from the freezer.
• Remove inner carton from the outer carton.
• Thaw BEQVEZ vials in the upright orientation in the inner carton for 1 hour at room temperature (15°C to 30°C).
• Vials may be gently swirled but not shaken or inverted.
• Prior to use, ensure that visible ice crystals are not present in the solution.
• The total time at room temperature between removing vials from frozen storage until the beginning of dose preparation should be no more than 3 hours.
• Visually inspect vials for particulates and discolouration before use. Do not use vials that contain visible particulates. The thawed solution in the vial should appear clear to slightly opalescent, colourless to slightly brown.
• Vials should not be re-frozen.

Preparation of solution for infusion

• Visually inspect thawed product for particulate matter prior to administration. Do not use vials that contain visible particulates.
• The formulation does not contain a preservative and is for single use only.
• Extract the calculated volume of BEQVEZ from the vials using aseptic technique and sterile componentry.
• Combine the extracted volume of BEQVEZ with the diluent solution (0.9% sodium chloride with 0.25% HSA) for a total infusion volume of 200 mL.
• Gently invert the prepared dosing solution in the IV infusion bag to mix. Minimize foaming and do not shake vigorously. Dosing solution should be well mixed.
• The solution for infusion should be equilibrated to ambient temperature before administration to the patient.

Administration

For intravenous use.

BEQVEZ is administered as a single-dose intravenous infusion over approximately 60 minutes.

An in-line 0.2 µm PES or Nylon IV filter may be used for administration.

After the entire content of the infusion bag is infused, the infusion line should be flushed using local site procedures.

For precautions to be taken after handling or administering this medicinal product, please see 7 WARNINGS AND PRECAUTIONS – General.

Monitoring post-infusion

After administration of BEQVEZ, regular monitoring is required. This includes examinations of:

• Liver enzymes to monitor for liver enzyme elevations which may indicate immune-mediated liver hepatotoxicity (see 7 WARNINGS AND PRECAUTIONS). Monitor ALT/AST levels by testing

  • recommended monitoring of liver function post-BEQVEZ infusion.

• Factor IX activity (e.g. twice weekly for at least 3 months).

  • Monitor patients regularly for their Factor IX activity (see 7 WARNINGS and PRECAUTIONS, Monitoring and Laboratory Tests and Table 2).
  • Use of exogenous Factor IX concentrates before and after BEQVEZ administration may affect an accurate estimation of BEQVEZ-derived Factor IX activity.
• Perform regular alpha-fetoprotein (AFP) level testing and abdominal ultrasound (e.g. annually) in patients with pre-existing risk factors for hepatocellular carcinoma (see 7 WARNINGS AND PRECAUTIONS).
• Monitor patients for human Factor IX inhibitors. Post-dose testing should be performed if plasma Factor IX activity levels are not achieved, decrease or if bleeding is not controlled or returns.

Corticosteroid regimen

An immune response to the AAVRh74var capsid proteins will occur after BEQVEZ administration (see 14.3 Immunogenicity). This may lead to elevations in liver transaminases (transaminitis) (see 7 WARNINGS AND PRECAUTIONS and 8 ADVERSE REACTIONS). Treatment with corticosteroids for immune-mediated hepatitis should be considered if any of the following criteria are met:

Transaminase increase

• Single increase ≥ 1.5-fold of the baseline or 2 × ULN transaminase value since the last value obtained prior to infusion.
• Consecutive increases (an increase in transaminases on 2 subsequent blood tests independent of Factor IX activity values).

Factor IX activity decrease

• In the absence of alternative etiology, a single significant decrease that could trigger the risk of bleeding.
• Consecutive decreases (a decline in Factor IX activity on 2 consecutive blood tests independent of transaminase values) particularly during the first 120 days post-infusion.

Table 3 gives the recommended tapering course of oral corticosteroids (i.e., prednisone/prednisolone) which will be the first consideration for suppression of apparent immune hepatitis. Reference to the corticosteroid product information for risks and required precautions is recommended.

Approximately 60 to 100 mg once a day of oral corticosteroids for the first week is recommended as the starting dose. The subsequent prednisolone/prednisone taper should not be started until the ALT and/or AST have declined for at least 2 consecutive lab draws or have returned to approximately baseline (pre-administration) levels and any decline in Factor IX activity has plateaued.

The following schedule of combined oral corticosteroids and intravenous corticosteroids (methylprednisolone) is recommended if there is no evidence of resolution of transaminase elevation while on oral corticosteroids treatment alone (see Table 4).

Discontinuation of continuous routine prophylaxis with exogenous human Factor IX

It may take several weeks before improved hemostatic control becomes apparent after BEQVEZ infusion (see 10.3 Pharmacokinetics). Therefore, continued hemostatic support with exogenous human Factor IX may be required during the first weeks after BEQVEZ administration to provide sufficient Factor IX coverage for the initial days post-treatment. Monitoring of the Factor IX activity (e.g. twice weekly for at least 3 months) is recommended post-dose to follow patient’s response to BEQVEZ (see Table 2). In the clinical studies, a prophylactic dose of Factor IX replacement was given prior to BEQVEZ infusion.

4.5 Missed Dose

BEQVEZ is to be administered only once.

5 OVERDOSAGE

No data from clinical studies are available regarding overdose of BEQVEZ.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

To help ensure the traceability of biologic products, health professionals should record the brand name and the non-proprietary (active ingredient) name as well as other product-specific identifiers such as the Drug Identification Number (DIN) and the batch/lot number of the product supplied.

BEQVEZ is supplied as a concentrate for solution for infusion in a plastic vial with an elastomeric stopper and plastic snap-fit cap. It is a clear to slightly opalescent, colourless to slightly brown solution.

Each vial contains 1 × 10¹³ vector genomes (vg) of fidanacogene elaparvovec in an extractable volume of 1 mL. BEQVEZ requires dilution prior to administration. BEQVEZ is a sterile solution and contains no preservative.

7 WARNINGS AND PRECAUTIONS

General

Precautions to be taken after handling or administering the medicinal product

BEQVEZ may be transmitted to persons other than the patient receiving the treatment through patient excretions and secretions (see 10.3 Pharmacokinetics). Vector shedding of intravenously administered AAV-based gene therapies such as BEQVEZ can occur in blood, semen, urine, feces, and saliva. To minimize the risk of transmission to other persons, patients should be instructed regarding proper hand hygiene when coming into direct contact with patient secretions or excretions. These precautions should be followed for 6 months after BEQVEZ infusion especially in the case of pregnancy or immunodeficiency of close contacts. Barrier contraception is recommended for 1 year after BEQVEZ administration for males and their female partners of child-bearing potential (see 7 WARNINGS AND PRECAUTIONS - Reproductive Health: Female and Male Potential). Caregivers should be advised on the proper handling of waste material generated from contaminated medicinal ancillaries during and after treatment with BEQVEZ (see 12 SPECIAL HANDLING INSTRUCTIONS).

Blood, organ and tissue donation

Advise BEQVEZ-treated patients not to donate blood, organs, tissues and cells for transplantation to minimize the risk of exposure to non-target individuals.

Driving and Operating Machinery

Patients treated with BEQVEZ may experience symptoms shortly after BEQVEZ administration that may affect their ability to drive and use machines. Patients should not drive or use machines until symptoms resolve.

Hematologic

Risk of Thromboembolic Events

In clinical studies with BEQVEZ, treatment-related thromboembolic events were not reported and there was no evidence of supraphysiological FIX activity.

Restoration of Factor IX activity following administration of BEQVEZ, which encodes for a hyperactive IX variant (Padua), may give rise to the potential risk for thromboembolic events. This potential risk is increased in Hemophilia B patients with pre-existing risk factors for thromboembolic events such as a history of cardiovascular disease, arteriosclerosis, hypertension, diabetes, and advanced age.

Hepatic/Biliary/Pancreatic

Hepatotoxicity

Hemophilia B patients with ALT, AST and ALP > 2X upper limit of normal (ULN), bilirubin ≥ 1.5 x ULN, unstable liver or biliary disease (defined by the presence of ascites, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis), active viral hepatitis, and/or pre-existing diagnosis of portal hypertension, splenomegaly, or hepatic encephalopathy were excluded from clinical studies with BEQVEZ. There should be careful consideration before administering BEQVEZ to these patients (see 4.1 Dosing Considerations).

Patients treated with BEQVEZ can develop liver transaminase elevations (transaminitis) (see 8 ADVERSE REACTIONS). Transaminitis, particularly when observed in the first 4 months after BEQVEZ administration, is presumed to occur due to immune-mediated injury of transduced hepatocytes and can reduce therapeutic efficacy of the AAV-vector based gene therapy. In clinical studies with BEQVEZ, most subjects had asymptomatic, and predominantly mild elevations in transaminases most often within 120 days after BEQVEZ administration (see 8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data).

To mitigate the risk of hepatotoxicity, monitor transaminases and Factor IX activity levels at baseline and twice weekly in the first 3 months following the administration of BEQVEZ (see Table 2 in 4.4 Administration). Consider corticosteroid treatment if liver enzyme elevations are observed and/or reductions in Factor IX activity (see 4.4 Administration). In clinical trials with BEQVEZ, patients requiring treatment with corticosteroids post-BEQVEZ infusion had numerically lower transgene FIX activity compared to patients who were not treated with corticosteroids (see 10.2 Pharmacodynamics).

Follow-up monitoring of transaminases in all patients who developed liver enzyme elevations is recommended on a regular basis until liver enzymes return to baseline (see 4.4 Administration).

Advise patients who are to be treated with BEQVEZ to avoid concomitant use of hepatotoxic medicinal substances, herbal supplements, and/or alcohol, as the efficacy of BEQVEZ could be reduced, and the risk of serious hepatic reactions may increase following BEQVEZ administration.

Hepatocellular carcinogenicity

There is a theoretical risk of hepatocellular carcinoma development resulting from the integration of liver-targeting AAV vector DNA into the genome. BEQVEZ is composed of a non-replicating AAVRh74var vector whose DNA remains largely in episomal form although DNA integration events have been reported in non-clinical studies (see 16 NON-CLINICAL TOXICOLOGY).

It is recommended that patients with pre-existing risk factors for hepatocellular carcinoma (such as hepatic cirrhosis, advanced hepatic fibrosis, hepatitis C or B disease, non-alcoholic fatty liver disease) receive regular abdominal ultrasound screenings and are regularly monitored (e.g. annually) for alpha- fetoprotein (AFP) elevations in the 5 years following administration (see 4.1 Dosing Considerations).

Immune

Pre-existing immunity against AAVRh74var

In AAV-vector based gene therapies, pre-existing neutralizing AAV antibodies may impede transgene expression at desired therapeutic levels. Anti-AAVRh74var antibody formation can take place after exposure to a virus that is similar to the vector. All patients must be tested for the presence of anti-AAVRh74var neutralizing antibodies prior to infusion with BEQVEZ (see 4.1 Dosing Considerations). It is recommended that patients should be dosed as close as possible (e.g., within approximately 8 weeks) following antibody testing confirming the absence of AAVRh74var neutralizing antibodies. Only patients negative for pre-existing anti-AAVRh74var neutralizing antibodies are eligible to receive BEQVEZ (see 1 INDICATIONS and 4.1 Dosing Considerations).

Infusion-related reactions

No acute hypersensitivity reactions or infusion-related reactions related to BEQVEZ were observed at the recommended dose.

Infusion related reactions, including hypersensitivity reactions and anaphylaxis, are possible following BEQVEZ administration. To minimize the risk of acute hypersensitivity reactions, closely monitor patients for signs and symptoms of infusion reactions throughout the infusion and for at least 3 hours post-infusion. Inform patients of the early and delayed symptoms and signs of hypersensitivity reactions and advise them to contact their physician and/or seek immediate emergency care if they experience any of these symptoms. In the event of an infusion reaction during administration, immediately pause and evaluate if discontinuation and/or the administration of appropriate treatment is needed. If infusion is paused, it may be restarted at a slower rate at healthcare provider discretion and based upon patient tolerability.

Monitoring and Laboratory Tests

Baseline laboratory testing is required before administration of BEQVEZ (see 4.1 Dosing Considerations). After BEQVEZ administration, a patient’s Factor IX activity should be regularly monitored (see 4.4 Administration).

Factor IX activity assays

A field study was conducted to investigate the variability in the range of values for Factor IX activity determined by laboratories at different sites using standard protocols, commercially available assay reagents, and instruments, to measure Factor IX activity in plasma from trial participants treated with fidanacogene elaparvovec. The results indicate inter-laboratory variability across the different one-stage reagents, with greater variability observed in samples with lower Factor IX activity levels (0.025 IU/mL). Furthermore, while all assay types were able to measure transgene derived Factor IX activity, the study demonstrated inter-assay differences in absolute Factor IX activity values with consistently higher FIX activity reported with silica-based one-stage assays when compared to one-stage assays using different activators/instruments or chromogenic assays. These results agree with publications that reported on Factor IX assay discrepancies in the setting of liver-directed gene therapy and also with the results observed in clinical trials of BEQVEZ (see Table 8 in 10.2 Pharmacodynamics).

It is recommended that patients’ Factor IX activity be monitored using the same assay format and the same laboratory over time. This is of particular importance during the timeframe for corticosteroid treatment decision making since changes in laboratory/assay format could erroneously suggest decreasing Factor IX activity.

Monitor patients through appropriate clinical observations and laboratory tests for the development of inhibitors to Factor IX after BEQVEZ administration. Perform an assay that detects Factor IX inhibitors if bleeding is not controlled, or plasma Factor IX activity levels decrease. If Factor IX activity decreases in the absence of FIX inhibitors, then loss of transgene expression in the liver should be suspected.

Perioperative Considerations

Management in the perioperative setting

Factor IX concentrates/hemostatic agents may be used in case of invasive procedures, surgery, trauma, or bleeds in accordance with current treatment guidelines for the management of hemophilia, and based on the patient’s current Factor IX activity levels.

Reproductive Health: Female and Male Potential

• Fertility

No information is available on the effects of BEQVEZ on female or male fertility.

Contraception after administration to males

In semen the maximum observed time for full vector DNA clearance (defined as 3 consecutive measurements below the limit of quantification) was 154 days. Male patients should be advised to be abstinent or use barrier contraception for 1 year after receiving BEQVEZ (see 10.3 Pharmacokinetics).

Women of childbearing potential

No dedicated animal fertility/embryofetal studies have been conducted. As BEQVEZ has not been studied in women, it is currently not recommended in this population.

7.1 Special Populations

7.1.1 Pregnant Women

BEQVEZ is not intended for administration in women and no women were enrolled in clinical studies with BEQVEZ.

7.1.2 Breast-feeding

BEQVEZ is not intended for administration in women and no women were enrolled in clinical studies with BEQVEZ.

7.1.3 Pediatrics

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4 Geriatrics

The safety and efficacy of BEQVEZ in patients ≥ 65 years of age have not been established.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

The safety of BEQVEZ was evaluated in 60 patients who received a single intravenous dose of 5 × 10¹¹ vector genomes/kg in 2 open-label clinical studies. The most frequently reported adverse reaction (incidence ≥5%) related to BEQVEZ in clinical trials (N=60) was transaminases increased (46.6%) (based on the following combined preferred terms: alanine transaminase (ALT) increased, aspartate transaminase (AST) increased, hepatic enzyme increased, hepatic function abnormal, liver function test abnormal, hypertransaminasemia, hepatotoxicity and transaminases increased) (see 8.4 Abnormal Laboratory Findings, Clinical Findings, and Other Quantitative Data). Serious adverse reactions related to BEQVEZ administration were anemia and duodenal ulcer hemorrhage in one patient after receiving corticosteroid treatment without gastric acid prophylaxis for the management of transaminase increases. For all treatment emergent adverse events (≥ 5%) refer to Table 6.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

For additional information, please refer to 8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data.

8.3 Less Common Clinical Trial Adverse Reactions

Cardiac disorders: angina pectoris (1.7%), palpitations (3.3%)

Hepatobiliary disorders: drug induced liver injury (1.7%), hepatitis (1.7%), liver disorder (1.7%)

Skin and subcutaneous tissue disorders: rash (1.7%)

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Hepatic laboratory abnormalities

Table 7 describes hepatic laboratory abnormalities following administration of BEQVEZ. Elevated transaminases may indicate the need to initiate corticosteroid treatment (see 4.4 Administration and 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).

Abbreviations: ULN = Upper Limit of Normal; CTCAE = Common Terminology Criteria for Adverse Events ^aHighest post-dose CTCAE Grades of values are presented

^bNot all patients with laboratory abnormality >ULN reached CTCAE Grade 1 due to elevated baseline levels ^cCTCAE Grade 1

^dCTCAE Grade 2

^eCTCAE Grade 3

8.5 Post-Market Adverse Reactions

Not Applicable

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

No drug interaction studies have been performed.

9.3 Drug-Behavioural Interactions

Interactions with behavioural risks have not been established.

9.4 Drug-Drug Interactions

Drug-drug interactions have not been established.

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Fidanacogene elaparvovec is a gene therapy designed to introduce a functional copy of a high activity variant of the Factor IX gene (FIX-R338L) into hepatocytes to address the cause of Hemophilia B.

Fidanacogene elaparvovec is a non-replicating recombinant AAV vector that utilizes the AAVRh74var capsid to deliver a functional human Factor IX transgene. The AAVRh74var capsid is derived from the Rh74 AAV, which is not known to cause disease in humans. AAVRh74var capsid is able to transduce hepatocytes, the natural site of Factor IX synthesis. The Factor IX gene present in fidanacogene elaparvovec is designed to reside predominately as episomal DNA within transduced cells. Expression of the transgene is driven by a liver specific promoter, which results in tissue specific expression. As a result, BEQVEZ helps to restore circulating Factor IX procoagulant activity and hemostatic potential in patients with Hemophilia B, which may limit bleeding episodes and the need for exogenous Factor IX treatment.

10.2 Pharmacodynamics

Factor IX Activity

The mean and median Factor IX activity observed after administration of fidanacogene elaparvovec is shown over time in Table 8. In the pivotal study C0371002, 45 patients with historical Factor IX activity <2% received fidanacogene elaparvovec. The participants’ FIX activities were measured over time by each of 3 assays (i.e., SynthAsil Reagent one-stage assay, Actin-FSL reagent one-stage assay, and chromogenic assay). The silica based (SynthAsil) assay consistently gave higher FIX activity values than either the one-stage actin-FSL assay or the chromogenic assay.

From week 12 to month 15, the levels of Factor IX remained relatively stable. At month 15, 86% patients (30 out of 35) were in or above the mild range (Factor IX activity >5%) based on Factor IX activity measured using the one-stage SynthAsil assay, and 68% and 71% were in or above the mild range based on one-stage Actin-FSL assay and chromogenic assay, respectively.

In the supportive studies C0371005/1003, Factor IX activity (without imputation) remained stable over time (up to 6 years), with mean Factor IX activity (One-stage Assay with Actin-FSL reagent) at 27.9% at Month 15 (n=9), 24.9% at Month 24 (n=14), 21.5% at Month 48 (Year 4, n=11) and 21.5% at Month 72 (Year 6, n=5). No patient had resumed FIX prophylaxis post-BEQVEZ infusion.

Overall in the clinical studies, thirty-one out of 60 (51.7%) patients received corticosteroids based on investigator discretion leveraging guidance provided in the protocol. In the pivotal study C0371002, twenty-eight out of 45 (62.2%) patients received corticosteroids due to liver enzyme elevations and/or a reduction in Factor IX activity. The mean time to corticosteroid initiation was 45 days (range: 11, 123). The mean duration of corticosteroid treatment was 113 days (range: 41, 276 days). Hemophilia B patients treated with BEQVEZ who received corticosteroids had numerically lower steady state (geometric mean of FIX activity from week 12 to month 15) Factor IX activity compared to Hemophilia B patients treated with BEQVEZ who did not require corticosteroids [see 7 Warnings and Precautions - Hepatic/Biliary/Pancreatic]. Steady state Factor IX activity by corticosteroid use (yes, n=28; no, n=17) after receiving BEQVEZ are shown in Table 9.

Any samples taken within 7 days (14 days if extended half-life product is used) of exogeneous FIX replacement therapy were not eligible.

If a participant withdrew consent, dropped out early from the study or resumed FIX prophylaxis, then the assessments at the visits following withdrawal/dropout/resumption were imputed as 1.9%.

Steady state FIX:C is calculated for each participant as geometric means of all eligible FIX:C measures from 12 weeks to 15 months after IP infusion.

* SynthAsil Reagent

10.3 Pharmacokinetics

Shedding of BEQVEZ vector DNA was evaluated and occurred in the blood, semen, saliva and urine of treated patients. Although the vector DNA remains largely episomal, events of integration into the genome have been observed in non-clinical studies in non-human primates and therefore there is a potential risk to human health.

Fidanacogene elaparvovec vector DNA levels were measured in studies C0371002 and C0371005/1003 and quantified in blood (peripheral blood mononuclear cells, serum/plasma), saliva, semen and urine using a quantitative polymerase chain reaction (qPCR) assay. The assay is sensitive and specific to fidanacogene elaparvovec vector DNA including fidanacogene elaparvovec DNA fragments and does not indicate whether DNA is present in the vector capsid, in cells or in the fluid phase of the matrix (e.g., blood plasma, seminal fluid) or whether intact vector is present.

Clinical pharmacokinetics and shedding

Vector shedding after infusion with BEQVEZ was assessed in 60 patients at multiple time points in clinical studies. Vector DNA was shed in peripheral blood mononuclear cells (PBMC), saliva, urine, semen, and serum/plasma. In general, peak levels of vector DNA occurred within the first 2 weeks after infusion. Highest peak vector DNA concentrations were found in serum/plasma compared to the other liquid matrices (saliva, urine, semen). Clearance of vector DNA was defined as having 3 consecutive results below the limit of quantification (LOQ). Based on this definition, vector DNA was cleared from serum, plasma, saliva, and semen within means of 3, 3, 1.5, and 3 months post-infusion, respectively. PBMC were slowest to clear vector DNA with an observed mean of 12 months. In semen, the maximum observed time for vector DNA to clear was 154 days.

Nonclinical biodistribution

In a monkey biodistribution study, 22 tissues were collected at 30 and 92 days following treatment. The highest levels of vector DNA were found in liver with levels approximately 20-fold higher than in spleen, the organ with the second most abundant levels of genomic DNA. There was very little biodistribution to testes.

Pharmacokinetics in special populations

No pharmacokinetic studies using BEQVEZ have been conducted in special populations.

11 STORAGE, STABILITY AND DISPOSAL

Store at −90 °C to −60 °C and transport at −100 °C to −60 °C.

Immediately following receipt, original packages removed from frozen transport packaging (−100 °C to −60 °C) may be stored at room temperature (up to 30 °C) for up to 5 minutes during transfer.

Store upright in the original package and avoid direct sunlight and ultraviolet light exposure. If cartons or individual vials are tipped over or inverted during storage and handling, place the carton or individual vials back in the upright orientation immediately.

After thawing, do not refreeze.

Unopened thawed vials

Frozen vials in the inner carton will take up to 1 hour to thaw at room temperature (up to 30 °C). The total time at room temperature (15°C to 30°C) between removing vials from frozen storage until the beginning of dose preparation should be no more than 3 hours.

Once thawed, the vial may be stored refrigerated at 2 °C to 8 °C in the inner carton for up to 24 hours.

The thawed vial cannot be re-frozen.

Diluted Solution for Infusion

Following dilution in 0.9% sodium chloride with 0.25% human serum albumin, chemical and physical in-use stability has been demonstrated for 24 hours at 2 °C to 30 °C. However, the prepared dose should be administered as soon as possible.

Special Precautions for Disposal

This medicinal product contains recombinant viral vector product.

Unused medicinal product and all materials (solid and liquid waste) that have been in contact with the recombinant viral vector product should be handled and disposed of as potentially infectious waste in a container dedicated to biohazard material, autoclaved and destroyed in accordance with local biosafety guidelines.

Non-disposable materials should be cleaned with a disinfectant with proven virucidal activity for nonenveloped viruses e.g. a chlorine releasing disinfectant like hypochlorite containing 0.1% available chlorine (1000 ppm) after usage and then autoclaved, if possible. Contact surfaces should be disinfected with a similar disinfectant.

Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned under 4.4 Administration.

12 SPECIAL HANDLING INSTRUCTIONS

Precautions to be taken before handling or administering BEQVEZ

BEQVEZ should be transported within the facility in closed, break-proof, and leak-proof containers.

This medicinal product contains recombinant viral vector product.

Appropriate precautions for the handling, disposal or accidental exposure of BEQVEZ should be followed:

• BEQVEZ should be handled aseptically under sterile conditions.
• Personal protective equipment (including gloves, safety goggles, laboratory coat and sleeves, and masks) should be worn while handling or administering BEQVEZ. Personnel should not work with BEQVEZ if their skin is cut or scratched.
• All work surfaces which have potentially been in contact with BEQVEZ must be decontaminated with an appropriate disinfectant with proven virucidal activity for non-enveloped viruses (e.g., wiped with an absorbent gauze pad using a bleach solution followed by alcohol wipes).

• All materials that may have come in contact with BEQVEZ (e.g., vials, all materials used for injection, including needles and any unused product) must be disposed of in accordance with

  • -up materials must be double bagged and disposed of per local guidelines for handling of biological waste.

• Accidental exposure to BEQVEZ must be avoided.

  • In the event of exposure to skin, the affected area must be thoroughly cleaned with soap and water for at least 15 minutes.
  • In the event of exposure to eyes, the affected area must be thoroughly flushed with water for at least 15 minutes.
  • In case of accidental needle stick exposure, encourage bleeding of the wound and wash injection area well with soap and water.
  • In case of accidental inhalation, move the person into fresh air.
  • In case of accidental oral exposure, abundantly rinse mouth with water.
  • In each case, obtain subsequent medical attention.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Fidanacogene elaparvovec

Structural formula: Fidanacogene elaparvovec is an adeno-associated viral (AAV)-based gene therapy that consists of a recombinant viral capsid (AAVRh74var) derived from a naturally occurring AAV serotype (Rh74) packaging genome containing the human coagulation Factor IX (FIX) transgene modified to a high-specific Factor IX activity variant known as FIX-R338L.

Physicochemical properties: Clear to slightly opalescent, colourless to slightly brown solution

Product Characteristics:

Fidanacogene elaparvovec is a non-replicating recombinant AAV vector serotype Rh74var containing a codon-optimized coding DNA sequence to deliver human coagulation Factor IX variant R338L (Padua) under the control of a liver promoter (ApoE/hAAT). It is produced by recombinant DNA technology.

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Adult Hemophilia B Patients without FIX Inhibitors

Study Results

The efficacy of BEQVEZ was evaluated in an ongoing open-label, single-dose, single-arm, multi-site study (C0371002). The study enrolled 45 adult male patients aged 18 to 62 years (at time of infusion) with moderately severe to severe Hemophilia B (Factor IX activity ≤ 2%). Eligible patients received a single intravenous infusion dose of BEQVEZ at 5 × 10¹¹ vg/kg of body weight. For participants with BMI >30 kg/m², the dose was calculated based on an adjusted body weight determination that assumes a maximum permissible BMI of 30 kg/m². Prior to infusion, all patients completed a lead-in study of at least 6 months with standard of care Factor IX prophylaxis.

Trial eligibility required all patients to be screened for neutralizing antibodies to AAVRh74var using a cell-based antibody-mediated neutralization assay. Patients who were positive for neutralizing antibodies (titer ≥ 1:1) were excluded from the trial resulting in the exclusion of 61.1% of screened patients. Patients were also excluded from the study if they were < 18 and > 65 years of age, had prior history of Factor IX inhibitor or positive Factor IX inhibitor test results at screening, active hepatitis B or C infection, ALT, AST, or ALP > 2 × ULN, bilirubin > 1.5 × ULN, unstable liver or biliary disease defined by the presence of ascites, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis, significant liver fibrosis or significant liver disease (defined as portal hypertension, splenomegaly and hepatic encephalopathy), creatinine > 2.0 mg/dL, platelets < 100000 cells/mcL and HIV infection with either CD4+ cell count ≤ 200 mm³ or viral load > 20 copies/mL . Thirty-three of 45 (73.3%) patients were White, 7 (15.6%) were Asian, 1 (2.2%) were Black or African American and 4 (8.9%) were not reported.

The primary efficacy endpoint was the Annualized Bleeding rate (ABR) for total bleeds (ABR_total; treated and untreated) from Week 12 to Month 15 versus usual care Factor IX prophylaxis replacement regimen, comparing pre- and post-BEQVEZ infusion.

The key secondary endpoints were ABR for treated bleeds (ABR_treat) and the annualized infusion rate (AIR) of exogenous Factor IX from Week 12 to Month 15.

Five out of 45 (11.1%) patients resumed Factor IX prophylaxis during Week 12 to Month 15 post-BEQVEZ infusion. In addition, as permitted by the protocol, six patients received exogenous Factor IX injections (ranging from 1 to 9 injections each) prior to a planned physical activity with a high risk of injury (e.g., surgery or sporting activity) during Week 12 to Month 15 following BEQVEZ infusion.

The efficacy results of BEQVEZ are shown in Table 11. Non-inferiority of BEQVEZ treatment was demonstrated as the upper bound for the 95% confidence interval of the treatment difference in ABR_total (post-BEQVEZ - lead-in prophylaxis) is lower than the pre-specified non-inferiority margin of 3.

14.3 Immunogenicity

A sustained increase in neutralizing anti-AAVRh74var antibodies has been observed after administration of BEQVEZ in all subjects who participated in clinical studies and had neutralizing antibody (nAb) assessment.

No patients developed Factor IX inhibitors during the clinical studies using BEQVEZ. There are currently no data regarding the efficacy of BEQVEZ when used in patients with a history of Factor IX inhibitors. Patients with Factor IX inhibitors should not receive BEQVEZ.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology:

No adverse findings were observed in a 92-day single-dose intravenous general toxicity study in cynomolgus monkeys at doses up to 5 × 10¹² vg/kg.

Carcinogenicity:

Carcinogenicity studies have not been conducted with BEQVEZ.

Genotoxicity:

Genotoxicity studies have not been conducted with BEQVEZ.

In a 2-year vector integration study in cynomolgus monkeys administered 5 × 10¹² vg/kg (10 times the recommended human dose), there was no indication that integration of vector DNA into host cell DNA (only liver samples were evaluated) resulted in altered liver function, or hepatocellular hyperplasia and carcinoma. The integration profile was considered low risk as the integrations were mostly uniformly distributed throughout the genome (enrichment observed in chromosome 7 and 19), with common insertion sites identified. There was minimal evidence of potential clonal expansion.

Reproductive and Developmental Toxicology:

Reproductive toxicity and impairment of fertility studies have not been conducted with BEQVEZ.