BEQVEZ Concentrate for solution for infusion Ref.[113529] Active ingredients: Fidanacogene elaparvovec

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Pre-existing immunity against AAVRh74var

Anti-AAVRh74var antibody formation can take place after exposure to a virus very similar to the modified virus. Before administration, the absence of antibodies to AAVRh74var must be demonstrated using an appropriately validated assay (see sections 4.1 and 4.2). It is recommended that patients should be dosed as close as possible (e.g., within 8 weeks) following antibody testing confirming the absence of anti-AAVRh74var antibodies.

Pre-treatment evaluation of hepatobiliary condition

Pre-treatment evaluation of hepatobiliary condition should confirm the absence of clinically significant hepatobiliary disease, as defined by any of the below:

• alanine transaminase (ALT), aspartate transaminase (AST), or alkaline phosphatase (ALP) levels >2 × upper limit of normal (ULN), bearing in mind that at least 2 readings may be required to interpret variability over time (at most within 4 weeks)
• bilirubin >1.5 × ULN (at most within 4 weeks)
• current liver-related coagulopathy, hypoalbuminemia, persistent jaundice, cirrhosis, active viral hepatitis
• history of portal hypertension, splenomegaly, or hepatic encephalopathy
• negative fibrosis assessment (at most 3 months before 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 administration.

Patients with active infections, either acute or uncontrolled chronic

There is no clinical experience with administration of fidanacogene elaparvovec in patients with acute infections (such as acute respiratory infections or acute hepatitis) or uncontrolled chronic infections (such as active chronic hepatitis B). It is possible that such acute or uncontrolled infections may affect the response to fidanacogene elaparvovec and reduce its efficacy and/or cause adverse reactions. In patients with such infections, fidanacogene elaparvovec treatment is contraindicated (see section 4.3). If there are signs or symptoms of acute or uncontrolled chronic active infections, fidanacogene elaparvovec treatment must be postponed until the infection has resolved or is controlled.

Limited clinical data are available in patients with controlled HIV infection treated with fidanacogene elaparvovec.

Infusion-related reactions

Infusion reactions, including hypersensitivity reactions and anaphylaxis, are possible during or shortly after fidanacogene elaparvovec infusion. Patients should be closely monitored for infusion reactions throughout the infusion period and at least for 3 hours after end of infusion. The recommended infusion rate should be closely adhered to, in order to ensure patient tolerability. Suspicion of an infusion reaction requires slowing or immediate stopping of the infusion (see section 4.2). Based on clinical judgement, management of infusion reactions should be done according to guidelines for management of allergic reactions, including the discontinuation and/or the administration of appropriate treatment.

To minimise the risk of acute hypersensitivity reactions, patients should be closely monitored for clinical signs and symptoms of infusion reactions and acute or delayed hypersensitivity reactions. Patients should be informed of the early symptoms and signs of hypersensitivity reactions and should be advised to contact their physician and/or seek immediate emergency care if they experience an infusion-related reaction.

Discontinuation of factor IX concentrates

Following fidanacogene elaparvovec infusion, patients should discontinue prophylaxis once the endogenous FIX:C activity levels are considered sufficient to prevent spontaneous bleeding.

Monitoring of factor IX activity and hepatic function

Following administration of fidanacogene elaparvovec, patients can develop transient and asymptomatic elevation of transaminases (see section 4.8). Although the exact aetiology of elevations has not yet been established, it is believed that immune-mediated elevations in liver function tests (LFTs) are the result of an AAV capsid triggered response with subsequent hepatocyte lysis and inflammation.

ALT/AST and factor IX activity levels should be monitored following the administration of fidanacogene elaparvovec (see Table 2). Monitoring of creatine phosphokinase (CPK) is recommended to evaluate for alternative causes for ALT elevations (including potentially hepatotoxic medications or agents, alcohol consumption, or strenuous exercise). Corticosteroid treatment should be instituted in response to aminotransferase elevations to control hepatic reactions and prevent or mitigate a potential reduction in transgene expression (see Table 3 and Table 4).

During the first six months after BEQVEZ administration, the purpose of hepatic and factor IX monitoring is to detect increases in transaminases which may be suggestive of or accompanied by decreased factor IX activity and may indicate the need to initiate corticosteroid treatment. Following the first 6 months post-BEQVEZ administration, hepatic and factor IX monitoring is intended to assess liver health and bleeding risk.

Table 2. Recommended hepatic function (ALT and AST) and factor IX activity monitoring*:

^* It is recommended where possible to use the same laboratory for monitoring over time, particularly during the timeframe for corticosteroid treatment decision making, to minimise the impact of inter-laboratory variability.
^a Weekly monitoring is recommended, and as clinically indicated, during corticosteroid tapering. Adjustment of the monitoring frequency may also be indicated depending on the individual patient situation.
^b Starting at week 65.

Variability of tests for factor IX activity

In regards to factor IX activity monitoring, results from a field study indicate inter-laboratory variability across the different one-stage reagents used in the study, with more variability at the lower levels (0.025 IU/mL). These results support prior data that demonstrated differences in factor IX activity from transgene-derived FIX-R338L variant in different one-stage assays and chromogenic assays, with consistently higher factor IX activity observed for the silica-based one-stage assays.

It is recommended where possible to use the same laboratory (chromogenic or one-stage assays) for factor IX activity monitoring over time, particularly during the timeframe for corticosteroid treatment decision making, to minimise the impact of inter-laboratory variability.

Based on an in vitro study, transgene FIX-R338L variant protein in fidanacogene elaparvovec participants' plasma samples did not interfere with the detection of FIX activity from plasma derived, recombinant, or recombinant extended-half-life FIX products which were spiked into the plasma samples and assessed with two one-stage (OS) assays (Actin FSL and SynthASil) as well as a chromogenic assay using Rox FIX. Glycol-pegylated recombinant FIX products were not assessed in the study. It is suggested not to use silica-based activated partial thromboplastin time (aPTT) assay for the measurement of FIX:C in presence of (recombinant) FIX products; the respective product information for monitoring guidance when using (recombinant) FIX products should be referred to.

Initiation and use of corticosteroids

Corticosteroid treatment should be initiated if aminotransferase elevations are observed or decrease in the activity of factor IX is observed to maintain the transgene expression by transduced hepatocytes (see Table 3 and Table 4). There is limited information with regards to the benefit of starting a new corticosteroid course after the first 6 months of BEQVEZ administration.

Table 3 gives the recommended tapering course of oral corticosteroids (i.e., prednisone/prednisolone) which will be the first consideration for suppression of hepatic laboratory abnormalities. Reference to the corticosteroid product information for risks and required precautions is recommended. In the absence of alternative aetiology, treatment with corticosteroids for vector induced hepatitis would be highly recommended if any of the following criteria are met:

Transaminase increase (ALT and AST):

• Transaminase value 2 × ULN or single increase ≥1.5-fold since the last value obtained prior to infusion (see section 4.2).
• Consecutive increases.

Factor IX activity decreas:

• A single significant decrease that could trigger the risk of bleeding, not associated with a recent infusion of external factor IX product or factor IX inhibitor.
• Consecutive decreases if occurring during the first 120 days post-infusion.

Table 3. Recommended treatment regimen for oral corticosteroids:

^* he 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.

If there is no evidence of resolution of transaminase elevation or in the decrease in activity of factor IX after the first week of oral corticosteroid treatment, consider to use a combination of intravenous methylprednisolone and oral corticosteroids and a hepatologist should be consulted as required (see Table 4).

Table 4. Recommended treatment regimen for combination intravenous and oral corticosteroids:

^* Day 1 of treatment escalation

Monitoring for factor IX inhibitor development

No clinical data is available in patients with detectable factor IX inhibitors treated with fidanacogene elaparvovec. BEQVEZ is not indicated for use in patients with a history of factor IX inhibitors (see section 4.1).

Patients should be monitored through appropriate clinical observations and laboratory tests for the development of inhibitors to factor IX after BEQVEZ administration. An assay that detects factor IX inhibitors if bleeding is not controlled, or plasma factor IX activity levels decrease, should be performed.

Risk of malignancy in relation to vector integration in the DNA of body cells

As there is a theoretical risk of malignant transformation leading to cancer resulting from AAV-mediated integration into the host cell DNA, considerations should be given to regular long-term follow-up monitoring (see long-term follow-up).

It is recommended that patients with pre-existing risk factors for hepatocellular carcinoma (such as hepatic fibrosis, hepatitis C or B disease, non-alcoholic fatty liver disease) undergo regular liver ultrasound screenings and are regularly monitored for alpha-fetoprotein (AFP) elevations on a yearly basis for at least 5 years after BEQVEZ administration (see section 4.3).

In the event that a malignancy occurs, the marketing authorisation holder should be contacted by the treating healthcare professional to obtain instructions on collecting patient samples for potential vector integration examination and integration site analysis.

Measures in relation to transgene DNA shedding

Male patients should be informed on the need for contraceptive measures for them or their female partners of childbearing potential. BEQVEZ is not recommended in women of childbearing potential (see section 4.6).

BEQVEZ may be transmitted to persons other than the patient receiving the treatment through patient excretions and secretions (see section 5.2). Temporary vector shedding of intravenously administered AAV-based gene therapies occurs primarily through urine, and to some extent saliva, and mucus.

To minimise 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.

Risk of thromboembolic events

In patients with haemophilia B with pre-existing risk factors for thromboembolic events, such as a history of cardiovascular or cardiometabolic disease, arteriosclerosis, hypertension, diabetes, advanced age, the potential risk of thrombogenicity may be higher after treatment.

Patients should be evaluated before and after administration of fidanacogene elaparvovec for risk factors for thrombosis and general cardiovascular risk factors. Based on factor IX activity levels achieved, patients should be advised according to their individual condition. Patients should seek immediate medical attention if they observe signs or symptoms that may indicate a thrombotic event.

Immunocompromised patients

No immunocompromised patients, including patients undergoing immunosuppressive treatment within 30 days before fidanacogene elaparvovec infusion, were enrolled in clinical studies with fidanacogene elaparvovec.

Safety and efficacy of this medicinal product in these patients have not been established. Use in immunocompromised patients is based on healthcare professional’s judgement, taking into account the patient’s general health and potential for corticosteroid use post-fidanacogene elaparvovec treatment.

Use of factor IX concentrates or haemostatic agents after treatment with fidanacogene elaparvovec

Following administration of fidanacogene elaparvovec:

• Factor IX concentrates/haemostatic agents may be used in the management of the perioperative setting and in case of invasive procedures, surgery, trauma, or bleeds, in accordance with current treatment guidelines for the management of haemophilia and based on the patient’s current factor IX activity levels.
• If the patient’s factor IX activity levels are consistently ≤2 IU/dL and the patient has experienced recurrent spontaneous bleeding episodes, physicians should consider the use of factor IX concentrates to minimise such episodes, consistent with current treatment guidelines for the management of haemophilia. Target joints should be treated in accordance with relevant treatment guidelines.

When monitoring a patient’s haemostatic activity, please refer to section 4.4 for laboratory tests following infusion of BEQVEZ.

Repeated treatment and impact to other AAV-mediated therapies

It is not yet known whether or under what conditions fidanacogene elaparvovec therapy may be repeated, and to what extent developed endogenous cross-reacting antibodies could interact with the capsids of AAV vectors used by other gene therapies, potentially impacting their treatment efficacy.

Blood, organ, tissue and cell donation

Patients treated with this medicinal product should not donate blood, organs, tissue and cells for transplantation. This information is provided in the Patient Card which should be given to the patient after treatment.

Long-term follow-up

Patients are expected to be enrolled in a registry to follow haemophilia patients for 15 years after infusion, to better understand the long-term safety and efficacy of this gene therapy.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium free’.

BEQVEZ will be diluted with sodium-containing solutions (see section 6.6) and this should be considered in relation to the total sodium from all sources that will be administered to the patient.

No interaction studies have been performed.

Hepatotoxic medicinal products or substances

Experience with use of fidanacogene elaparvovec in patients receiving hepatotoxic medicinal product or using hepatotoxic substances is limited. Care should be exercised when administering potential hepatotoxic medicinal substances, herbal supplements, and alcohol to patients treated with fidanacogene elaparvovec, as the efficacy of fidanacogene elaparvovec may be reduced, and the risk of serious hepatic reactions may increase following fidanacogene elaparvovec administration.

Prior to fidanacogene elaparvovec administration, the patient’s existing concomitant medicinal products should be reviewed to determine if they should be modified to prevent possible anticipated interactions. After fidanacogene elaparvovec administration, patients' concomitant medications should be monitored particularly during the first year, and the need to change concomitant medicinal products based on patients' hepatic health status and risk should be evaluated. When a new medication is started, close monitoring of ALT and factor IX activity levels (e.g., weekly to every 2 weeks for the first month) is recommended to assess potential effects on both levels.

Interactions with medicinal products that may reduce or increase plasma concentrations of corticosteroids

Medicinal products that may reduce or increase the plasma concentration of corticosteroids (e.g., medicinal products that induce or inhibit cytochrome P450 3A4) can decrease the efficacy of the corticosteroid regimen or increase their side effects (see section 4.4).

Vaccinations

Prior to fidanacogene elaparvovec infusion, the patient’s vaccinations should be confirmed to be up to date. The patient’s vaccination schedule may need to be adjusted to accommodate concomitant immunomodulatory therapy. Live vaccines should not be administered to patients while on immunomodulatory therapy.

Women of childbearing potential

No dedicated animal fertility/embryofoetal studies have been conducted to substantiate whether the use in women of childbearing potential and during pregnancy could be harmful for the newborn child (theoretical risk of viral vector integration in foetal cells through vertical transmission). Moreover, no data are available to recommend a specific duration of contraceptive measures in women of childbearing potential. Therefore, BEQVEZ is not recommended in women of childbearing potential.

Contraception after administration to males

For 6 months after administration of fidanacogene elaparvovec, treated patients of reproductive potential and their female partners of childbearing potential must prevent or postpone pregnancy using barrier contraception and avoid contact with semen. Males treated with fidanacogene elaparvovec must not donate semen to minimise the potential risk of paternal germline transmission (see section 4.4).

Pregnancy

Experience regarding the use of this medicinal product during pregnancy is not available. Animal reproduction studies have not been conducted. Fidanacogene elaparvovec is not recommended during pregnancy.

Breast-feeding

It is unknown whether fidanacogene elaparvovec is excreted in human milk. A risk to the newborns/infants cannot be excluded. BEQVEZ should not be used during breast-feeding.

Fertility

No information is available on the effects of fidanacogene elaparvovec on female or male fertility (see section 5.3).

Infusion of fidanacogene elaparvovec may have a minor influence on the ability to drive and use machines. Because of potential adverse reactions such as headaches and dizziness that have occurred shortly after fidanacogene elaparvovec administration, patients should be advised to use caution when driving and operating machinery until they are certain that this medicinal product does not adversely affect them (see section 4.8).

Summary of the safety profile

The most frequently reported adverse reaction following administration was transaminases increased (43.3%).

Tabulated list of adverse reactions

The safety of fidanacogene elaparvovec was evaluated in 60 patients who received the recommended dose (5 × 10¹¹ vector genomes/kg) in 2 open-label clinical studies. The adverse reactions identified with fidanacogene elaparvovec are presented in Table 5.

Adverse reactions are classified according to MedDRA system organ classification and frequency. Frequency categories are derived according to the following conventions: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 5. Tabulated list of adverse reactions to fidanacogene elaparvovec:

^* Includes terms alanine transaminase (ALT) increased, aspartate transaminase (AST) increased, hepatic enzyme increased, hepatic function abnormal, liver function test abnormal, transaminases increased.
^** Includes abdominal pain and epigastric pain.

Description of selected adverse reactions

Hepatic laboratory abnormalities

Forty-three of the 60 (71.7%) patients had ALT elevations and 44 of the 60 (73.3%) patients had AST elevations. Thirty-seven of the 60 (61.7%) patients with ALT elevations also experienced AST elevations. The median onset time of first ALT elevation was 39 days (range: 2 to 2186 days) and the median time to resolution of the first ALT elevation was 13 days (range: 4 to 1373 days). All ALT elevation episodes (52/52) from all participants (36/36) that started within 120 days of fidanacogene elaparvovec infusion resolved. Thirty-one participants had 58 ALT elevation episodes post day 120, and 83% of the episodes had resolved at the time of data cut. Of those unresolved only 3 patients remained > ULN.

Thirty-one out of 60 (51.7%) patients received corticosteroids. The mean time to corticosteroid initiation was 46 days. The mean duration of corticosteroid treatment was 112 days (range: 41 to 276 days). Among those who received corticosteroids (n=31), no patients experienced Grade 3 or above ALT or bilirubin elevations as shown in Table 6 below.

Table 6. Number (%) of patients with ALT or bilirubin elevation and shift in elevation grade between before corticosteroid initiation and post-cessation of corticosteroid treatment:

^* Participants who received corticosteroids.
^ The last ALT and bilirubin ALT liver enzyme results prior to the initiation of corticosteroid treatment.
^& The peak ALT and bilirubin ALT liver enzyme results post-cessation of corticosteroid treatment.
CTCAE grades for ALT elevation: Grade 1: > ULN to 3.0 × ULN if baseline was normal; 1.5 to 3.0 × baseline if baseline was abnormal. Grade 2: > 3.0 to 5.0 × ULN if baseline was normal; > 3.0 to 5.0 × baseline if baseline was abnormal. Grade 3: > 5.0 to 20.0 × ULN if baseline was normal; > 5.0 to 20.0 × baseline if baseline was abnormal. Grade 4: > 20.0 × ULN if baseline was normal; > 20.0 × baseline if baseline was abnormal.
CTCAE grades for bilirubin elevation: Grade 1: > ULN to 1.5 × ULN if baseline was normal; 1.0 to 1.5 × baseline if baseline was abnormal; Grade 2: > 1.5 to 3.0 × ULN if baseline was normal; > 1.5 to 3.0 × baseline if baseline was abnormal; Grade 3: > 3.0 to 10.0 × ULN if baseline was normal; > 3.0 to 10.0 × baseline if baseline was abnormal; Grade 4: > 10.0 × ULN if baseline was normal; > 10.0 × baseline if baseline was abnormal.

Immunogenicity

The administration of fidanacogene elaparvovec has the potential to generate immunity in the form of neutralising antibodies against the vector capsid, the transgene (viral-derived factor IX) and as a cellular response against the transduced cells producing factor IX.

No patients developed factor IX inhibitors during the clinical studies using fidanacogene elaparvovec. There are currently no data regarding the efficacy of fidanacogene elaparvovec when used in patients with history of factor IX inhibitors.

A sustained increase in neutralising anti-AAVRh74var antibodies has been observed after administration of fidanacogene elaparvovec in all subjects who participated in clinical studies and had neutralising antibody assessment. In the Phase 3 clinical study, the mean neutralising anti-AAVRh74var antibodies titre value at week 52 was 28 531.10 and remained generally elevated at week 156 assessment.

Fidanacogene elaparvovec-treated patients were tested for cellular immune responses to overall capsid pool and overall factor IX pool using an IFN-γ ELISpot assay. ELISpot results did not show a trend of presumed T-cell response (based on positive ELISpot) as a function of time during the 1-year post-infusion period in either the Phase 3 or Phase ½ clinical studies.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.