4.1. Therapeutic indications

Hemgenix is indicated for the treatment of severe and moderately severe Haemophilia B (congenital Factor IX deficiency) in adult patients without a history of Factor IX inhibitors.

4.2. Posology and method of administration

Treatment should be initiated under the supervision of a physician experienced in the treatment of Haemophilia and/or bleeding disorders. This medicinal product should be administered in a setting where personnel and equipment are immediately available to treat infusion related reactions (see sections 4.4 and 4.8).

Hemgenix should only be administered to patients who have demonstrated absence of Factor IX inhibitors. In case of a positive test result for human Factor IX inhibitors, 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 Hemgenix.

In addition, before administration of Hemgenix, baseline testing of liver health and assessment of pre-existing neutralising anti-AAV5 antibody titre should be performed; see section 4.4.

Posology

The recommended dose of Hemgenix is a single dose of 2 x 1013 gc/kg body weight corresponding to 2 mL/kg body weight, administered as an intravenous infusion after dilution with sodium chloride 9 mg/mL (0.9%) solution for injection (see section 4.2 below and section 6.6).

Hemgenix can be administered only once.

Discontinuation of prophylaxis with exogenous human Factor IX

The onset of effect from etranacogene dezaparvovec treatment may occur within several weeks post-dose (see section 5.1). Therefore, haemostatic support with exogenous human Factor IX may be needed during the first weeks after etranacogene dezaparvovec infusion to provide sufficient Factor IX coverage for the initial days post-treatment. Monitoring of the Factor IX activity (e.g. weekly for 3 months) is recommended post-dose to follow the patient`s response to etranacogene dezaparvovec.

When using an in vitro activated partial thromboplastin time (aPTT)-based one-stage clotting assay for determining Factor IX activity in patients' blood samples, plasma Factor IX activity results can be affected by both the type of aPTT reagent and the reference standard used in the assay. This is important to consider particularly when changing the laboratory and/or reagents used in the assay (see section 4.4). Therefore, the same assay and reagents are recommended to be used to monitor Factor IX activity over time.

In case increased plasma Factor IX activity levels are not achieved, decrease, or bleeding is not controlled or returns, post-dose testing for Factor IX inhibitors is recommended along with Factor IX activity testing.

Special populations

Elderly population

No dose adjustments are recommended in elderly patients. Limited data are available in patients aged 65 years and older (see section 5.1).

Renal impairment

No dose adjustments are recommended in patients with any level of renal impairment.

The safety and efficacy of etranacogene dezaparvovec in patients with severe renal impairment and end-stage renal disease have not been studied (see section 5.2).

Hepatic impairment

No dose adjustments are recommended in patients with hepatic disorders (see sections 4.3 and 5.2).

The safety and efficacy of etranacogene dezaparvovec in patients with severe hepatic impairment have not been studied. Etrancogene dezaparvovec is contraindicated in patients with acute or uncontrolled chronic hepatic infections, or in patients with known advanced liver fibrosis, or cirrhosis (see section 4.3). This medicinal product is not recommended for use in patients with other significant hepatic disorders (see sections 4.4 and 5.2).

Patient with HIV

No dose adjustments are recommended in HIV-positive patients. Limited data are available in patients with controlled HIV infection.

Paediatric population

The safety and efficacy of etranacogene dezaparvovec in children aged 0 to 18 years have not been studied. No data are available.

Method of administration

Hemgenix is administered as a single-dose intravenous infusion after dilution of the required dose with sodium chloride 9 mg/mL (0.9%) solution for infusion. Etranacogene dezaparvovec must not be administered as an intravenous push or bolus.

For instructions on dilution of the product prior to administration, see section 6.6.

Infusion rate

The diluted product should be administered at a constant infusion rate of 500 mL/hour (8 mL/min).

• In the event of an infusion reaction during administration, the infusion rate should be slowed or stopped to ensure patient tolerability. If the infusion is stopped, it may be restarted at a slower rate when the infusion reaction is resolved (see section 4.4).

• If the infusion rate needs to be reduced, or the infusion stopped and restarted, the etranacogene dezaparvovec solution should be infused within 24 hours after the dose preparation (see section 6.3).

For detailed instructions on preparation, handling, measures to take in case of accidental exposure and disposal of Hemgenix, see section 6.6.

4.3. Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Active infections, either acute or uncontrolled chronic (see section 4.4).

- Patients with known advanced hepatic fibrosis, or cirrhosis (see section 4.4).

4.4. Special warnings and precautions for use

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.

Initiation of treatment with Hemgenix

Patients with pre-existing antibodies to the AAV5 vector capsid

Prior to the treatment with Hemgenix, patients should be assessed for the titre of pre-existing neutralising anti-AAV5 antibodies.

Pre-existing neutralising anti-AAV5 antibodies above a titre of 1:898, based on the neutralising anti-AAV5 antibody assay with extended measuring range (equivalent to 1:678 titre based on the previous clinical study assay), may impede transgene expression at desired therapeutic levels and thus reduce the efficacy of Hemgenix therapy (see section 5.1).

There is limited data in patients with neutralising anti-AAV5 antibodies above 1:898 (equivalent to the 1:678 titre based on the clinical study assay). In the clinical studies with etranacogene dezaparvovec, in 1 patient with a pre-existing neutralising anti-AAV5 antibody titre of 1:3212 (tested using the clinical study assay equivalent to 1:4417 titre based on the neutralising anti-AAV5 antibody assay with extended measuring range), no Factor IX expression was observed and restarting of exogenous Factor IX prophylaxis was needed (see section 5.1).

In the clinical studies with etranacogene dezaparvovec, for the patient sub-group with detectable pre-existing neutralising anti-AAV5 antibodies up to a titre of 1:678 (tested using the clinical study assay, equivalent to 1:898 titre based on the neutralising anti-AAV5 antibody assay with extended measuring range), mean Factor IX activity levels were within the same range but numerically lower compared to those of the patient sub-group without detectable pre-existing neutralising anti-AAV5 antibodies. However, both patient groups, with and without detectable pre-existing neutralising anti-AAV5 antibodies, demonstrated an improved haemostatic protection compared to the standard of care Factor IX prophylaxis after etranacogene dezaparvovec administration (see section 5.1).

Baseline hepatic function

Prior to the treatment with Hemgenix, patient's liver transaminases should be assessed and liver ultrasound and elastography performed, along with laboratory tests to evaluate for active Hepatitis B and C. This includes:

• Enzyme testing (alanine aminotransferase (ALT), aspartate aminotransferase (AST) alkaline phosphatase (ALP) and total bilirubin). ALT test results no later than within 3 months prior to treatment should be obtained, and ALT testing repeated at least once prior to Hemgenix administration to establish patient's ALT baseline.

• Hepatic ultrasound and elastography assessment obtained no later than within 6 months before Hemgenix administration.

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 Hemgenix administration (see information on hepatic function and Factor IX monitoring below). In patients with active Hepatitis B or C, etranacogene dezaparvovec treatment must be postponed until the infection is no longer active (see section 4.3).

Infusion-related reactions – During or shortly after Hemgenix infusion

Infusion reactions, including hypersensitivity reactions and anaphylaxis, are possible (see section 4.8). 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 provided in section 4.2 should be closely adhered to ensure patient tolerability.

Suspicion of an infusion reaction requires slowing or stopping of the infusion (see section 4.2). Based on clinical judgement, treatment with e.g. a corticosteroid or antihistamine may be considered for management of an infusion reaction.

Monitoring after the treatment with Hemgenix

Hepatotoxicity

Intravenous administration of a liver-directed AAV vector may potentially lead to liver transaminase elevations (transaminitis). The transaminitis is presumed to occur due to immune-mediated injury of transduced hepatocytes and may reduce the therapeutic efficacy of the gene therapy.

In clinical studies with etranacogene dezaparvovec, transient, asymptomatic, and predominantly mild liver transaminase elevations were observed, most often in the first 3 months after etranacogene dezaparvovec administration. These transaminase elevations resolved either spontaneously or with corticosteroid treatment (see section 4.8).

To mitigate the risk of potential hepatotoxicity, patient`s liver transaminases should be evaluated and liver ultrasound and elastography performed before treatment (see section 4.2). After Hemgenix administration, transaminases should be closely monitored, e.g. once per week for at least 3 months. A course of corticosteroid taper should be considered in the event of ALT increase to above the upper limit of normal or to double the patient's baseline levels, along with human Factor IX activity examinations (see section 4.4 “Hepatic function and Factor IX monitoring”). 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 values.

The safety of etranacogene dezaparvovec in patients with severe hepatic impairment, including cirrhosis, severe liver fibrosis (e.g. suggestive of or equal to METAVIR [Meta-analysis of Histological Data in Viral Hepatitis] Stage 3 disease or a liver elastography (FibroScan) score of ≥9 kPa), or uncontrolled Hepatitis B and C, have not been studied (see sections 4.3 and 5.2).

Factor IX assays

The results of Factor IX activity tests are lower if measured with chromogenic substrate assay (CSA) compared to one-stage clotting assay (OSA).

In clinical studies, the post-dose Factor IX activity measured with CSA returned lower values with the mean CSA to OSA Factor IX activity ratio ranging from 0.408 to 0.547 (see section 5.1).

Hepatic function and Factor IX monitoring

In the first 3 months after Hemgenix administration, the purpose of hepatic and Factor IX monitoring is to detect increases in ALT, which may be accompanied by decreased Factor IX activity and may indicate the need to initiate corticosteroid treatment (see sections 4.2 and 4.8). After the first 3 months of administration, hepatic and Factor IX monitoring is intended to routinely assess liver health and bleeding risk, respectively.

A baseline assessment of liver health (including liver function tests within 3 months and recent fibrosis assessment using either imaging modalities, such as ultrasound elastography, or laboratory assessments, within 6 months) should be obtained before administration of Hemgenix. Consider obtaining at least two ALT measurements prior to administration, or use an average of prior ALT measurements (for example within 4 months) to establish patient's baseline ALT. It is recommended that the hepatic function is evaluated through a multidisciplinary approach with involvement of a hepatologist to best adjust the monitoring to the patient's individual condition.

It is recommended (where possible) to use the same laboratory for hepatic testing at baseline and monitoring over time, particularly during the timeframe for corticosteroid treatment decision making, to minimise the impact of inter‑laboratory variability.

After administration, the patient's ALT and Factor IX activity levels should be monitored according to Table 1. To assist in the interpretation of ALT results, monitoring of ALT should be accompanied by monitoring of AST and creatine phosphokinase (CPK) to help rule out alternative causes for ALT elevations (including potentially hepatotoxic medicinal products or agents, alcohol consumption, or strenuous exercise). Based on patient's ALT elevations, corticosteroid treatment may be indicated (see Corticosteroid regimen). Weekly monitoring is recommended, and as clinically indicated, during corticosteroid tapering.

Treating physicians should ensure the availability of patients for frequent monitoring of hepatic laboratory parameters and Factor IX activity after administration.

Table 1: Hepatic function and Factor IX activity monitoring

Measurements

Timeframe

Monitoring frequencya

Before administration

Liver function tests

Within 3 months prior to infusion

Baseline measurement

Recent fibrosis assessment

Within 6 months prior to infusion

After administration

ALTb and Factor IX activity

First 3 months

Weekly

Months 4 to 12 (Year 1)

Every 3 months

Year 2

• Every 6 months for patients with Factor IX activity levels > 5 IU/dL (see Factor IX assays)

• Consider more frequent monitoring in patients with Factor IX activity levels ≤ 5 IU/dL and consider the stability of Factor IX levels and evidence of bleeding.

After Year 2

• Every 12 months for patients with Factor IX activity levels > 5 IU/dL (see Factor IX assays)

• Consider more frequent monitoring in patients with Factor IX activity levels ≤ 5 IU/dL and consider the stability of Factor IX levels and evidence of bleeding.

a Weekly monitoring is recommended, or as clinically indicated, during corticosteroid tapering. Adjustment of the monitoring frequency may also be indicated depending on the individual situation.

b Monitoring of ALT should be accompanied by monitoring of AST and CPK, to rule out alternative causes for ALT elevations (including potentially hepatotoxic medications or agents, alcohol consumption, or strenuous exercise).

If a patient returns to prophylactic use of Factor IX concentrates/haemostatic agents for haemostatic control, consider following monitoring and management consistent with instructions for those agents. An annual health check‑up should include liver function tests.

Corticosteroid regimen

An immune response to the AAV5 capsid protein will occur after administration of etranacogene dezaparvovec. This may in some cases lead to elevation in liver transaminases (transaminitis) (see above and section 4.8). In case of elevated ALT levels above the upper limit of normal or doubling of the patient's baseline within the first 3 months post-dose, a corticosteroid treatment should be considered to dampen the immune response, e.g. starting with oral 60 mg/day prednisolone or prednisone (see Table 2).

It is further recommended to assess possible alternative causes of the ALT elevation including administration of potentially hepatotoxic medicinal products or agents, alcohol consumption, or strenuous exercise. Retesting of ALT levels within 24 to 48 hours and, if clinically indicated, performing additional tests to exclude alternative aetiologies should be considered.

Table 2. Recommended prednisolone treatment in response to ALT elevations:

Timeline

Prednisolone oral dose (mg/day)*

Week 1

60

Week 2

40

Week 3

30

Week 4

30

Maintenance dose until ALT level returns to baseline level

20

Taper dose after baseline level has been reached

Reduce daily dose by 5 mg/week

*Medicinal products equivalent to prednisolone may also be used. A combined immunosuppressant regimen or the use of other immunosuppressive therapy can also be considered in case of prednisolone treatment failure or contraindication (see section 4.5). It is further recommended to set a multidisciplinary consultation involving a hepatologist, to best adjust the alternative to corticosteroids and the monitoring to the patient's individual condition.

Risk of thromboembolic events

Patients with Haemophilia B have, compared to the general population, a reduced potential for thromboembolic events (e.g. pulmonary thromboembolism or deep venous thrombosis) due to inborn deficiency in the clotting cascade. Alleviating symptoms of Haemophilia B by restoring Factor IX activity may expose patients to the potential risk of thromboembolism, as observed in the general non-haemophilic population.

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.

In the clinical studies with etranacogene dezaparvovec, treatment-related thromboembolic events were not reported (see section 5.1). In addition, no supraphysiological Factor IX activity levels were observed.

Contraceptive measures in relation to transgene DNA shedding in semen

Male patients should be informed on the need for contraceptive measures for them or their female partners of child bearing potential (see section 4.6).

Blood, organ, tissue and cell donation

Patients treated with Hemgenix must not donate blood, organs, tissues and cells for transplantation. This information is provided in the Patient Card which must be given to the patient after treatment.

Immunocompromised patients

No immunocompromised patients, including patients undergoing immunosuppressive treatment within 30 days before etranacogene dezaparvovec infusion, were enrolled in clinical studies with etranacogene dezaparvovec. Safety and efficacy of this medicinal product in these patients have not been established. Use in immunocompromised patients is based on healthcare professional`s judgment, taking into account the patient's general health and potential for corticosteroid use post-etranacogene dezaparvovec treatment.

HIV positive patients

Limited clinical data are available in patients with controlled HIV infection treated with etranacogene dezaparvovec (see sections 4.2 and 5.1).

The safety and efficacy in patients with HIV infection not controlled with anti-viral therapy, as shown by CD4+ counts ≤200/μL, was not established in clinical studies with etranacogene dezaparvovec (see section 4.3).

Patients with active or uncontrolled chronic infections

There is no clinical experience with administration of etranacogene dezaparvovec in patients with acute infections (such as acute respiratory infections or acute hepatitis) or uncontrolled chronic infections (such as active chronic Hepatitis B or Hepatitis C). It is possible that such acute or uncontrolled infections may affect the response to Hemgenix and reduce its efficacy and/or cause adverse reactions. In patients with such infections, Hemgenix treatment is contraindicated (see section 4.3).

If there are signs or symptoms of acute or uncontrolled chronic active infections, Hemgenix treatment must be postponed until the infection has resolved or is controlled.

Patients with Factor IX inhibitors, Monitoring for Factor IX inhibitor development

There is no clinical experience with administration of etranacogene dezaparvovec in patients who have or had inhibitors to Factor IX. It is not known whether or to what extent such pre-existing Factor IX inhibitors may affect the safety or efficacy of Hemgenix. In patients with a history of Factor IX inhibitors, Hemgenix treatment is not indicated (see section 4.1).

In the clinical studies with etranacogene dezaparvovec, patients had no detectable Factor IX inhibitors at baseline, and formation of inhibitors to etranacogene dezaparvovec was not observed after treatment (see section 5.1).

Patients should be monitored through appropriate clinical observations and laboratory tests for the development of inhibitors to Factor IX after Hemgenix administration.

Use of Factor IX concentrates or haemostatic agents after treatment with etranacogene dezaparvovec

Following administration of etranacogene dezaparvovec:

• Factor IX concentrates/haemostatic agents may be used in case of invasive procedures, surgery, trauma, or bleeds, consistent 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 below 5 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.

Repeated treatment and impact to other AAV-mediated therapies

It is not yet known whether or under what conditions Hemgenix 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 (see section 4.4 further above).

Risk of malignancy as a result of vector integration

Integration site analysis was performed on liver samples from one patient treated with Hemgenix in clinical studies. Samples were collected one year post-dose. Vector integration into human genomic DNA was observed in all samples.

The clinical relevance of individual integration events is not known to date, but it is acknowledged that individual integration into human genome could potentially contribute to a risk of malignancy.

In the clinical studies, no malignancies were identified in relation to treatment with etranacogene dezaparvovec (see sections 5.1 and 5.3). 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.

It is recommended that patients with preexisting 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 (e.g. annually) for at least 5 years after Hemgenix administration (see also section 4.3).

Long-term follow up

Patients are expected to be enrolled in a follow-up study to follow Haemophilia patients for 15 years, to substantiate the long-term safety and efficacy of Hemgenix gene therapy.

Sodium and potassium content

This medicinal product contains 35.2 mg sodium per vial, equivalent to 1.8% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

This medicinal product contains potassium, less than 1 mmol (39 mg) per vial, that is to say essentially potassium-free.

4.5. Interaction with other medicinal products and other forms of interaction

Prior to etranacogene dezaparvovec administration, the patient's existing medicinal products should be reviewed to determine if they should be modified to prevent anticipated interactions described in this section.

Patients' concomitant medications should be monitored after etranacogene dezaparvovec administration, particularly during the first year, and the need to change concomitant medicinal products based on patient's 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.

No in vivo interaction studies have been performed.

Hepatotoxic medicinal products or substances

Experience with use of this medicinal product in patients receiving hepatotoxic medications or using hepatotoxic substances is limited. Safety and efficacy of etranacogene dezaparvovec in these circumstances have not been established (see section 4.4).

Before administering etranacogene dezaparvovec to patients receiving potentially hepatotoxic medicinal products or using other hepatotoxic agents (including alcohol, potentially hepatotoxic herbal products and nutritional supplements) and when deciding on the acceptability of such agents after treatment with etranacogene dezaparvovec, physicians should consider that they may reduce the efficacy of etranacogene dezaparvovec and increase the risk for more serious hepatic reactions, particularly during the first year following etranacogene dezaparvovec administration (see section 4.4).

Interactions with agents that may reduce or increase plasma concentrations of corticosteroids

Agents that may reduce or increase the plasma concentration of corticosteroids (e.g. agents 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 etranacogene dezaparvovec infusion, ensure that the patient's vaccinations are up to date. The patient's vaccination schedule may need to be adjusted to accommodate concomitant immunomodulatory therapy (see section 4.4). Live vaccines should not be administered to patients while on immunomodulatory therapy.

4.6. Fertility, pregnancy and lactation

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).

No data are available to recommend a specific duration of contraceptive measures in women of childbearing potential. Therefore, Hemgenix is not recommended in women of childbearing potential.

Contraception after administration in males

In clinical studies, after administration of etranacogene dezaparvovec, transgene DNA was temporarily detectable in semen (see section 5.2).

For 12 months after administration of etranacogene dezaparvovec treated patients of reproductive potential and their female partners of childbearing potential must prevent or postpone pregnancy using barrier contraception.

Males treated with Hemgenix 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 with Hemgenix. It is not known whether this medicinal product can cause foetal harm when administered to a pregnant woman or can affect reproductive capacity. Hemgenix should not be used during pregnancy.

Breast-feeding

It is unknown whether etranacogene dezaparvovec is excreted in human milk. A risk to the newborns/infants cannot be excluded. Hemgenix should not be used during breast feeding.

Fertility

Effects on male fertility have been evaluated in animal studies with mice. No adverse impact on the fertility was observed (see section 5.3).

4.7. Effects on ability to drive and use machines

Infusion of etranacogene dezaparvovec may have a minor influence on the ability to drive and use machines. Because of potential adverse reactions such as temporary dizziness, fatigue, and headache that have occurred shortly after etranacogene dezaparvovec 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).

4.8. Undesirable effects

Summary of the safety profile

The most frequently reported adverse drug reactions (ADRs) in clinical studies with etranacogene dezaparvovec were headache (very common; 31.6% of patients), ALT elevations (very common; 22.8% of patients), AST elevations (very common; 17.5% of patients), and influenza-like illness (very common; 14% of patients).

Tabulated list of adverse reactions

The safety of etranacogene dezaparvovec was evaluated in clinical studies involving 57 adult patients, who received a single intravenous dose of etranacogene dezaparvovec and were followed up for a period of 5 years (see section 5.1). The Table 3 shows the overview of the ADRs from the clinical trials with etranacogene dezaparvovec. The ADRs are classified according the MedDRA System Organ Class and frequency. The ADRs are listed based on the following convention for frequency categories: 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), and not known (cannot be estimated from the available data). Within each frequency category, adverse reactions are presented in order of decreasing frequency.

Table 3. Adverse drug reactions obtained from clinical studies with etranacogene dezaparvovec

MedDRA System Organ Class (SOC)

ADR

(Preferred term)

Frequency per patient

Nervous system disorders

Headache

Very common

Dizziness

Common

Gastrointestinal disorders

Nausea

Common

General disorders and administration site conditions

Influenza like illness

Very common

Fatigue, malaise

Common

Investigations

Alanine aminotransferase increased, aspartate aminotransferase increased, C-reactive protein increased

Very common

Blood creatine phosphokinase increased, blood bilirubin increased

Common

Injury, poisoning and procedural complications

Infusion related reaction (Hypersensitivity, infusion site reaction, dizziness, eye pruritus, flushing, abdominal pain upper, urticaria, chest discomfort, pyrexia)

Very common*

*The frequency results from pooled infusion related reactions of similar medical concept. Individual infusion reactions occurred in 1 to 2 subjects with common frequency (incidence of 1.8 to 3.5%) within 24 hours post-dose.

Hepatic laboratory abnormalities

Table 4 describes hepatic laboratory abnormalities following administration of Hemgenix. ALT increases are further characterised, as they may be accompanied by decreased Factor IX activity and may indicate the need to initiate corticosteroid treatment (see section 4.4).

Table 4. Hepatic laboratory abnormalities in patients administered 2 x 1013 gc/kg body weight etranacogene dezaparvovec in clinical studies

Laboratory Parameter Increasesa

Number of patients (%)

N = 57 f

ALT increases > ULNb

23 (40.4%)

> ULN – 3.0 x ULNc

17 (29.8%)

> 3.0 – 5.0 x ULNd

1 (1.8%)

> 5.0 – 20.0 x ULNe

1 (1.8%)

AST increases > ULNb

24 (42.1%)

> ULN – 3.0 x ULNc

19 (33.3%)

> 3.0 – 5.0 x ULNd

4 (7.0%)

Bilirubin increases > ULNb

14 (24.6%)

> ULN – 1.5 x ULNc

12 (21.1%)

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

fAdverse event data are derived from patients followed for up to two years post-dose.

Description of selected adverse reactions

Infusion related reactions

In the clinical studies with etranacogene dezaparvovec, infusion-related reactions of mild to moderate severity have been observed in 7/57 (12.3%) subjects. The infusion was temporarily interrupted in 3 patients and resumed at a slower infusion rate upon treatment with antihistamines and/or corticosteroids. In 1 patient, infusion was stopped and not resumed (see section 5.1).

Treatment-emergent transaminitis

In the clinical studies, treatment-emergent adverse reactions of ALT increases occurred in 13/57 (22.8%) patients. The onset of ALT elevations ranged from day 22 to 787 post-dose (see section 4.4). Nine of the 13 patients with ALT elevations received a tapered course of corticosteroid. The mean corticosteroid treatment duration for those patients was 81.4 days (range: 51 to 130). Nine of the 13 patients with ALT elevations also experienced AST elevations. All treatment-emergent adverse events of elevated ALTs were non-serious and resolved within 3 to 127 days.

After month 6 post-dose, no persistence of treatment-related transaminitis was observed and no steroid treatment was required.

No delayed hepatotoxicity was observed (see section 4.4).

Immunogenicity

In the clinical studies with etranacogene dezaparvovec, no Factor IX inhibitor development was observed.

An expected sustained humoral immune response to the infused AAV5 capsid was observed in all patients treated with etranacogene dezaparvovec. Anti-AAV5 antibody levels raised above the upper limit of quantification, as tested using the clinical study assay, by week 3 post-dose and remained elevated above the upper limit of quantification, as measured up to the end of the study (see section 5.1)

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 UK Yellow Card Scheme at http://www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

There are no clinical study data regarding overdose with etranacogene dezaparvovec.