ZOLGENSMA 2x10^13vector genomes / ml infusion solution medication leaflet

Zolgensma 2 × 1013 vector genomes/mL solution for infusion

2.1 General description

Onasemnogene abeparvovec is a gene therapy medicinal product that expresses the human survivalmotor neuron (SMN) protein. It is a non-replicating recombinant adeno-associated virus serotype 9(AAV9) based vector containing the cDNA of the human SMN gene under the control of thecytomegalovirus enhancer/chicken-β-actin-hybrid promoter.

Onasemnogene abeparvovec is produced in human embryonic kidney cells by recombinant DNAtechnology.

2.2 Qualitative and quantitative composition

Each mL contains onasemnogene abeparvovec with a nominal concentration of 2 × 1013 vectorgenomes (vg). Vials will contain an extractable volume of not less than either 5.5 mL or 8.3 mL. Thetotal number of vials and combination of fill volumes in each finished pack will be customised to meetdosing requirements for individual patients depending on their weight (see sections 4.2 and 6.5).

This medicinal product contains 0.2 mmol sodium per mL.

For the full list of excipients, see section 6.1.

Solution for infusion.

A clear to slightly opaque, colourless to faint white solution.

Zolgensma is indicated for the treatment of:

- patients with 5q spinal muscular atrophy (SMA) with a bi-allelic mutation in the SMN1 geneand a clinical diagnosis of SMA Type 1, or

- patients with 5q SMA with a bi-allelic mutation in the SMN1 gene and up to 3 copies of the

SMN2 gene.

Treatment should be initiated and administered in clinical centres and supervised by a physicianexperienced in the management of patients with SMA.

Before administration of onasemnogene abeparvovec, baseline laboratory testing is required,including, but not limited to:

* AAV9 antibody testing using an appropriately validated assay,

* liver function: alanine aminotransferase (ALT), aspartate aminotransferase (AST), totalbilirubin, albumin, prothrombin time, partial thromboplastin time (PTT), and internationalnormalised ratio (INR),

* creatinine,

* complete blood count (including haemoglobin and platelet count), and

* troponin-I.

The need for close monitoring of liver function and platelet count after administration and the need forcorticosteroid treatment are to be considered when establishing the timing of onasemnogeneabeparvovec treatment (see section 4.4).

Due to the increased risk of serious systemic immune response, it is recommended that patients areclinically stable in their overall health status (e.g. hydration and nutritional status, absence ofinfection) prior to onasemnogene abeparvovec infusion. In case of acute or chronic uncontrolled activeinfections, treatment should be postponed until the infection has resolved and the patient is clinicallystable (see sub-sections 4.2 ‘Immunomodulatory regimen’ and 4.4 ‘Systemic immune response’).

For single-dose intravenous infusion only.

Patients will receive a dose of nominal 1.1 x 1014 vg/kg onasemnogene abeparvovec. The total volumeis determined by patient body weight.

Table 1 gives the recommended dosing for patients who weigh 2.6 kg to 21.0 kg.

Table 1 Recommended dosing based on patient body weight

Patient weight range (kg) Dose (vg) Total volume of dose a (mL)2.6 - 3.0 3.3 × 1014 16.53.1 - 3.5 3.9 × 1014 19.33.6 - 4.0 4.4 × 1014 22.04.1 - 4.5 5.0 × 1014 24.84.6 - 5.0 5.5 × 1014 27.55.1 - 5.5 6.1 × 1014 30.35.6 - 6.0 6.6 × 1014 33.06.1 - 6.5 7.2 × 1014 35.86.6 - 7.0 7.7 × 1014 38.57.1 - 7.5 8.3 × 1014 41.37.6 - 8.0 8.8 × 1014 44.08.1 - 8.5 9.4 × 1014 46.88.6 - 9.0 9.9 × 1014 49.59.1 - 9.5 1.05 × 1015 52.39.6 - 10.0 1.10 × 1015 55.010.1 - 10.5 1.16 × 1015 57.810.6 - 11.0 1.21 × 1015 60.511.1 - 11.5 1.27 × 1015 63.311.6 - 12.0 1.32 × 1015 66.012.1 - 12.5 1.38 × 1015 68.812.6 - 13.0 1.43 × 1015 71.513.1 - 13.5 1.49 × 1015 74.313.6 - 14.0 1.54 × 1015 77.014.1 - 14.5 1.60 × 1015 79.814.6 - 15.0 1.65 × 1015 82.515.1 - 15.5 1.71 × 1015 85.315.6 - 16.0 1.76 × 1015 88.016.1 - 16.5 1.82 × 1015 90.816.6 - 17.0 1.87 × 1015 93.517.1 - 17.5 1.93 × 1015 96.317.6 - 18.0 1.98 × 1015 99.018.1 - 18.5 2.04 × 1015 101.818.6 - 19.0 2.09 × 1015 104.519.1 - 19.5 2.15 × 1015 107.319.6 - 20.0 2.20 × 1015 110.020.1 - 20.5 2.26 × 1015 112.820.6 - 21.0 2.31 × 1015 115.5a NOTE: Number of vials per kit and required number of kits is weight-dependent. Dose volume iscalculated using the upper limit of the patient weight range.

Immunomodulatory regimen

An immune response to the AAV9 capsid will occur after administration of onasemnogeneabeparvovec (see section 4.4). This can lead to elevations in liver aminotransferases, elevations oftroponin I, or decreased platelet counts (see sections 4.4 and 4.8). To dampen the immune responseimmunomodulation with corticosteroids is recommended. Where feasible, the patient’s vaccinationschedule should be adjusted to accommodate concomitant corticosteroid administration prior to andfollowing onasemnogene abeparvovec infusion (see section 4.5).

Prior to initiation of the immunomodulatory regimen and prior to administration of onasemnogeneabeparvovec, the patient must be checked for signs and symptoms of active infectious disease of anynature.

Starting 24 hours prior to infusion of onasemnogene abeparvovec it is recommended to initiate animmunomodulatory regimen following the schedule below (see Table 2). If at any time patients do notrespond adequately to the equivalent of 1 mg/kg/day oral prednisolone, based on the patient’s clinicalcourse, prompt consultation with a paediatric gastroenterologist or hepatologist and adjustment to therecommended immunomodulatory regimen, including increased dose, longer duration or prolongationof corticosteroid taper, should be considered (see section 4.4). If oral corticosteroid therapy is nottolerated intravenous corticosteroid may be considered as clinically indicated.

Table 2 Pre- and post-infusion immunomodulatory regimen

Pre-infusion 24 hours prior to onasemnogene Prednisolone orally 1 mg/kg/dayabeparvovec (or equivalent if anothercorticosteroid is used)

Post-infusion 30 days (including the day of administration Prednisolone orally 1 mg/kg/dayof onasemnogene abeparvovec) (or equivalent if anothercorticosteroid is used)

Followed by 28 days: Systemic corticosteroids should betapered gradually.

For patients with unremarkable findings(normal clinical exam, total bilirubin, and Tapering of prednisolone (orwhose ALT and AST values are both below equivalent if another corticosteroid2 × upper limit of normal (ULN) at the end is used), e.g. 2 weeks atof the 30 days period: 0.5 mg/kg/day and then 2 weeks at0.25 mg/kg/day oral prednisoloneor

For patients with liver function Systemic corticosteroidsabnormalities at the end of the 30 days (equivalent to oral prednisoloneperiod: continuing until the AST and ALT 1 mg/kg/day)values are below 2 × ULN and all otherassessments (e.g. total bilirubin) return to Systemic corticosteroids should benormal range, followed by tapering over tapered gradually.

28 days or longer if needed.

Liver function (ALT, AST, total bilirubin) should be monitored at regular intervals for at least3 months following onasemnogene abeparvovec infusion (weekly in the first month and during theentire corticosteroid taper period, followed by every two weeks for another month), and at other timesas clinically indicated. Patients with worsening liver function test results and/or signs or symptoms ofacute illness should be promptly clinically assessed and monitored closely (see section 4.4).

If another corticosteroid is used by the physician in place of prednisolone, similar considerations andapproach to taper the dose after 30 days should be taken as appropriate.

The safety and efficacy of onasemnogene abeparvovec have not been established in patients with renalimpairment and onasemnogene abeparvovec therapy should be carefully considered. A doseadjustment should not be considered.

Patients with ALT, AST, total bilirubin levels (except due to neonatal jaundice) >2 × ULN or positiveserology for hepatitis B or hepatitis C have not been studied in clinical studies with onasemnogeneabeparvovec. Onasemnogene abeparvovec therapy should be carefully considered in patients withhepatic impairment (see sections 4.4 and 4.8). A dose adjustment should not be considered.

0SMN1/1SMN2 genotype

No dose adjustment should be considered in patients with a bi-allelic mutation of the SMN1 gene andonly one copy of SMN2 (see section 5.1).

Anti-AAV9 antibodies

No dose adjustment should be considered in patients with baseline anti-AAV9 antibody titres above1:50 (see section 4.4).

The safety and efficacy of onasemnogene abeparvovec in premature neonates before reaching full-term gestational age have not been established. No data are available. Administration ofonasemnogene abeparvovec should be carefully considered because concomitant treatment withcorticosteroids may adversely affect neurological development.

There is limited experience in patients 2 years of age and older or with body weight above 13.5 kg.

The safety and efficacy of onasemnogene abeparvovec in these patients have not been established.

Currently available data are described in section 5.1. A dose adjustment should not be considered (see

Table 1).

For intravenous use.

Onasemnogene abeparvovec is administered as a single-dose intravenous infusion. It should beadministered with a syringe pump as a single intravenous infusion with a slow infusion ofapproximately 60 minutes. It must not be administered as an intravenous push or bolus.

Insertion of a secondary (‘back-up’) catheter is recommended in case of blockage in the primarycatheter. Following completion of infusion, the line should be flushed with sodium chloride 9 mg/mL(0.9%) solution for injection.

This medicinal product contains a genetically-modified organism. Healthcare professionals shouldtherefore take appropriate precautions (use of gloves, safety goggles, laboratory coat and sleeves)when handling or administering the product (see section 6.6).

For detailed instructions on the preparation, handling, accidental exposure and disposal (includingproper handling of bodily waste) of onasemnogene abeparvovec, see section 6.6.

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

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

Pre-existing immunity against AAV9

Anti-AAV9 antibody formation can take place after natural exposure. There have been several studieson the prevalence of AAV9 antibodies in the general population that show low rates of prior exposureto AAV9 in the paediatric population. Patients should be tested for the presence of AAV9 antibodiesprior to infusion with onasemnogene abeparvovec. Re-testing may be performed if AAV9 antibodytitres are reported as above 1:50. It is not yet known whether or under what conditions onasemnogeneabeparvovec can be safely and effectively administered in the presence of anti-AAV9 antibodiesabove 1:50 (see sections 4.2 and 5.1).

Advanced SMA

Since SMA results in progressive and non-reversible damage to motor neurons, the benefit ofonasemnogene abeparvovec in symptomatic patients depends on the degree of disease burden at thetime of treatment, with earlier treatment resulting in potential higher benefit. While advancedsymptomatic SMA patients will not achieve the same gross motor development as unaffected healthypeers they may clinically benefit from gene replacement therapy, dependent on the advancement ofdisease at the time of treatment (see section 5.1).

The treating physician should consider that the benefit is seriously reduced in patients with profoundmuscle weakness and respiratory failure, patients on permanent ventilation, and patients not able toswallow.

The benefit/risk profile of onasemnogene abeparvovec in patients with advanced SMA, kept alivethrough permanent ventilation and without the ability to thrive, is not established.

Infusion-related reactions and anaphylactic reactions

Infusion-related reactions, including anaphylactic reactions, have occurred during, and/or shortly after,infusion of onasemnogene abeparvovec (see section 4.8). Patients should be monitored closely forclinical signs and symptoms of infusion-related reactions. If a reaction occurs, the infusion should beinterrupted and treatment should be provided as needed. Based on clinical evaluation and standardpractices, administration may be cautiously resumed.

An immune response to the AAV9 capsid will occur after infusion of onasemnogene abeparvovec,including antibody formation against the AAV9 capsid and T-cell mediated immune response, despitethe immunomodulatory regimen recommended in section 4.2 (see also sub-section ‘Systemic immuneresponse’ below).

Immune-mediated hepatotoxicity is generally manifested as elevated ALT and/or AST levels. Acuteserious liver injury and acute liver failure, including fatal cases, have been reported withonasemnogene abeparvovec use, typically within 2 months after infusion and despite receivingcorticosteroids before and after infusion. Immune-mediated hepatotoxicity may require adjustment ofthe immunomodulatory regimen including longer duration, increased dose, or prolongation of thecorticosteroid taper (see section 4.8).

* The risks and benefits of onasemnogene abeparvovec therapy should be carefully considered inpatients with pre-existing hepatic impairment.

* Patients with pre-existing hepatic impairment or acute hepatic viral infection may be at higherrisk of acute serious liver injury (see section 4.2).

* Data from a small study in children weighing ≥8.5 kg to ≤21 kg (aged approximately 1.5 to9 years), indicate a higher frequency of AST or ALT elevations (in 23 out of 24 patients)compared with frequencies of AST/ALT elevations observed in other studies in patientsweighing <8.5 kg (in 31 out of 99 patients) (see section 4.8).

* Administration of AAV vector often results in aminotransferase elevations.

* Acute serious liver injury and acute liver failure have occurred with onasemnogeneabeparvovec. Cases of acute liver failure with fatal outcome have been reported (seesection 4.8).

* Prior to infusion, liver function of all patients should be assessed by clinical examination andlaboratory testing (see section 4.2).

* In order to mitigate potential aminotransferase elevations, a systemic corticosteroid should beadministered to all patients before and after onasemnogene abeparvovec infusion (seesection 4.2).

* Liver function should be monitored at regular intervals for at least 3 months after infusion, andat other times as clinically indicated (see section 4.2).

* Patients with worsening liver function test results and/or signs or symptoms of acute illnessshould be promptly clinically assessed and monitored closely.

* In case hepatic injury is suspected, prompt consultation with a paediatric gastroenterologist orhepatologist, adjustment of the recommended immunomodulatory regimen and further testing isrecommended (e.g. albumin, prothrombin time, PTT, and INR).

AST/ALT/total bilirubin should be assessed weekly for the first month after onasemnogeneabeparvovec infusion and during the entire corticosteroid taper period. Tapering of prednisoloneshould not be considered until AST/ALT levels are less than 2 × ULN and all other assessments (e.g.

total bilirubin) return to normal range (see section 4.2). If the patient is clinically stable withunremarkable findings at the end of the corticosteroid taper period, liver function should continue tobe monitored every two weeks for another month.

Transient decreases in platelet counts, some of which met the criteria for thrombocytopenia, wereobserved in onasemnogene abeparvovec clinical studies. In most cases, the lowest platelet valueoccurred the first week following onasemnogene abeparvovec infusion.

Post-marketing cases with platelet count <25 x 109/L have been reported to occur within three weeksfollowing administration.

Platelet counts should be obtained before onasemnogene abeparvovec infusion and should be closelymonitored within the first three weeks following infusion and on a regular basis afterwards, at leastweekly for the first month and every other week for the second and third months until platelet countsreturn to baseline.

Data from a small study in children weighing ≥8.5 kg to ≤21 kg (aged approximately 1.5 to 9 years),indicate a higher frequency of thrombocytopenia (in 20 out of 24 patients) compared with frequenciesof thrombocytopenia observed in other studies in patients weighing <8.5 kg (in 22 out of 99 patients)(see section 4.8).

Elevated troponin-I

Increases in cardiac troponin-I levels following infusion with onasemnogene abeparvovec wereobserved (see section 4.8). Elevated troponin-I levels found in some patients may indicate potentialmyocardial tissue injury. Based on these findings and the observed cardiac toxicity in mice, troponin-Ilevels should be obtained before onasemnogene abeparvovec infusion and monitored as clinicallyindicated. Consider consultation with a cardiac expert as needed.

Thrombotic microangiopathy

Several cases of thrombotic microangiopathy (TMA) have been reported with onasemnogeneabeparvovec (see section 4.8). Cases generally occurred within the first two weeks afteronasemnogene abeparvovec infusion. TMA is an acute and life-threatening condition, which ischaracterised by thrombocytopenia and microangiopathic haemolytic anaemia. Fatal outcomes havebeen reported. Acute kidney injury has also been observed. In some cases, concurrent immune systemactivation (e.g. infections, vaccinations) has been reported (see sections 4.2 and 4.5 for information onadministration of vaccinations).

Thrombocytopenia is a key feature of TMA, therefore platelet counts should be closely monitoredwithin the first three weeks following infusion and on a regular basis afterwards (see sub-section‘Thrombocytopenia’). In case of thrombocytopenia, further evaluation including diagnostic testing forhaemolytic anaemia and renal dysfunction should be undertaken promptly. If patients show clinicalsigns, symptoms or laboratory findings consistent with TMA, a specialist should be consultedimmediately to manage TMA as clinically indicated. Caregivers should be informed about signs andsymptoms of TMA and should be advised to seek urgent medical care if such symptoms occur.

Systemic immune response

Due to the increased risk of serious systemic immune response, it is recommended that patients areclinically stable in their overall health status (e.g. hydration and nutritional status, absence ofinfection) prior to onasemnogene abeparvovec infusion. Treatment should not be initiated concurrentlyto active infections, either acute (such as acute respiratory infections or acute hepatitis) or uncontrolledchronic (such as chronic active hepatitis B), until the infection has resolved and the patient is clinicallystable (see sections 4.2 and 4.4).

The immunomodulatory regimen (see section 4.2) might also impact the immune response toinfections (e.g. respiratory), potentially resulting in more severe clinical courses of the infection.

Patients with infection were excluded from participation in clinical trials with onasemnogeneabeparvovec. Increased vigilance in the prevention, monitoring, and management of infection isrecommended before and after onasemnogene abeparvovec infusion. Seasonal prophylactictreatments, that prevent respiratory syncytial virus (RSV) infections, are recommended and should beup to date. Where feasible, the patient’s vaccination schedule should be adjusted to accommodateconcomitant corticosteroid administration prior to and following onasemnogene abeparvovec infusion(see section 4.5).

If the duration of corticosteroid treatment is prolonged or the dose is increased, the treating physicianshould be aware of the possibility of adrenal insufficiency.

Risk of tumourigenicity as a result of vector integration

There is a theoretical risk of tumourigenicity due to integration of AAV vector DNA into the genome.

Onasemnogene abeparvovec is composed of a non-replicating AAV9 vector whose DNA persistslargely in episomal form. Rare instances of random vector integration into human DNA are possiblewith recombinant AAV. The clinical relevance of individual integration events is unknown, but it isacknowledged that individual integration events could potentially contribute to a risk oftumourigenicity.

So far, no cases of malignancies associated with onasemnogene abeparvovec treatment have beenreported. In the event of a tumour, the marketing authorisation holder should be contacted forguidance on collecting patient samples for testing.

Shedding

Temporary onasemnogene abeparvovec shedding occurs, primarily through bodily waste. Caregiversand patient families should be advised on the following instructions for the proper handling of patientstools:

* good hand-hygiene is required when coming into direct contact with patient bodily waste for aminimum of 1 month after onasemnogene abeparvovec treatment.

* disposable nappies can be sealed in double plastic bags and disposed of in household waste (seesection 5.2).

Blood, organ, tissue and cell donation

Patients treated with Zolgensma should not donate blood, organs, tissues or cells for transplantation.

This medicinal product contains 4.6 mg sodium per mL, equivalent to 0.23% of the WHOrecommended maximum daily intake of 2 g sodium for an adult. Each 5.5 mL vial contains 25.3 mgsodium, and each 8.3 mL vial contains 38.2 mg sodium.

No interaction studies have been performed.

Experience with use of onasemnogene abeparvovec in patients receiving hepatotoxic medicinalproducts or using hepatotoxic substances is limited. Safety of onasemnogene abeparvovec in thesepatients have not been established.

Experience with use of concomitant 5q SMA targeting agents is limited.

Where feasible, the patient’s vaccination schedule should be adjusted to accommodate concomitantcorticosteroid administration prior to and following onasemnogene abeparvovec infusion (seesections 4.2 and 4.4). Seasonal RSV prophylaxis is recommended (see section 4.4). Live vaccines,such as MMR and varicella, should not be administered to patients on an immunosuppressive steroiddose (i.e., ≥ 2 weeks of daily receipt of 20 mg or 2 mg/kg body weight of prednisolone or equivalent).

Human data on use during pregnancy or lactation are not available and animal fertility or reproductionstudies have not been performed.

Onasemnogene abeparvovec has no or negligible influence on the ability to drive and use machines.

The safety of onasemnogene abeparvovec was evaluated in 99 patients who received onasemnogeneabeparvovec at the recommended dose (1.1 x 1014 vg/kg) in 5 open-label clinical studies. The mostfrequently reported adverse reactions following administration were hepatic enzyme increased(24.2%), hepatotoxicity (9.1%), vomiting (8.1%), thrombocytopenia (6.1%), troponin increased(5.1%), and pyrexia (5.1%) (see section 4.4).

The adverse reactions identified with onasemnogene abeparvovec in all patients treated withintravenous infusion at the recommended dose with a causal association to treatment are presented in

Table 3. Adverse reactions are classified according to MedDRA system organ classification andfrequency. 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 eachfrequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 3 Tabulated list of adverse reactions to onasemnogene abeparvovec

Adverse Reactions by MedDRA SOC/PT and Frequency

Common Thrombocytopenia1)

Uncommon Thrombotic microangiopathy2)3)

Rare Anaphylactic reactions

Common Vomiting

Common Hepatotoxicity4)

Uncommon Acute liver failure2)3)

Common Pyrexia

Uncommon Infusion-related reactions

Very common Hepatic enzyme increased5)

Common Troponin increased6)1)Thrombocytopenia includes thrombocytopenia and platelet count decreased.2)Treatment-related adverse reactions reported outside of pre-marketing clinical studies, includingin the post-marketing setting.3)Includes fatal cases.4)Hepatotoxicity includes hepatic steatosis and hypertransaminasaemia.5)Hepatic enzyme increased includes: alanine aminotransferase increased, ammonia increased,aspartate aminotransferase increased, gamma-glutamyltransferase increased, hepatic enzymeincreased, liver function test increased and transaminases increased.6)Troponin increased includes troponin increased, troponin-T increased, and troponin-I increased(reported outside of clinical studies, including in the post-marketing setting).

In the clinical development program (see section 5.1), elevated transaminases > 2 × ULN (and in somecases > 20 × ULN) were observed in 31% of patients treated at the recommended dose. These patientswere clinically asymptomatic and none of them had clinically significant elevations of bilirubin.

Serum transaminase elevations usually resolved with prednisolone treatment and patients recoveredwithout clinical sequelae (see sections 4.2 and 4.4).

In the post-marketing setting, there have been reports of children developing signs and symptoms ofacute liver failure (e.g. jaundice, coagulopathy, encephalopathy) typically within 2 months oftreatment with onasemnogene abeparvovec, despite receiving corticosteroids before and after infusion.

Cases of acute liver failure with fatal outcome have been reported.

In a study (COAV101A12306) including 24 children weighing ≥8.5 kg to ≤21 kg (aged approximately1.5 to 9 years; 21 discontinued previous SMA treatment) increased transaminases were observed in 23out of 24 patients. The patients were asymptomatic and there were no elevations of bilirubin. The ASTand ALT elevations were managed with the use of corticosteroids, typically with prolonged duration(at Week 26, 17 patients were continuing prednisolone, at Week 52, 6 patients were still receivingprednisolone) and/or a higher dose.

Transient thrombocytopenia

In the clinical development program (see section 5.1), transient thrombocytopenia was observed atmultiple time points post-dose and normally resolved within two weeks. Decreases in platelet countswere more prominent during the first week of treatment. Post-marketing cases with transient decreasein platelet count to levels <25 x 109/L within three weeks of administration have been reported (seesection 4.4).

In a study (COAV101A12306) including 24 children weighing ≥8.5 kg to ≤21 kg (aged approximately1.5 to 9 years), thrombocytopenia was observed in 20 out of 24 patients.

Increases in troponin-I levels

Increases in cardiac troponin-I levels up to 0.2 mcg/L following onasemnogene abeparvovec infusionwere observed. In the clinical study program, there were no clinically apparent cardiac findingsobserved following administration of onasemnogene abeparvovec (see section 4.4).

Pre- and post-gene therapy titres of anti-AAV9 antibodies were measured in the clinical studies (seesection 4.4). All patients that received onasemnogene abeparvovec had anti-AAV9 titres at orbelow 1:50 before treatment. Mean increases from baseline in AAV9 titre were observed in all patientsat all but 1 time-point for antibody titre levels to AAV9 peptide, reflecting normal response to non-selfviral antigen. Some patients experienced AAV9 titres exceeding the level of quantification, howevermost of these patients did not have potentially clinically significant adverse reactions. Thus, norelationship has been established between high anti-AAV9 antibody titres and the potential for adversereactions or efficacy parameters.

In the AVXS-101-CL-101 clinical study, 16 patients were screened for anti-AAV9 antibody titre:

13 had titres less than 1:50 and were enrolled in the study; three patients had titres greater than 1:50,two of whom were retested following cessation of breast-feeding and their titres were measured at lessthan 1:50 and both were enrolled in the study. There is no information on whether breastfeedingshould be restricted in mothers who may be seropositive for anti-AAV9 antibodies. Patients all hadless than or equal to 1:50 AAV9 antibody titre prior to treatment with onasemnogene abeparvovec andsubsequently demonstrated an increase in anti-AAV9 antibody titres to at least 1:102 400 and up togreater than 1:819 200.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.

In addition, the observed incidence of antibody (including neutralising antibody) positivity in an assaymay be influenced by several factors including assay methodology, sample handling, timing of samplecollection, concomitant medicinal products and underlying disease.

No onasemnogene abeparvovec-treated patient demonstrated an immune response to the transgene.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No data from clinical studies are available regarding overdose of onasemnogene abeparvovec.

Adjustment of the dose of prednisolone, close clinical observation and monitoring of laboratoryparameters (including clinical chemistry and haematology) for systemic immune response arerecommended (see section 4.4).

Pharmacotherapeutic group: Other drugs for disorders of the musculo-skeletal system, ATC code:

M09AX09

Onasemnogene abeparvovec is a gene therapy designed to introduce a functional copy of the survivalmotor neuron gene (SMN1) in the transduced cells to address the monogenic root cause of the disease.

By providing an alternative source of SMN protein expression in motor neurons, it is expected topromote the survival and function of transduced motor neurons.

Onasemnogene abeparvovec is a non-replicating recombinant AAV vector that utilizes AAV9 capsidto deliver a stable, fully functional human SMN transgene. The ability of the AAV9 capsid to cross theblood brain barrier and transduce motor neurons has been demonstrated. The SMN1 gene present inonasemnogene abeparvovec is designed to reside as episomal DNA in the nucleus of transduced cellsand is expected to be stably expressed for an extended period of time in post-mitotic cells. The

AAV9 virus is not known to cause disease in humans. The transgene is introduced to target cells as aself-complementary double-stranded molecule. Expression of the transgene is driven by a constitutivepromoter (cytomegalovirus enhanced chicken-β-actin-hybrid), which results in continuous andsustained SMN protein expression. Proof of the mechanism of action has been supported by non-clinical studies and by human biodistribution data.

AVXS-101-CL-303 Phase 3 study in patients with Type 1 SMA

AVXS-101-CL-303 (Study CL-303) is a Phase 3 open-label, single-arm, single-dose study ofintravenous administration of onasemnogene abeparvovec at the therapeutic dose (1.1 × 1014 vg/kg).

Twenty-two patients were enrolled with Type 1 SMA and 2 copies of SMN2. Before treatment withonasemnogene abeparvovec, none of the 22 patients required non-invasive ventilator (NIV) support,and all patients could exclusively feed orally (i.e., did not need non-oral nutrition). The mean

Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) scoreat baseline was 32.0 (range, 18 to 52). The mean age of the 22 patients at the time of treatment was3.7 months (0.5 to 5.9 months).

Of the 22 enrolled patients, 21 patients survived without permanent ventilation (i.e., event-freesurvival) to ≥10.5 months of age, 20 patients survived to ≥14 months of age (co-primary efficacyendpoint), and 20 patients survived event-free to 18 months of age.

Three patients did not complete the study, of which 2 patients had an event (death or permanentventilation) leading to 90.9% (95% CI: 79.7%, 100.0%) event-free survival (alive without permanentventilation) at 14 months of age, see Figure 1.

Figure 1 Time (months) to death or permanent ventilation pooled from onasemnogeneabeparvovec IV studies (CL-101, CL-302, CL-303, CL-304-2 copy cohort)

With number of subjects at risk+ Censored

Age (months)

Study

PNCR = Pediatric Neuromuscular Clinical Research natural history cohort

NeuroNext = Network for Excellence in Neuroscience Clinical Trials natural history cohort

For the 14 patients in Study CL-303 that achieved the milestone of independent sitting for at least30 seconds at any visit during the study, the median age when this milestone was first demonstratedwas 12.6 months (range: 9.2 to 18.6 months). Thirteen patients (59.1%) confirmed the milestone ofindependent sitting for at least 30 seconds at the 18-month visit (co-primary endpoint, p<0.0001). Onepatient achieved the milestone of sitting independently for 30 seconds at 16 months of age, but thismilestone was not confirmed at the Month 18 visit. The video-confirmed developmental milestones forpatients in Study CL-303 are summarised in Table 4. Three patients did not achieve any motormilestones (13.6%) and another 3 patients (13.6%) achieved head control as the maximum motormilestone before the 18 months of age final study visit.

Table 4 Median time to video documented achievement of motor milestones Study CL-303

Video documented Number of patients Median age to 95% Confidence intervalmilestone achieving milestone the milestonen/N (%) achievement(months)

Head control 17/20* (85.0) 6.8 (4.77, 7.57)

Rolls from back to sides 13/22 (59.1) 11.5 (7.77, 14.53)

Sits without support for 14/22 (63.6) 12.5 (10.17, 15.20)30 seconds (Bayley)

Sitting without support 14/22 (63.6) 13.9 (11.00, 16.17)for at least 10 seconds(WHO)

* 2 patients were reported to have Head Control by clinician assessment at baseline.

Probability of event-free survival

One patient (4.5%) could also walk with assistance at 12.9 months. Based on the natural history of thedisease, patients who met the study entry criteria would not be expected to attain the ability to sitwithout support. In addition, 18 of the 22 patients were independent of ventilatory support at18 months of age.

Motor function improvements were also observed as measured by the CHOP-INTEND, see Figure 2.

Twenty-one patients (95.5%) achieved a CHOP-INTEND score ≥ 40, 14 patients (63.6%) hadachieved a CHOP-INTEND score ≥ 50, and 9 patients (40.9%) had achieved a CHOP-INTEND score≥ 58. Patients with untreated SMA Type 1 almost never achieve a CHOP-INTEND score ≥ 40. Motormilestone achievement was observed in some patients despite plateauing of CHOP-INTEND. No clearcorrelation was observed between CHOP-INTEND scores and motor milestone achievement.

Figure 2 CHOP-INTEND motor function scores - Study CL-303 (N=22)0 2 4 6 8 10 12 14 16 18 20

Age (months)001-001 001-002 001-003 002-001 003-001 004-002 005-001 005-002 006-001 008-001 008-003008-004 008-005 009-001 009-002 010-001 010-002 012-001 014-001 014-002 014-003 015-001

AVXS-101-CL-302 Phase 3 study in patients with Type 1 SMA

AVXS-101-CL-302 (Study CL-302) is a Phase 3, open-label, single-arm, single-dose study ofintravenous administration of onasemnogene abeparvovec at the therapeutic dose (1.1 × 1014 vg/kg).

Thirty-three patients were enrolled with Type 1 SMA and 2 copies of SMN2. Before treatment withonasemnogene abeparvovec, 9 patients (27.3%) reported ventilatory support and 9 patients (27.3%)reported feeding support. The mean CHOP-INTEND score of the 33 patients at baseline was 27.9(range, 14 to 55). The mean age of the 33 patients at the time of treatment was 4.1 months (range, 1.8to 6.0 months).

Of the 33 enrolled patients (Efficacy Completers population), one patient (3%) was dosed outside ofprotocol age range and was therefore not included in the intent-to-treat (ITT) population. Of the32 patients in the ITT population, one patient (3%) died during the study, due to disease progression.

Of the 32 patients in the ITT population, 14 patients (43.8%) achieved the milestone of sitting withoutsupport for at least 10 seconds at any visit up to and including the 18 month visit (primary efficacyendpoint). The median age when this milestone was first achieved was 15.9 months (range, 7.7 to18.6 months). Thirty-one patients (96.9%) in the ITT population survived without permanentventilation (i.e., event-free survival) to ≥ 14 months of age (secondary efficacy endpoint).

The additional video-confirmed developmental milestones for patients in the Efficacy Completerspopulation in Study CL-302 at any visit up to and including the 18 month visit are summarised in

Table 5.

CHOP-INTEND score

Table 5 Median time to video documented achievement of motor milestones in Study CL-302(Efficacy Completers population)

Video documented Number of patients Median age to 95% Confidence intervalmilestone achieving milestone the milestonen/N (%) achievement(months)

Head control 23/30* (76.7) 8.0 (5.8, 9.2)

Rolls from back to sides 19/33 (57.6) 15.3 (12.5, 17.4)

Sits without support for 16/33 (48.5) 14.3 (8.3, 18.3)at least 30 seconds

* 3 patients were reported to have head control by clinician assessment at baseline.

One patient (3%) achieved the motor milestones of crawling, standing with assistance, stands alone,walking with assistance, and walking alone all by the age of 18 months.

Of the 33 enrolled patients, 24 patients (72.7%) achieved a CHOP-INTEND score ≥ 40, 14 patients(42.4%) achieved a CHOP-INTEND score ≥ 50, and 3 patients (9.1%) achieved a CHOP-INTENDscore ≥ 58 (see Figure 3). Patients with untreated SMA Type 1 almost never achieve a

CHOP-INTEND score ≥ 40.

Figure 3 CHOP-INTEND motor function scores in Study CL-302 (Efficacy Completerspopulation; N=33)*

Age (Months)

*Note: The total score programmatically calculated for one patient ( ) at Month 7 (totalscore=3) is considered invalid. All items were not scored and the total score should have been set to

Missing (i.e. not calculated).

AVXS-101-CL-101 Phase 1 study in patients with Type 1 SMA

The results seen in Study CL-303 are supported by study AVXS-101-CL-101 (Study CL-101) aphase 1 study in patients with Type 1 SMA, in which onasemnogene abeparvovec was administered asa single intravenous infusion in 12 patients from 3.6 kg to 8.4 kg (0.9 to 7.9 months of age). At14 months of age, all treated patients were event-free; i.e. survived without permanent ventilation,compared to 25% in the natural history cohort. At the end of the study (24 months post-dose), alltreated patients were event-free, compared to less than 8% in the natural history, see Figure 1.

CHOP-INTEND Score

At 24 months of follow up post-dose, 10 out of 12 patients were able to sit without support for≥ 10 seconds, 9 patients were able to sit without support for ≥ 30 seconds and 2 patients were able tostand and walk without assistance. One out of 12 patients did not achieve head control as themaximum motor milestone before the age of 24 months. Ten of 12 patients from Study CL-101continue to be followed in a long-term study (for up to 6.6 years after dosing) and all 10 patients werealive and free of permanent ventilation as of 23 May 2021. All patients have either maintainedpreviously attained milestones or gained new milestones such as sitting with support, standing withassistance and walking alone. Five of the 10 patients received concomitant nusinersen or risdiplamtreatment at some point during the long-term study. Maintenance of efficacy and achievement ofmilestones can therefore not be solely attributed to onasemnogene abeparvovec in all patients. Themilestone of standing with assistance was newly acquired by 2 patients who had not receivednusinersen or risdiplam at any point prior to the time this milestone was achieved.

AVXS-101-CL-304 Phase 3 study in patients with pre-symptomatic SMA

Study CL-304 is a global, Phase 3, open-label, single-arm, single-dose study of intravenousadministration of onasemnogene abeparvovec in pre-symptomatic newborn patients up to 6 weeks ofage with 2 (cohort 1, n=14) or 3 (cohort 2, n=15) copies of SMN2.

Cohort 1

The 14 treated patients with 2 copies of SMN2 were followed to 18 months of age. All patientssurvived event-free to ≥ 14 months of age without permanent ventilation.

All 14 patients achieved independent sitting for at least 30 seconds at any visit up to the 18 months ofage visit (primary efficacy endpoint), at ages ranging from 5.7 to 11.8 months, with 11 of the14 patients who achieved independent sitting at or before 279 days of age, the 99th percentile fordevelopment of this milestone. Nine patients achieved the milestone of walking alone (64.3%). All14 patients achieved a CHOP-INTEND score ≥ 58 at any visit up to the 18 months of age visit. Nopatients required any ventilatory support or any feeding support during the study.

Cohort 2

The 15 treated patients with 3 copies of SMN2 were followed to 24 months of age. All patientssurvived event-free to 24 months of age without permanent ventilation.

All 15 patients were able to stand alone without support for at least 3 seconds (primary efficacyendpoint), at ages ranging from 9.5 to 18.3 months, with 14 of the 15 patients who achieved standingalone at or before 514 days of age, the 99th percentile for development of this milestone. Fourteenpatients (93.3%) were able to walk at least five steps independently. All 15 patients achieved a scaledscore of ≥ 4 on Bayley-III Gross and Fine Motor Subtests within 2 standard deviations of the mean forage at any post-baseline visit up to 24 months of age. No patients required any ventilatory support orany feeding support during the study.

COAV101A12306 Phase 3 study in patients with SMA weighing ≥ 8.5 kg to ≤ 21 kg

Study COAV101A12306 is a completed, Phase 3, open-label, single-arm, single-dose, multi-centrestudy of intravenous administration of onasemnogene abeparvovec at the therapeutic dose(1.1 × 1014 vg/kg) in 24 paediatric patients with SMA weighing ≥ 8.5 kg to ≤ 21 kg (median weight:

15.8 kg). The patients ranged in age from approximately 1.5 to 9 years at the time of administration.

Patients had 2 to 4 copies of SMN2 (two [n=5], three [n=18], four [n=1] copies). Before treatment withonasemnogene abeparvovec, 19/24 patients had previously received nusinersen for a median durationof 2.1 years (range 0.17 to 4.81 years), and 2/24 patients had previously received risdiplam for amedian duration of 0.48 years (range 0.11 to 0.85 years). At baseline, patients had a mean

Hammersmith Functional Motor Scale - Expanded (HFMSE) score of 28.3 and a mean Revised Upper

Limb Module (RULM) score of 22.0. In addition, all patients demonstrated the milestones of headcontrol and sitting with support, twenty-one were able to sit without support, and six demonstrated thehighest possible achievable milestones of standing alone and walking alone.

At Week 52, the mean change from baseline in overall HFMSE total score was 3.7 (18/24 patients).

The mean increase in overall RULM total score was 2.0 (17/24 patients) at Week 52. Four patientsachieved new developmental milestones. Milestones observed at the baseline visit were maintained to

Week 52 for the majority of patients. Two patients who did not demonstrate previously achieveddevelopmental milestones showed improvement in the HFMSE score from baseline to Week 52.

Onasemnogene abeparvovec has not been studied in patients with a bi-allelic mutation of the

SMN1 gene and only one copy of SMN2 in clinical studies.

The European Medicines Agency has deferred the obligation to submit the results of studies withonasemnogene abeparvovec in one or more subsets of the paediatric population in spinal muscularatrophy for the granted indication (see section 4.2 for information on paediatric use).

Onasemnogene abeparvovec vector shedding studies, which assess the amount of vector eliminatedfrom the body through saliva, urine, faeces and nasal secretions were performed.

Onasemnogene abeparvovec vector DNA was detectable in shedding samples post-infusion.

Onasemnogene abeparvovec shedding was primarily via faeces. Peak shedding in most patients wasobserved within 7 days post-dose for faeces, and within 2 days post-dose for saliva, urine, and nasalsecretions. The majority of the vector is cleared within 30 days after dose administration.

Biodistribution was evaluated in 2 patients who died 5.7 months and 1.7 months, respectively, afterinfusion of onasemnogene abeparvovec at the dose of 1.1 x 1014 vg/kg. Both cases showed that thehighest levels of vector DNA were found in the liver. Vector DNA was also detected in the spleen,heart, pancreas, inguinal lymph node, skeletal muscles, peripheral nerves, kidney, lung, intestines,gonads, spinal cord, brain, and thymus. Immunostaining for SMN protein showed generalized SMNexpression in spinal motor neurons, neuronal and glial cells of the brain, and in the heart, liver,skeletal muscles, and other tissues evaluated.

Following intravenous administration in neonatal mice, vector was widely distributed, with the highestvector DNA levels generally detected in the heart, liver, lungs and skeletal muscle. The expression oftransgene mRNA showed similar patterns. Following intravenous administration in juvenilenon-human primates, vector was widely distributed with subsequent expression of transgene mRNA,with the highest concentrations of vector DNA and transgene mRNA tending to occur in the liver,muscle, and heart. Vector DNA and transgene mRNA in both species was detected in the spinal cord,brain, and gonads.

In pivotal 3-month mouse toxicology studies, the main target organs of toxicity identified were theheart and liver. Onasemnogene abeparvovec-related findings in the ventricles of the heart werecomprised of dose-related inflammation, oedema and fibrosis. In the atria of the heart, inflammation,thrombosis, myocardial degeneration/necrosis and fibroplasia were observed. A No Adverse Effect

Level (NoAEL) was not identified for onasemnogene abeparvovec in mouse studies as ventricularmyocardial inflammation/oedema/fibrosis and atrial inflammation were observed at the lowest dosetested (1.5 × 1014 vg/kg). This dose is regarded as the Maximum Tolerated Dose and approximately1.4-fold the recommended clinical dose. Onasemnogene abeparvovec-related mortality was, in themajority of mice, associated with atrial thrombosis, and observed at 2.4 × 1014 vg/kg. The cause of themortality in the rest of the animals was undetermined, although microscopic degeneration/regenerationin the hearts of these animals was found.

Liver findings in mice were comprised of hepatocellular hypertrophy, Kupffer cell activation, andscattered hepatocellular necrosis. In long-term toxicity studies with intravenous and intrathecal (notindicated for use) administration of onasemnogene abeparvovec in juvenile non-human primates, liverfindings, including single cell necrosis of hepatocytes and oval cell hyperplasia, demonstrated partial(IV) or complete (IT) reversibility.

In a 6-month toxicology study conducted in juvenile non-human primates, administration of a singledose of onasemnogene abeparvovec at the clinically recommended intravenous dose, with or withoutcorticosteroid treatment, resulted in acute, minimal to slight mononuclear cell inflammation andneuronal degeneration in the dorsal root ganglia (DRG) and trigeminal ganglia (TG), as well as axonaldegeneration and/or gliosis in the spinal cord. At 6 months, these non-progressive findings resulted infull resolution in the TG, and partial resolution (decreased incidence and/or severity) in the DRG andspinal cord. Following intrathecal administration of onasemnogene abeparvovec (not indicated foruse), these acute, non-progressive findings were noted with minimal to moderate severity in juvenilenon-human primates with partial to full resolution at 12 months. These findings in non-humanprimates had no correlative clinical observations, therefore the clinical relevance in humans isunknown.

Genotoxicity, carcinogenicity and reproduction toxicity studies have not been conducted withonasemnogene abeparvovec.

Tromethamine

Magnesium chloride

Sodium chloride

Poloxamer 188

Hydrochloric acid (for pH adjustment)

Water for injections

In the absence of compatibility studies, this medicinal product should not be mixed with othermedicinal products.

2 years

After thawing

Once thawed, the medicinal product should not be re-frozen and may be stored refrigerated at 2°C to8°C in the original carton for 14 days.

Once the dose volume is drawn into the syringe it must be infused within 8 hours. Discard the vectorcontaining syringe if not infused within the 8-hour timeframe.

Store and transport frozen (≤ -60°C).

Store in a refrigerator (2°C to 8°C) immediately upon receipt.

Store in the original carton.

For storage conditions after thawing of the medicinal product, see section 6.3.

The date of receipt should be marked on the original carton before the product is stored in therefrigerator.

Onasemnogene abeparvovec is supplied in a vial (10 mL polymer crystal zenith) with stopper (20 mmchlorobutyl rubber) and seal (aluminum, flip-off) with a coloured cap (plastic), in two different vial fillvolume sizes, either 5.5 mL or 8.3 mL.

The dose of onasemnogene abeparvovec and exact number of vials required for each patient iscalculated according to the patient’s weight (see section 4.2 and Table 6 below).

Table 6 Carton/kit configurations

Patient weight (kg) 5.5 mL viala 8.3 mL vialb Total vials per carton2.6 - 3.0 0 2 23.1 - 3.5 2 1 33.6 - 4.0 1 2 34.1 - 4.5 0 3 34.6 - 5.0 2 2 45.1 - 5.5 1 3 45.6 - 6.0 0 4 46.1 - 6.5 2 3 56.6 - 7.0 1 4 57.1 - 7.5 0 5 57.6 - 8.0 2 4 68.1 - 8.5 1 5 68.6 - 9.0 0 6 69.1 - 9.5 2 5 79.6 - 10.0 1 6 710.1 - 10.5 0 7 710.6 - 11.0 2 6 811.1 - 11.5 1 7 811.6 - 12.0 0 8 812.1 - 12.5 2 7 912.6 - 13.0 1 8 913.1 - 13.5 0 9 913.6 - 14.0 2 8 1014.1 - 14.5 1 9 1014.6 - 15.0 0 10 1015.1 - 15.5 2 9 1115.6 - 16.0 1 10 1116.1 - 16.5 0 11 1116.6 - 17.0 2 10 1217.1 - 17.5 1 11 1217.6 - 18.0 0 12 1218.1 - 18.5 2 11 1318.6 - 19.0 1 12 1319.1 - 19.5 0 13 1319.6 - 20.0 2 12 14

Patient weight (kg) 5.5 mL viala 8.3 mL vialb Total vials per carton20.1 - 20.5 1 13 1420.6 - 21.0 0 14 14a Vial nominal concentration is 2 × 1013 vg/mL and contains an extractable volume of not lessthan 5.5 mL.b Vial nominal concentration is 2 × 1013 vg/mL and contains an extractable volume of not lessthan 8.3 mL.

Receipt and thawing vials

* Vials will be transported frozen (≤ -60ºC). Upon receipt vials should be refrigerated at2°C to 8°C immediately, and in the original carton. Onasemnogene abeparvovec therapy shouldbe initiated within 14 days of receipt of vials.

* Vials must be thawed before use. Do not use onasemnogene abeparvovec unless thawed.

* For packaging configurations containing up to 9 vials, product will be thawed afterapproximately 12 hours in the refrigerator. For packaging configurations containing up to14 vials, product will be thawed after approximately 16 hours in the refrigerator. Alternatively,and for immediate use, thawing may be performed at room temperature.

* For packaging configurations containing up to 9 vials, thawing will occur from frozen state afterapproximately 4 hours at room temperature (20°C to 25°C). For packaging configurationscontaining up to 14 vials, thawing will occur from frozen state after approximately 6 hours atroom temperature (20°C to 25°C)

* Before drawing the dose volume into the syringe, gently swirl the thawed product. Do NOTshake.

* Do not use this medicine if you notice any particles or discolouration once the frozen producthas thawed and prior to administration.

* Once thawed, the medicinal product should not be re-frozen.

* After thawing, onasemnogene abeparvovec should be given as soon as possible. Once the dosevolume is drawn into the syringe it must be infused within 8 hours. Discard thevector-containing syringe if not infused within the 8-hour timeframe.

Administration of onasemnogene abeparvovec to the patient

To administer onasemnogene abeparvovec, draw the entire dose volume into the syringe. Remove anyair in the syringe before intravenous infusion through a venous catheter.

Precautions to be taken for the handling, disposal and accidental exposure to the medicinal product

This medicinal product contains genetically-modified organisms. Appropriate precautions for thehandling, disposal or accidental exposure of onasemnogene abeparvovec should be followed:

* The onasemnogene abeparvovec syringe should be handled aseptically under sterile conditions.

* Personal protective equipment (to include gloves, safety goggles, laboratory coat and sleeves)should be worn while handling or administering onasemnogene abeparvovec. Personnel shouldnot work with onasemnogene abeparvovec if skin is cut or scratched.

* All spills of onasemnogene abeparvovec must be wiped with absorbent gauze pad and the spillarea must be disinfected using a bleach solution followed by alcohol wipes. All clean upmaterials must be double bagged and disposed of per local guidelines for handling of biologicalwaste.

* Any unused medicinal product or waste material should be disposed of in accordance with localguidelines on handling of biological waste.

* All materials that may have come in contact with onasemnogene abeparvovec (e.g. vial, allmaterials used for injection, including sterile drapes and needles) must be disposed of inaccordance with local guidelines on handling of biological waste.

* Accidental exposure to onasemnogene abeparvovec must be avoided. In the event of exposureto skin, the affected area must be thoroughly cleaned with soap and water for at least15 minutes. In the event of exposure to eyes, the affected area must be thoroughly flushed withwater for at least 15 minutes.

Shedding

Temporary onasemnogene abeparvovec shedding may occur, primarily through bodily waste.

Caregivers and patient families should be advised on the following instructions for the proper handlingof patient bodily fluids and waste:

* Good hand-hygiene (wearing protective gloves and washing hands thoroughly afterwards withsoap and warm running water, or an alcohol-based hand sanitiser) is required when coming intodirect contact with patient bodily fluids and waste for a minimum of 1 month afteronasemnogene abeparvovec treatment.

* Disposable nappies should be sealed in double plastic bags and can be disposed of in householdwaste.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/20/1443/001

EU/1/20/1443/002

EU/1/20/1443/003

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Date of first authorisation: 18 May 2020

Date of latest renewal: 17 May 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.