ZOLGENSMA 2 X 10^13 VECTOR GENOMES/ML SOLUTION FOR INFUSION - summary of medicine characteristics

Zolgensma 2 × 1013 vector genomes/mL solution for infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

2.1 General description

Onasemnogene abeparvovec is a gene therapy medicinal product that expresses the human survival motor 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 the cytomegalovirus enhancer/chicken-P-actin-hybrid promoter.

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

2.2 Qualitative and quantitative composition

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

Excipient with known effect

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.

4.1 Therapeutic indications

Zolgensma is indicated for the treatment of:

– patients with 5q spinal muscular atrophy (SMA) with a bi-allelic mutation in the SMN1 gene and 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.

4.2 Posology and method of administration

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

Before administration of onasemnogene abeparvovec, baseline laboratory testing is required, including:

AAV9 antibody testing using an appropriately validated assay,

liver function: alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin,

creatinine,

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

troponin-I.

The need for close monitoring of liver function, platelet count and troponin-I after administration and the need for corticosteroid treatment are to be considered when establishing the timing of onasemnogene abeparvovec treatment (see section 4.4).

In case of acute or chronic uncontrolled active infections, treatment should be postponed until the infection has resolved or is controlled (see sub-sections 4.2 and 4.4 immunomodu­latory regimen).

Posology

For single-dose intravenous infusion only.

Patients will receive a dose of nominal 1.1 × 1014 vg/kg onasemnogene abeparvovec.

The total volume is 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

NOTE: Number of vials per kit and required number of kits is weight-dependent. Dose volume is calculated using the upper limit of the patient weight range.

Immunomodulatory regimen

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

Prior to initiation of the immunomodulatory regimen and prior to administration of onasemnogene abeparvovec, the patient must be checked for symptoms of active infectious disease of any nature.

Starting 24 hours prior to infusion of onasemnogene abeparvovec it is recommended to initiate an immunomodulatory regimen following the schedule below (see Table 2). Deviations from these recommendations are at the discretion of the treating physician (see section 4.4).

Table 2 Pre- and post-infusion immunomodulatory regimen

A paediatric gastroenterologist or hepatologist should be consulted if patients do not respond adequately to the equivalent of 1 mg/kg/day oral prednisolone (see section 4.4). If oral corticosteroid therapy is not tolerated intravenous corticosteroid may be considered as clinically indicated.

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

Special populations

Renal impairment

The safety and efficacy of onasemnogene abeparvovec have not been established in patients with renal impairment and onasemnogene abeparvovec therapy should be carefully considered. A dose adjustment should not be considered.

Hepatic impairment

Patients with ALT, AST, or total bilirubin levels (except due to neonatal jaundice) >2 x ULN have not been studied in clinical studies with onasemnogene abeparvovec. Onasemnogene abeparvovec therapy should be carefully considered in patients with hepatic 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 and only 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 above 1:50 (see section 4.4).

Paediatric population

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 of onasemnogene abeparvovec should be carefully considered because concomitant treatment with corticosteroids 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).

Method of administration

For intravenous use.

Onasemnogene abeparvovec is administered as a single-dose intravenous infusion. It should be administered with a syringe pump as a single intravenous infusion with a slow infusion of approximately 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 primary catheter. Following completion of infusion, the line should be flushed with sodium chloride 9 mg/mL (0.9%) solution for injection.

Precautions to be taken before handling or administering the medicinal product

This medicinal product contains a genetically-modified organism. Healthcare professionals should therefore 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 (including proper handling of bodily waste) of onasemnogene abeparvovec, see section 6.6.

4.3 Contraindications

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

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.

Pre-existing immunity against AAV9

Anti-AAV9 antibody formation can take place after natural exposure. There have been several studies on the prevalence of AAV9 antibodies in the general population that show low rates of prior exposure to AAV9 in the paediatric population. Patients should be tested for the presence of AAV9 antibodies prior to infusion with onasemnogene abeparvovec. Re-testing may be performed if AAV9 antibody titres are reported as above 1:50. It is not yet known whether or under what conditions onasemnogene abeparvovec can be safely and effectively administered in the presence of anti-AAV9 antibodies above 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 of onasemnogene abeparvovec in symptomatic patients depends on the degree of disease burden at the time of treatment, with earlier treatment resulting in potential higher benefit. While advanced symptomatic SMA patients will not achieve the same gross motor development as unaffected healthy peers they may clinically benefit from gene replacement therapy, dependent on the advancement of disease at the time of treatment (see section 5.1).

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

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

Immunogenicity

An immune response to the AAV9 capsid will occur after infusion of onasemnogene abeparvovec, including antibody formation against the AAV9 capsid despite the immunomodulatory regimen recommended in section 4.2, and T-cell mediated immune response.

Systemic immune response, including immune-mediated hepatotoxicity, generally manifested as elevated ALT and/or AST levels and at times as acute serious liver injury or acute liver failure, has been reported with onasemnogene abeparvovec use. Immune-mediated hepatotoxicity may require adjustment of the immunomodulatory regimen including longer duration, increased dose, or prolongation of the corticosteroid taper. Refer to section 4.2 for immunomodulatory regimen, and to the sub-sections ‘Hepatotoxicity’ and ‘Immunomodulatory regimen’ below for details.

Hepatotoxicity

Administration of AAV vector may result in aminotransferase elevations, which may be serious.

Acute serious liver injury and acute liver failure have occurred (see section 4.8).

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

Prior to infusion, liver function of all patients should be assessed by clinical examination and laboratory testing (e.g. hepatic aminotransferases AST and ALT, and total bilirubin (see section 4.2)).

In order to mitigate potential aminotransferase elevations, a systemic corticosteroid should be administered to all patients before and after onasemnogene abeparvovec infusion (see section 4.2).

Liver function should be monitored for at least 3 months after infusion.

The risks and benefits of infusion with onasemnogene abeparvovec in patient with pre-existing hepatic impairment should be weighed carefully against the risks of not treating the patient.

AST/ALT/bilirubin should be assessed weekly for 30 days and every two weeks for an additional 60 days post administration of onasemnogene abeparvovec through to

the end of the corticosteroid taper period, or longer if needed. Tapering of

prednisolone should not be considered until AST/ALT levels are less than 2 x ULN.

Thrombocytopenia

Transient decreases in platelet counts, some of which met the criteria for thrombocytopenia, were observed in onasemnogene abeparvovec clinical studies. In most cases, the lowest platelet value occurred the first week following onasemnogene abeparvovec infusion. Platelet counts should be obtained before onasemnogene abeparvovec infusion and should be closely monitored in the week following infusion and on a regular basis afterwards, weekly for the first month and every other week for the second and third months until platelet counts return to baseline.

Thrombotic microangiopathy

Cases of thrombotic microangiopathy (TMA) have been reported to occur approximately one week after onasemnogene abeparvovec infusion in the postmarketing setting (see section 4.8). TMA is an acute and life-threatening condition, which is characterised by thrombocytopenia and microangiopathic haemolytic anaemia. Acute kidney injury has also been observed. In some cases, concurrent immune system activation (e.g. infections, vaccinations) has been reported (see sections 4.2 and 4.5 for information on administration of vaccinations).

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

Elevated troponin-I

Increases in cardiac troponin-I levels following infusion with onasemnogene abeparvovec were observed (see section 4.8). Elevated troponin-I levels found in some patients may indicate potential myocardial tissue injury. Based on these findings and the observed cardiac toxicity in mice, troponin-I levels should be obtained before onasemnogene abeparvovec infusion and monitored for at least 3 months following onasemnogene abeparvovec infusion or until levels return to within normal reference range for SMA patients. Consider consultation with a cardiac expert as needed.

Immunomodulatory regimen

Immunomodulatory treatment should not be initiated concurrently to active infections, either acute (such as acute respiratory infections or acute hepatitis) or uncontrolled chronic (such as chronic active hepatitis B) (see sections 4.2 and 4.4).

The immunomodulatory regimen (see section 4.2) might also impact the immune response to concurrent infections (e.g. respiratory), potentially resulting in more severe clinical courses of the concurrent infection. Added caution is advised regarding the timing of onasemnogene abeparvovec dosing in the presence of prodrome or resolving infection. Increased vigilance in the diagnosis and active management of infection is recommended. Seasonal prophylactic treatments, that prevent respiratory syncytial virus (RSV) infections, are recommended and should be up to date. Where feasible, the patient’s vac­cination schedule should be adjusted to accommodate concomitant 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 physician should be aware of the possibility of adrenal insufficiency.

Shedding

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

Good hand-hygiene is required when coming into direct contact with patient bodily waste for a minimum of 1 month after onasemnogene abeparvovec treatment.

Disposable nappies can be sealed in double plastic bags and disposed of in household waste.

Blood, organ, tissue and cell donation

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

Sodium content

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

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

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

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

Vaccinations

Where feasible, the patient’s vac­cination schedule should be adjusted to accommodate concomitant corticosteroid administration prior to and following onasemnogene abeparvovec infusion (see sections 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 steroid dose (i.e., > 2 weeks of daily receipt of 20 mg or 2 mg/kg body weight of prednisolone or equivalent).

4.6 Fertility, pregnancy and lactation

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

5   PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other drugs for disorders of the musculo-skeletal system, ATC code: M09AX09

Mechanism of action

Onasemnogene abeparvovec is a gene therapy designed to introduce a functional copy of the survival motor 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 to promote the survival and function of transduced motor neurons.

Onasemnogene abeparvovec is a non-replicating recombinant AAV vector that utilizes AAV9 capsid to deliver a stable, fully functional human SMN transgene. The ability of the AAV9 capsid to cross the blood brain barrier and transduce motor neurons has been demonstrated. The SMN1 gene present in onasemnogene abeparvovec is designed to reside as episomal DNA in the nucleus of transduced cells and 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 a self-complementary double-stranded molecule.

Expression of the transgene is driven by a constitutive promoter (cytomegalovirus enhanced chicken-P-actin-hybrid), which results in continuous and sustained SMN protein expression. Proof of the mechanism of action has been supported by non-clinical studies and by human biodistributi­on data.

Clinical efficacy and safety

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 of intravenous 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 with onasemnogene 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) score at baseline was 32.0 (range, 18 to 52). The mean age of the 22 patients at the time of treatment was 3.7 months (0.5 to 5.9 months).

Of the 22 enrolled patients, 21 patients survived without permanent ventilation (i.e., event-free survival) to >10.5 months of age, 20 patients survived to >14 months of age (co-primary efficacy endpoint), 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 permanent ventilation) leading to 90.9% (95% CI: 79.7%, 100.0%) event-free survival (alive without permanent ventilation) at 14 months of age, see Figure 1.

0.4 –

304/2 Copy NeuroNext PNCR

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

With Number of Subjects at Risk

0.8 –

0.6 –

0.2 –

303

PNCR

101/Coh 2

304/2 Copy

302 * NeuroNext

PNCR = Pediatric Neuromuscular Clinical Research natural history cohort

NeuroNext = Network for Excellence in Neuroscience Clinical Trials natural history cohort * AVXS-101-CL-302 is an ongoing Phase 3 multicenter, open-label, single-arm, single-dose study of AVXS-101 (gene replacement therapy) in patients with SMA Type 1 with 1 or 2 copies of the SMN2 gene similar to study AVXS-101-CL-303. At the time of the 11 June 2020 data cutoff, the 33 enrolled and treated patients had been in the study for an average of 13.07 months (range: 1.8 to 16.4 months).

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

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

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

One patient (4.5%) could also walk with assistance at 12.9 months. Based on the natural history of the disease, patients who met the study entry criteria would not be expected to attain the ability to sit without support. In addition, 18 of the 22 patients were independent of ventilatory support at 18 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%) had achieved 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. Motor milestone achievement was observed in some patients despite plateauing of CHOP-INTEND. No clear correlation was observed between CHOP-INTEND scores and motor milestone achievement.

Figure 2

CHOP-INTEND motor function scores – Study CL-303

--001–001    --001–002    --001–003    -— 002–001    --003–00i    --004–002    --005–001    --005–002    --0Q6–00i    --008–001    --008–003

--008–004   –008–005   --009–001   -—009–002   --010–001   --010–002   --012–001   --014–001    --014–002   --014–003   -*-015–001

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

The results seen in Study 303 are supported by study AVXS-101-CL-101 (Study CL-101) a phase 1 study in patients with Type 1 SMA, in which onasemnogene abeparvovec was administered as a single intravenous infusion in 12 patients from 3.6 kg to 8.4 kg (0.9 to 7.9 months of age). At 14 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), all treated patients were event-free, compared to less than 8% in the natural history, see Figure 1.

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 to stand and walk without assistance. One out of12 patients did not achieve head control as the maximum motor milestone before the age of 24 months. Ten of 12 patients from Study CL-101 continue to be followed in a long-term study (for up to 5.5 years after dosing) and all have either maintained previously attained milestones or gained new milestones such as sitting with support, standing with assistance and walking alone. Four of the 10 patients received concomitant nusinersen treatment at some point during the long-term study. Maintenance of efficacy and achievement of milestones can therefore not be solely attributed to onasemnogene abeparvovec in all patients. The milestone of standing with assistance was newly acquired by 2 patients who were not receiving nusinersen.

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

Study CL-304 is an ongoing, global, Phase 3, open-label, single-arm, single-dose, multicenter study of IV AVXS-101 in pre-symptomatic newborn patients up to 6 weeks of age with 2 (cohort 1, n=14) or 3 (cohort 2, n=15) copies of SMN2.

Cohort 1

At the time of the last study visit prior to 11 June 2020, the 14 treated patients with 2 copies of SMN2 had a median age of 15.6 months (range: 8.8 to 18.8 months) and had been in the study for amedian of 14.9months (range: 8.0 to 18.4 months). All patients were alive and free of permanent ventilation as of their last study visit prior to 11 June 2020.

Elevan patients achieved independent sitting for at least 30 seconds, at ages ranging from 5.7 to 11.8 months, with 10 of the 11 patients achieving independent sitting at or before 9.2 months of age, the 99th percentile for development of this milestone. Four patients achieved the milestone of walking alone (28.6%). Thirteen patients (92.9%) achieved a CHOP-INTEND score > 58 as of the 11 June 2020 data cut-off.

Cohort 2

At the time of the last study visit prior to 11 June 2020, the 15 treated patients with 3 copies of SMN2 had a median age of 15.2 months (range: 3.3 to 21.1 months) and had been in the study for a median of 14.5 months (range: 2.0 to 19.9 months). All patients were alive and free of permanent ventilation as of their last study visit prior to 11 June 2020.

Thirteen of 15 patients were able to sit without support for at least 30 seconds, 8 patients were able to stand alone without support for at least 3 seconds, and 6 patients were able to walk at least five steps independently.

At the time of the 11 June 2020 data cut-off, patients with 3 copies of SMN2 who have not yet achieved the Cohort 2 primary endpoint developmental milestone of standing alone without support for at least 3 seconds were 3.3 to 16.4 months of age as of the last attended visit. Based on the age at the time of the last attended visit, these patients remain within the normal age development window for these milestones. Due to the large heterogeneity in clinical presentation of patients with 3 SMN2 copies, no definitive conclusions about the benefit in this patient population can be drawn based on the interim follow-up data.

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.

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.

The licensing authority has deferred the obligation to submit the results of studies with onasemnogene abeparvovec in one or more subsets of the paediatric population in spinal muscular atrophy for the granted indication (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

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

Onasemnogene abeparvovec was detectable in shedding samples post-infusion. Clearance of onasemnogene abeparvovec was primarily via faeces and the majority is cleared within 30 days after dose administration.

Biodistribution was evaluated in 2 patients who died 5.7 months and 1.7 months, respectively, after infusion of onasemnogene abeparvovec at the dose of 1.1 × 1014 vg/kg. Both cases showed that the highest 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 SMN expression in spinal motor neurons, neuronal and glial cells of the brain, and in the heart, liver, skeletal muscles, and other tissues evaluated.

5.3 Preclinical safety data

Following intravenous administration in neonatal mice, vector and transgene were widely distributed with the highest expression generally observed in heart and liver, and substantial expression in the brain and spinal cord. In pivotal 3-month mouse toxicology studies, the main target organs of toxicity identified were the heart and liver. Onasemnogene abeparvovec-related findings in the ventricles of the heart were comprised of dose-related inflammation, oedema and fibrosis. In the atria of the heart, inflammation, thrombosis, myocardial degeneration/ne­crosis and fibroplasia were observed. Liver findings were comprised of hepatocellular hypertrophy, Kupffer cell activation, and scattered hepatocellular necrosis. A No Adverse Effect Level (NoAEL) was not identified for onasemnogene abeparvovec in mouse studies as ventricular myocardial inflammation/o­edema/fibrosis and atrial inflammation were observed at the lowest dose tested (1.5 × 1014 vg/kg). This dose is regarded as the Maximum Tolerated Dose and approximately 1.4-fold the recommended clinical dose. Onasemnogene abeparvovec-related mortality was, in the majority of mice, associated with atrial thrombosis, and observed at 2.4 × 1014 vg/kg. The cause of the mortality in the rest of the animals was undetermined, although microscopic degeneration/re­generation in the hearts of these animals was found.

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

In a toxicology study conducted in young adult non-human primates, administration of a single dose of 3 × 1013 vg/NHP (median dose 1.08 × 1013 vg/kg) onasemnogene abeparvovec intrathecally with Trendelenburg position, without corticosteroid treatment, resulted in minimal to marked mononuclear cell inflammation (primarily lymphocytes) in some dorsal root ganglia from all examined spinal cord levels, with neuronal satellitosis, neuronal necrosis, or complete neuronal loss with rare mineralization. The clinical relevance of this finding is unknown.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tromethamine

Magnesium chloride

Sodium chloride

Poloxamer 188

Hydrochloric acid (for pH adjustment)

Water for injections

6.2 Incompatibilities

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

6.3 Shelf life

1 year

After thawing

Once thawed, the medicinal product should not be re-frozen and may be stored refrigerated at 2°C to 8°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 vector containing syringe if not infused within the 8-hour timeframe.

6.4 Special precautions for storage

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 the refrigerator.

6.5 Nature and contents of container

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

The dose of onasemnogene abeparvovec and exact number of vials required for each patient is calculated according to the patient’s weight (see section 4.2 and Table 5 below).

Table 5____________­_Carton/kit configurations

a

b

Vial nominal concentration is 2 × 1013 vg/mL and contains an extractable volume of not less than 5.5 mL.

Vial nominal concentration is 2 × 1013 vg/mL and contains an extractable volume of not less than 8.3 mL.