onasemnogene abeparvovec: prescribing information – dosing, contraindications, interactions, side effects

Itvisma is indicated for the treatment of 5q spinal muscular atrophy (SMA) with a bi-allelic mutation in the SMN1 gene in patients 2 years of age and older.

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 Itvisma, baseline laboratory testing is required, including, but not limited to:
- AAV9 antibody testing using an appropriately validated assay (see section 4.4),
- liver function: alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (see section 4.4),
- creatinine, and
- complete blood count (including haemoglobin and platelet count) (see section 4.4).

It is recommended that patients are clinically stable in their overall health status prior to injection (see section 4.4). The benefit-risk profile of Itvisma in patients with respiratory failure, on permanent ventilation, and/or unable to swallow is not established.

Because the treatment persists in non-dividing cells, patients previously treated with onasemnogene abeparvovec (any route of administration) should not be treated with Itvisma (see section 5.1).

Posology

Itvisma is administered as a single dose of 1.2 × 1014 vg.

Immunomodulatory regimen
To dampen an immune response, immunomodulation with corticosteroids is recommended. Elevations in liver aminotransferases or decreased platelet counts may occur following treatment (see sections 4.4 and 4.8). Where feasible, the patient’s vaccination schedule should be adjusted to accommodate concomitant corticosteroid administration prior to and following Itvisma injection (see section 4.5).

Table 1 shows the recommended immunomodulatory regimen prior to and following injection.

Table 1
Recommended immunomodulatory regimen pre- and post-injection

Pre-injection
24 hours prior to Itvisma injection
Prednisolone orally 1 mg/kg/day
(or equivalent)
Post-injection
30 days (including the day of Itvisma administration)
Prednisolone orally 1 mg/kg/day
(or equivalent)
Followed by 28 days:

For patients with unremarkable findings
(normal clinical exam, total bilirubin, and whose ALT and AST values are both below 2 × upper limit of normal (ULN)) at the end of the 30 days period:

or

Systemic corticosteroids should be tapered gradually.

Taper prednisolone (or equivalent if another corticosteroid is used), e.g. by decrements of 0.20 mg/kg/day per week over at least 4 weeks for oral prednisolone For patients with liver function abnormalities at the end of the 30 days period: continuing until the AST and ALT values are below 2 × ULN and all other assessments (e.g. total bilirubin) return to normal range, followed by tapering over 28 days or longer if needed.
Systemic corticosteroids
(equivalent to oral prednisolone
1 mg/kg/day)

Systemic corticosteroids should be tapered gradually.

If at any time patients do not respond adequately to the equivalent of 1 mg/kg/day oral prednisolone, based on the patient’s clinical course, prompt consultation with a gastroenterologist or hepatologist and adjustment to the recommended immunomodulatory regimen, including increased dose, longer duration or prolongation of corticosteroid taper, may be considered (see section 4.4). If oral corticosteroid therapy is not tolerated or not effective, intravenous corticosteroids 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 corticosteroid dose after 30 days should be taken as appropriate.

Special populations
Renal impairment
The safety and efficacy of Itvisma have not been established in patients with renal impairment. A dose adjustment should not be considered.

Hepatic impairment
Itvisma therapy should be carefully considered in patients with hepatic impairment (see section 4.4). A dose adjustment should not be considered.

Paediatric population
The safety and efficacy of Itvisma in children aged under 2 years have not been established. Currently available data are described in sections 4.8 and 5.1 but no recommendation on a posology can be made in children aged 6 months to ˂ 2 years. No data are available in children aged ˂ 6 months.

Adult population
No clinical study data are available in patients aged 18 years and older.

Method of administration

For intrathecal use. Treatment should be administered intrathecally using a lumbar puncture by healthcare professionals experienced in performing lumbar punctures.

• Immediately prior to dosing, draw the content from the vial into the syringe, remove air from the syringe, confirm the dose volume of 3 mL in the syringe, cap the syringe and deliver to the patient injection location.
• If indicated by the patient’s clinical status, sedation should be considered.
• Imaging techniques to guide intrathecal injection may be considered.
• The patient should be evaluated prior to and after intrathecal injection for the presence of potential conditions related to lumbar puncture, to avoid serious procedural complications.
• Prior to administration, remove 3 mL of cerebrospinal fluid (CSF) using a lumbar puncture needle.
• Itvisma is administered as a single-dose bolus intrathecal injection over approximately 1 to 2 minutes.
• Following intrathecal injection, placement in Trendelenburg position (depending on the patient’s clinical status) is recommended.

For detailed instructions on the preparation, handling, accidental exposure and disposal of the medicinal product, see section 6.6.

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

Summary of the safety profile

The safety data described in this section are from 127 patients from studies COAV101B12301, COAV101B12302 and COAV101A12102 over a 52-week follow-up period (see section 5.1). The most frequently reported adverse reactions following Itvisma administration were upper respiratory tract infection (41.7%), pyrexia (36.2%), vomiting (28.3%), headache (13.4%), and increased hepatic enzyme (9.4%). The most frequently reported serious adverse reactions were vomiting (2.4%), increased hepatic enzyme (1.6%), headache (1.6%) and pyrexia (1.6%). The adverse reactions reported were similar across studies.

Tabulated list of adverse reactions

The adverse reactions identified with Itvisma in patients treated with intrathecal injection at the recommended dose are presented in Table 2. Adverse reactions are classified according to MedDRA system organ classification and frequency. Frequency categories are derived according to the following conventions: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2
Tabulated list of adverse reactions to Itvisma

Adverse reactions by MedDRA SOC/PT and frequency
Infections and infestations
Very common
Upper respiratory tract infectiona)
Blood and lymphatic system disorders
Common
Thrombocytopeniab)
Nervous system disorders
Very common
Headachec)
Common
Dizzinessc)
Common
Peripheral sensory neuropathyd)
Common
Hypoaesthesia
Common
Paraesthesia
Gastrointestinal disorders
Very common
Vomiting
Hepatobiliary disorders
Common
Hepatic enzyme increasede)
General disorders and administration site conditions
Very common
Pyrexia a) Upper respiratory tract infection includes upper respiratory tract infection, viral upper respiratory tract infection, rhinitis, and oropharyngeal pain.
b) Thrombocytopenia includes thrombocytopenia and platelet count decreased.
c) Adverse reactions considered related to the lumbar puncture procedure.
d) Peripheral sensory neuropathy includes peripheral sensory neuropathy and neuropathy peripheral.
e) Hepatic enzyme increased includes hepatic enzyme increased, alanine aminotransferase increased, aspartate aminotransferase increased, hepatitis, hypertransaminasaemia and hepatic function abnormal.

Description of selected adverse reactions

Peripheral sensory neuropathy
In clinical studies, cases of peripheral sensory neuropathy (1.6%) have been observed within approximately three weeks following Itvisma administration. Patients presented with hypoaesthesia and paraesthesia. These cases required prolonged symptom management and some symptoms had not fully resolved at the end of the study (see section 4.4).

Hepatic laboratory abnormalities
In clinical studies, all patients received prophylaxis with corticosteroids. The majority of patients received the recommended immunomodulatory regimen with a median duration of approximately 60 days (see section 4.2). AST or ALT elevations > 3 × ULN were observed in 4.7% of patients following Itvisma administration. Serum transaminase elevations resolved with prednisolone treatment and patients recovered without clinical sequelae.

Immunogenicity
In the clinical studies COAV101B12301 and COAV101B12302, following a one-time Itvisma injection, increases from baseline in serum anti-AAV9 antibody titres occurred in all patients. Median serum anti-AAV9 antibody titres at 12 months following Itvisma injection were ˃ 1:800 000 in both studies. No clear association between post-administration anti-AAV9 antibody level and safety findings or loss of efficacy was seen in the studied population over the follow-up period of 12 months post-dose.

During the 12-month period following Itvisma injection in studies COAV101B12301 and COAV101B12302, positive anti-SMN antibodies were observed in 5/75 (6.7%) and 2/27 (7.4%) Itvisma-treated patients, respectively. No clear association can be made between a positive anti-SMN antibody response and safety or efficacy of Itvisma over the follow-up period of 12 months post-dose.

Reporting of suspected adverse reactions

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

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.

Reasons to postpone treatment

Due to the risk of serious immune response, it is recommended that patients are clinically stable in their overall health status (e.g. hydration and nutritional status, absence of infection, respiratory status) prior to injection. Itvisma should be postponed in patients with infection, either acute (e.g. respiratory) or chronic uncontrolled, until the infection has resolved and the patient is clinically stable. Clinical signs or symptoms of infection should not be evident at the time of injection.

Pre-existing immunity against AAV9

In Itvisma clinical studies, patients were required to have baseline serum anti-AAV9 antibody titres ≤ 1:50. The safety and efficacy of Itvisma in patients with elevated anti-AAV9 antibody titres have not been evaluated in humans.

Hepatotoxicity

Hepatotoxicity, which generally manifested as elevated ALT and/or AST levels, has occurred with onasemnogene abeparvovec intrathecal injection (see section 4.8). In order to mitigate potential aminotransferase elevations, a systemic corticosteroid should be administered to all patients before and after intrathecal injection. Immune-mediated hepatotoxicity may require adjustment of the immunomodulatory regimen including longer duration, increased dose, or prolongation of the corticosteroid taper (see section 4.2).

Patients with pre-existing hepatic impairment or acute hepatic viral infection may be at higher risk of liver injury. Patients with elevated liver function tests have not been studied in clinical studies with onasemnogene abeparvovec intrathecal injection.

Prior to onasemnogene abeparvovec intrathecal injection, liver function of all patients should be assessed by clinical examination and laboratory testing. Liver function should be monitored for at least 3 months after onasemnogene abeparvovec intrathecal injection administration, and at other times as clinically indicated. AST, ALT and total bilirubin should be assessed weekly for the first month after onasemnogene abeparvovec intrathecal injection administration and during the corticosteroid taper period. If the patient is clinically stable with unremarkable findings at the end of the corticosteroid taper period, liver function should continue to be monitored every two weeks for another month.
Tapering of systemic corticosteroids should not be considered until AST/ALT levels are less than 2 × ULN (see section 4.2).

Patients with worsening liver function test results and/or signs or symptoms of acute illness should be promptly clinically assessed and monitored closely. In case hepatic injury is suspected, further testing is recommended (e.g. albumin, prothrombin time, PTT and INR). Prompt consultation with a gastroenterologist or hepatologist is recommended, as necessary.

Thrombocytopenia

Transient decreases in platelet counts were typically observed within the first week after onasemnogene abeparvovec intrathecal injection administration. In most cases, platelet counts were ˃ 75 × 109/L and returned to baseline two weeks following onasemnogene abeparvovec intrathecal injection.

Platelet counts should be obtained before onasemnogene abeparvovec intrathecal injection and should be monitored on a regular basis afterwards, at least weekly for the first month and as clinically indicated until platelet counts return to baseline.

Thrombotic microangiopathy

Thrombotic microangiopathy (TMA) may occur. TMA is characterised by thrombocytopenia, microangiopathic haemolytic anaemia and acute kidney injury. Concurrent immune system activation (e.g. infections, vaccinations) may be a contributing factor.

Prompt attention to signs and symptoms of TMA is advised, as TMA can result in life-threatening or fatal outcomes.

Thrombocytopenia is a key feature of TMA, therefore platelet counts should be monitored on a regular basis following onasemnogene abeparvovec intrathecal injection, as well as signs and symptoms of TMA, such as hypertension, bruising easily, seizures or decreased urine output. In case these signs and symptoms occur in the presence of thrombocytopenia, further diagnostic evaluation for haemolytic anaemia and renal dysfunction should be promptly undertaken. If clinical signs, symptoms and/or laboratory findings consistent with TMA occur, a haematologist and/or nephrologist should be consulted immediately to manage TMA as clinically indicated. Patients and caregivers should be informed about signs and symptoms of TMA and should be advised to seek urgent medical care if such symptoms occur.

Peripheral sensory neuropathy

Peripheral sensory neuropathy has occurred with onasemnogene abeparvovec intrathecal injection.
Administration of onasemnogene abeparvovec intrathecal injection may result in sensory symptoms (e.g. numbness, tingling, prickling or pain in the arms, hands, legs and/or feet), with onset seen at approximately three weeks post-injection in clinical studies. Symptoms requiring management with additional therapies may persist, but can also gradually improve over time (see section 4.8). Sensory symptoms suggestive of peripheral sensory neuropathy may also occur as part of the natural course of SMA.

Complete neurological evaluation and other testing and/or symptom management should be considered based on the patient’s clinical presentation. Patients and caregivers should be informed about the signs and symptoms of peripheral sensory neuropathy and be advised to notify their physician promptly if such symptoms occur.

Risk of tumourigenicity as a result of vector integration

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

Onasemnogene abeparvovec intrathecal injection is composed of a non-replicating AAV9 vector whose DNA persists largely in episomal form. Random integration of recombinant AAV-vector DNA into human DNA has been reported with AAV gene therapies. The clinical relevance of individual integration events is unknown, but it is acknowledged that individual integration events could potentially contribute to a risk of tumourigenicity.

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

Blood, organ, tissue and cell donation

Patients treated with onasemnogene abeparvovec intrathecal injection should not donate blood, organs, tissues or cells for transplantation.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per 3 mL dose, that is to say essentially ‘sodium-free’.

No interaction studies have been performed.

Vaccinations

Where feasible, the patient’s vaccination schedule should be adjusted to accommodate concomitant corticosteroid administration prior to and following onasemnogene abeparvovec intrathecal injection.
Seasonal respiratory syncytial virus (RSV) prophylaxis is recommended. Live vaccines, such as measles, mumps and rubella (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).

Pregnancy

There are no data from the use of onasemnogene abeparvovec in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). It is not known whether onasemnogene abeparvovec has the potential to be transferred to the foetus in humans. Therefore, women who are pregnant or may become pregnant should only be treated with Itvisma after a thorough benefit-risk evaluation.

Breast-feeding

There is no information available on the presence of onasemnogene abeparvovec in human milk, the effects on the breast-fed infant or the effects on milk production. A decision must be made whether to discontinue breast-feeding, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data on the effect of onasemnogene abeparvovec on human fertility. In animal fertility studies, onasemnogene abeparvovec did not impact fertility in male or female mice at doses up to 1.1 × 1014 vg/kg administered intravenously (see section 5.3).

Onasemnogene abeparvovec intrathecal injection may have a minor influence on the ability to drive and use machines. Patients experiencing dizziness (see section 4.8) should avoid driving and using machines.

No data from clinical studies are available regarding overdose of Itvisma. The dose of Itvisma is a single, fixed dose and is administered only once, therefore overdose is considered unlikely.

5.
PHARMACOLOGICAL 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 spinal muscular atrophy (SMA). 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 utilises AAV9 capsid to deliver a stable, fully functional human SMN transgene. The SMN1 gene present in onasemnogene abeparvovec is designed to reside as episomal DNA in the nucleus of transduced cells and is stably expressed in post-mitotic cells. 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-β-actin-hybrid), which results in continuous and sustained SMN expression. Proof of the mechanism of action mainly derives from non-clinical studies.

Clinical efficacy and safety

COAV101B12301 (STEER) phase III study in patients with SMA
This is a 52-week, randomised, double-blind, sham-controlled, multicentre study.

Efficacy was assessed in 126 patients with SMA aged 2 to < 18 years who were treatment-naïve and able to sit but never able to walk independently. Patients were randomised 3:2 and received Itvisma (1.2 × 1014 vg) by lumbar intrathecal injection (n=75) or sham procedure (n=51). Randomisation was stratified by age and pre-treatment Hammersmith Functional Motor Scale – Expanded (HFMSE) score at screening. Patients with elevated (reference to ˃ 1:50) baseline serum anti-AAV9 antibody titre were excluded.

The primary endpoint was the change from baseline in HFMSE total score at the end of follow-up, defined as the average of the week 48 and week 52 assessment, in the overall study population (2 to < 18 years age group) with Itvisma compared to sham. A secondary endpoint was the proportion of patients with at least a 3-point improvement from baseline in HFMSE total score at the end of follow- up. The HFMSE evaluates motor function in patients with SMA who have limited ambulation, comprising 33 graded items assessing movements ranging from sitting to using the stairs. Each item is scored from 0 to 2, with a maximum total score of 66. Higher scores indicate better motor function.
Another secondary endpoint was the change from baseline in Revised Upper Limb Module (RULM) at the end of follow-up. The RULM is a SMA-specific assessment used to assess upper limb (proximal and distal) motor function. The RULM contains 19 graded items (18 scored from 0 to 2 and 1 scored from 0 to 1), and there is a maximum achievable score of 37, with higher scores indicating greater motor function.

Onasemnogene abeparvovec vector shedding studies, which assess the amount of vector DNA eliminated from the body through saliva, urine, faeces and nasal secretions, were performed following intrathecal administration.

Vector DNA was detectable in shedding samples following intrathecal injection of onasemnogene abeparvovec. Shedding (excretion) of onasemnogene abeparvovec was primarily via faeces. The majority of the vector DNA (˃ 90%) is excreted within 2 weeks after dose administration. Peak shedding in faeces was estimated to be between 0.005% to 0.03% of total dose. The maximal shedding concentration in faeces was ~70-fold lower following intrathecal administration of 1.2 × 1014 vg in COAV101B12301 compared with intravenous administration of 1.1 × 1014 vg/kg (studies AVXS-101- CL-302 and AVXS-101-CL-303).

In subjects aged 6 months to ˂ 2 years, the CSF volume increases between 1.0- to 1.6-fold. Based on this, onasemnogene abeparvovec exposure in the CSF in paediatric patients aged 6 months to ˂ 2 years may be up to 1.6-fold higher compared to patients aged ≥ 2 years.

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.

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, but not limited to:
- AAV9 antibody testing using an appropriately validated assay,
- liver function: alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, albumin, prothrombin time, partial thromboplastin time (PTT), and international normalised 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 for corticosteroid treatment are to be considered when establishing the timing of onasemnogene abeparvovec treatment (see section 4.4).

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

Posology

For single-dose intravenous infusion only.

Patients will receive a dose of nominal 1.1 x 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
Patient weight range (kg)
Dose (vg)
Total volume of dose a (mL)

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

Summary of the safety profile
The safety of onasemnogene abeparvovec was evaluated in 99 patients who received onasemnogene abeparvovec at the recommended dose (1.1 x 1014 vg/kg) in 5 open-label clinical studies. The most frequently 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).

Tabulated list of adverse reactions
The adverse reactions identified with onasemnogene abeparvovec in all patients treated with intravenous 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 and frequency. Frequency categories are derived according to the following conventions: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000);
very rare (<1/10 000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 3
Tabulated list of adverse reactions to onasemnogene abeparvovec
Adverse Reactions by MedDRA SOC/PT and Frequency
Blood and lymphatic system disorders
Common
Thrombocytopenia1)
Uncommon
Thrombotic microangiopathy2)3)
Immune system disorders
Rare
Anaphylactic reactions
Gastrointestinal disorders
Common
Vomiting
Hepatobiliary disorders
Common
Hepatotoxicity4)
Uncommon
Acute liver failure2)3)
General disorders and administration site conditions
Common
Pyrexia
Uncommon
Infusion-related reactions
Investigations
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, including in 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 enzyme increased, 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).

Description of selected adverse reactions

Hepatobiliary disorders
In the clinical development program (see section 5.1), elevated transaminases > 2 × ULN (and in some cases > 20 × ULN) were observed in 31% of patients treated at the recommended dose. These patients were clinically asymptomatic and none of them had clinically significant elevations of bilirubin.
Serum transaminase elevations usually resolved with prednisolone treatment and patients recovered without clinical sequelae (see sections 4.2 and 4.4).

In the post-marketing setting, there have been reports of children developing signs and symptoms of acute liver failure (e.g. jaundice, coagulopathy, encephalopathy) typically within 2 months of treatment 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 approximately 1.5 to 9 years; 21 discontinued previous SMA treatment) increased transaminases were observed in 23 out of 24 patients. The patients were asymptomatic and there were no elevations of bilirubin. The AST and 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 receiving prednisolone) and/or a higher dose.

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

In a study (COAV101A12306) including 24 children weighing ≥8.5 kg to ≤21 kg (aged approximately 1.5 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 infusion were observed. In the clinical study program, there were no clinically apparent cardiac findings observed following administration of onasemnogene abeparvovec (see section 4.4).

Immunogenicity
Pre- and post-gene therapy titres of anti-AAV9 antibodies were measured in the clinical studies (see section 4.4). All patients that received onasemnogene abeparvovec had anti-AAV9 titres at or below 1:50 before treatment. Mean increases from baseline in AAV9 titre were observed in all patients at all but 1 time-point for antibody titre levels to AAV9 peptide, reflecting normal response to non-self viral antigen. Some patients experienced AAV9 titres exceeding the level of quantification, however most of these patients did not have potentially clinically significant adverse reactions. Thus, no relationship has been established between high anti-AAV9 antibody titres and the potential for adverse reactions 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 less than 1:50 and both were enrolled in the study. There is no information on whether breastfeeding should be restricted in mothers who may be seropositive for anti-AAV9 antibodies. Patients all had less than or equal to 1:50 AAV9 antibody titre prior to treatment with onasemnogene abeparvovec and subsequently demonstrated an increase in anti-AAV9 antibody titres to at least 1:102 400 and up to greater 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 assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medicinal products and underlying disease.

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

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

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.

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 for clinical signs and symptoms of infusion-related reactions. If a reaction occurs, the infusion should be interrupted and treatment should be provided as needed. Based on clinical evaluation and standard practices, administration may be cautiously resumed.

Immunogenicity
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, despite the immunomodulatory regimen recommended in section 4.2 (see also sub-section ‘Systemic immune response’ below).

Hepatotoxicity
Immune-mediated hepatotoxicity is generally manifested as elevated ALT and/or AST levels. Acute serious liver injury and acute liver failure, including fatal cases, have been reported with onasemnogene abeparvovec use, typically within 2 months after infusion and despite receiving corticosteroids before and after infusion. Immune-mediated hepatotoxicity may require adjustment of the immunomodulatory regimen including longer duration, increased dose, or prolongation of the corticosteroid taper (see section 4.8).

• The risks and benefits of onasemnogene abeparvovec therapy should be carefully considered in patients with pre-existing hepatic impairment.
• 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).
• 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 AST or ALT elevations (in 23 out of 24 patients) compared with frequencies of AST/ALT elevations observed in other studies in patients weighing <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 onasemnogene abeparvovec. Cases of acute liver failure with fatal outcome have been reported (see section 4.8).
• Prior to infusion, liver function of all patients should be assessed by clinical examination and laboratory testing (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 at regular intervals for at least 3 months after infusion, and at other times as clinically indicated (see section 4.2).
• Patients with worsening liver function test results and/or signs or symptoms of acute illness should be promptly clinically assessed and monitored closely.
• In case hepatic injury is suspected, prompt consultation with a paediatric gastroenterologist or hepatologist, adjustment of the recommended immunomodulatory regimen and further testing is recommended (e.g. albumin, prothrombin time, PTT, and INR).

AST/ALT/total bilirubin should be assessed weekly for the first month after onasemnogene abeparvovec infusion and during the entire corticosteroid taper period. Tapering of prednisolone should 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 with unremarkable findings at the end of the corticosteroid taper period, liver function should continue to be monitored every two weeks for another month.

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.

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

Platelet counts should be obtained before onasemnogene abeparvovec infusion and should be closely monitored within the first three weeks following infusion and on a regular basis afterwards, at least weekly for the first month and every other week for the second and third months until platelet counts return 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 frequencies of 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 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 as clinically indicated. Consider consultation with a cardiac expert as needed.

Thrombotic microangiopathy
Several cases of thrombotic microangiopathy (TMA) have been reported with onasemnogene abeparvovec (see section 4.8). Cases generally occurred within the first two weeks after onasemnogene abeparvovec infusion. TMA is an acute and life-threatening condition, which is characterised by thrombocytopenia and microangiopathic haemolytic anaemia. Fatal outcomes have been reported. 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 within 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 for haemolytic anaemia and renal dysfunction should be undertaken promptly. 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.

Systemic immune response
Due to the increased risk of serious systemic immune response, it is recommended that patients are clinically stable in their overall health status (e.g. hydration and nutritional status, absence of infection) prior to onasemnogene abeparvovec infusion. 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), until the infection has resolved and the patient is clinically stable (see sections 4.2 and 4.4).

The immunomodulatory regimen (see section 4.2) might also impact the immune response to infections (e.g. respiratory), potentially resulting in more severe clinical courses of the infection.
Patients with infection were excluded from participation in clinical trials with onasemnogene abeparvovec. Increased vigilance in the prevention, monitoring, and management of infection is recommended before and after onasemnogene abeparvovec infusion. 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.

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 persists largely in episomal form. Rare instances of random vector integration into human DNA are possible with recombinant AAV. The clinical relevance of individual integration events is unknown, but it is acknowledged that individual integration events could potentially contribute to a risk of tumourigenicity.

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

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 (see section 5.2).

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.

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 concomitant 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).

Pregnancy

There are no data from the use of onasemnogene abeparvovec in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). It is not known whether onasemnogene abeparvovec has the potential to be transferred to the foetus in humans. Zolgensma is not intended for administration to women of childbearing potential.

Breast-feeding

There is no information available on the presence of onasemnogene abeparvovec in human milk, the effects on the breast-fed infant or the effects on milk production. Zolgensma is not intended for administration to women of childbearing potential.

Fertility

There are no data on the effect of onasemnogene abeparvovec on human fertility. In animal fertility studies, onasemnogene abeparvovec did not impact fertility in male or female mice at doses up to 1.1 × 1014 vg/kg administered intravenously (see section 5.3).

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

No data from clinical studies are available regarding overdose of onasemnogene abeparvovec.
Adjustment of the dose of prednisolone, close clinical observation and monitoring of laboratory parameters (including clinical chemistry and haematology) for systemic immune response are recommended (see section 4.4).

5.
PHARMACOLOGICAL 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-β-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.

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)

PNCR = Pediatric Neuromuscular Clinical Research natural history cohort

Onasemnogene abeparvovec vector shedding studies, which assess the amount of vector eliminated from 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 was observed within 7 days post-dose for faeces, and within 2 days post-dose for saliva, urine, and nasal secretions. 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, after infusion of onasemnogene abeparvovec at the dose of 1.1 x 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.