ZOLGENSMA Solution for infusion Ref.[10923] Active ingredients: Onasemnogene abeparvovec

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).

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

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

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:

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.

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