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.

Immunogenicity

An immune response to the adeno-associated viral vector serotype 9 (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.

A systemic immune response, including immune-mediated hepatotoxicity, has been reported in the onasemnogene abeparvovec clinical program and may require adjustment of the immunomodulatory regimen including longer duration or increased dose. Refer to section 4.2 for immunomodulatory regimen, and to the sub-sections ‘Hepatic injury’ and ‘Immunomodulatory regimen’ below for details.

Hepatic injury

• Administration of AAV vector may result in transaminase elevations, which may be serious.
• Acute serious liver injury has occurred (see section 4.8).
• Patients with pre-existing liver impairment or acute hepatic viral infection may be at higher risk of liver injury.
• 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 transaminase 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 pre-existent 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 are less than 2 × ULN.

Thrombocytopenia

Transient decreases in platelet counts, some of which met the criteria for thrombocytopenia, were observed in onasemnogene abeparvovec clinical trials. 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 monitored 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.

Elevated troponin-I

Increases in cardiac troponin-I levels following infusion with onasemnogene abeparvovec were observed. 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 (respiratory) infections, 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 (viral) illness. Increased vigilance in the diagnosis and active management of (viral) respiratory 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).

The treating physician should be aware of the possibility of adrenal insufficiency related to longer duration of treatment with corticosteroids which might impact the proposed immunomodulatory regimen.

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

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 medication 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).

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 most frequently reported adverse reaction following administration was transient hepatic transaminase increase (12.4%) and vomiting (8.2%), see section 4.4.

Tabulated list of adverse reactions

The adverse reactions identified with onasemnogene abeparvovec in all patients treated with intravenous infusion 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:

Description of selected adverse reactions

Hepatobiliary disorders

Elevated transaminases >2 × ULN were reported in up to 12% of patients treated at the recommended dose and were considered study-drug related. Two patients had AST and ALT elevations of >20 × ULN (one of these patients was experiencing a viral infection). These patients were clinically asymptomatic, did not exhibit jaundice or a clinically significant elevation of bilirubin and did not meet Hy’s Law criteria. Serum transaminase elevations resolved with prednisolone treatment (see sections 4.2 and 4.4), and patients recovered without clinical sequelae.

Outside of clinical trials, a case of acute serious liver injury was reported with onasemnogene abeparvovec where the patient was continuing treatment with nusinersen and had AST and ALT elevations of >3 × ULN before treatment with onasemnogene abeparvovec. The patient recovered with additional steroid therapy.

Transient thrombocytopenia

Transient decreases from baseline in mean platelet counts (4.1%) were 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. No patients had clinical symptoms associated with decreased platelets (see section 4.4).

Increases of troponin-I levels

Increases in cardiac troponin-I levels (3.1%) up to 0.2 mcg/L following onasemnogene abeparvovec infusion were observed. In the clinical trial 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 expected 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.