SKYSONA Dispersion for infusion Ref.[49634] Active ingredients: Elivaldogene autotemcel

Traceability

The traceability requirements of cell-based advanced therapy medicinal products must apply. To ensure traceability the name of the product, the batch number and the name of the treated patient should be kept for a period of 30 years after expiry date of the product.

Autologous use

Skysona is intended solely for autologous use and should under no circumstances be administered to other patients. Skysona must not be infused if the information on the patient-specific label on the infusion bag(s), Lot Information Sheet and metal cassette(s) do not match the intended patient.

Mobilisation and myeloablative conditioning medicinal products

Warnings and precautions of the mobilisation agents and the conditioning agents must be considered.

Hypersensitivity reactions

The dimethyl sulfoxide (DMSO) in Skysona may cause severe hypersensitivity reactions, including anaphylaxis.

Engraftment failure as measured by neutrophil engraftment

Treatment with Skysona involves the infusion and engraftment of CD34+ HSCs that have been genetically modified ex vivo with a Lentiviral vector (LVV). Failure of neutrophil engraftment is a short-term but potentially severe risk, defined as failure to achieve 3 consecutive absolute neutrophil counts (ANC) ≥500 cells/µL obtained on different days by Day 43 after infusion of Skysona (see section 5.1). Patients who experience neutrophil engraftment failure should receive rescue treatment with the back-up collection (see section 4.2).

Prolonged cytopenias

Patients may exhibit cytopenias for several months following conditioning and Skysona infusion and cases of pancytopenia have been reported. In clinical studies with Skysona, Grade 3 or higher cytopenias after Day 60 following infusion occurred in 26% of patients and included decreased platelet count (13%), decreased neutrophil count (17%), and decreased hemoglobin (2%). After 100 days following infusion, 16% of patients had any Grade 3 or higher cytopenia, including decreased platelet count (9%), decreased neutrophil count (11%); no patient had Grade 3 or higher decreased haemoglobin (0%). Blood counts should be monitored after Skysona infusion and patients should be evaluated for signs and symptoms of bleeding and infection.

Risk of insertional oncogenesis

There are no reports of LVV-mediated insertional mutagenesis resulting in oncogenesis, including myelodysplasia, leukaemia, or lymphoma, associated with Skysona. Nevertheless, there is a theoretical risk after treatment with Skysona. Clonal expansion resulting in clonal predominance without clinical evidence of malignancy has been detected in some patients treated with Skysona.

Patients should be monitored at least annually for myelodysplasia, leukaemia, or lymphoma (including with a complete blood count) for 15 years post treatment with Skysona. If myelodysplasia, leukaemia, or lymphoma is detected in a patient who received Skysona, blood samples should be collected for integration site analysis.

Serological testing

All patients should be tested for HIV-1/-2 prior to mobilisation and apheresis to ensure acceptance of the apheresis material for Skysona manufacturing (see section 4.2).

Anti-retroviral use

Patients should not take anti-retroviral medicinal products from at least one month prior to mobilisation (see section 4.5). If a patient requires anti-retrovirals for HIV prophylaxis, Skysona treatment, including mobilisation and apheresis of CD34+ cells through Skysona infusion, should be delayed until an HIV infection could be adequately ruled out according to local guidance for HIV testing.

Interference with serology testing

It is important to note that patients who have received Skysona are likely to test positive by polymerase chain reaction (PCR) assays for HIV due to LVV provirus insertion, resulting in a false positive test for HIV. Therefore, patients who have received Skysona should not be screened for HIV infection using a PCR-based assay.

Blood, organ, tissue and cell donation

Patients treated with Skysona should not donate blood, organs, tissues, or cells for transplantation at any time in the future. This information is provided in the Patient Information Leaflet and also in the Patient Alert Card which must be given to the patient.

After Skysona administration

There are no data showing an effect of Skysona treatment on the adrenal insufficiency related to ALD. Replacement therapy should be continued.

Patients are expected to enrol in a registry-based study and will be followed in the registry in order to better understand the long-term safety and efficacy of Skysona.

Sodium content

This medicinal product contains 391-1564 mg sodium per dose, equivalent to 20-78% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Patients should not take anti-retroviral medicinal products from at least one month prior to mobilisation until at least apheresis is completed (see section 4.4).

No formal drug interaction studies have been performed. Skysona is not expected to interact with the hepatic cytochrome P-450 family of enzymes or drug transporters.

Live vaccines

The safety of immunisation with live viral vaccines during or following Skysona treatment has not been studied. Vaccination with live virus vaccines is not recommended during the 6 weeks preceding the start of myeloablative conditioning, and until haematological recovery following treatment with Skysona.

Women of childbearing potential/Contraception in males and females

There are insufficient exposure data to provide a precise recommendation on duration of contraception following treatment with Skysona. Women of childbearing potential and men capable of fathering a child and their female partners must use an effective method of contraception (intrauterine device or combination of hormonal and barrier contraception) from start of mobilisation through at least 6 months after administration of Skysona. The SmPC of the conditioning agents should be consulted for information on the need for effective contraception in patients who undergo conditioning.

A negative serum pregnancy test in women of childbearing potential must be confirmed prior to the start of mobilisation and re-confirmed prior to conditioning procedures and before medicinal product administration.

Pregnancy

No clinical data on exposed pregnancies are available.

Reproductive and developmental toxicity studies with Skysona were not performed. Skysona must not be used during pregnancy because of conditioning (see section 4.3). It is unknown whether Skysona transduced cells have the potential to be transferred in utero to a foetus. Pregnancy after treatment with Skysona should be discussed with the treating physician.

There is no opportunity for germline transmission of the LVV that encodes an ABCD1 cDNA for human ALDP after treatment with Skysona, therefore the likelihood that an offspring would have general somatic expression of the lentiviral vector that encodes an ABCD1 cDNA for human ALDP is considered negligible.

Breast-feeding

It is unknown whether Skysona is excreted in human milk. The effect of administration of Skysona to mothers on their breast-fed children has not been studied.

Skysona must not be administered to women who are breast-feeding.

Fertility

There are no data on the effects of Skysona on human fertility. Effects on male and female fertility have not been evaluated in animal studies.

Data are available on the risk of infertility with conditioning. It is therefore advised to consider cryopreservation of semen or ova before treatment.

Skysona has no influence on the ability to drive or use machines.

The effect of the mobilisation agents and the conditioning agents on the ability to drive or use machines, or engage in activities such as cycling or skateboarding, must be considered.

Summary of the safety profile

The safety of Skysona was evaluated in 51 patients with CALD in Studies ALD-102, ALD-104, and LTF-304 (see section 5.1). The most serious adverse reaction attributed to Skysona was pancytopenia (3.9%). Given the small patient population and size of cohorts, adverse reactions in the table below do not provide a complete perspective on the nature and frequency of these events. Information related to safety endpoints used in the studies is provided in section 5.1.

Tabulated list of adverse reactions

Adverse reactions are listed by MedDRA body system organ class and by frequency. Frequencies are defined as: very common (≥1/10) and common (≥1/100 and <1/10). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Tables 1, 2, and 3 are lists of adverse reactions attributed to mobilisation/apheresis, conditioning, and Skysona, respectively, experienced by patients with CALD in clinical studies with Skysona.

Table 1. Adverse reactions attributed to mobilisation/apheresis:

Table 2. Adverse reactions attributed to conditioning:

Table 3. Adverse reactions attributed to Skysona:

Description of selected adverse reactions

Haematopoietic reconstitution

Two serious reactions of pancytopenia occurred in two patients, with onset following neutrophil engraftment. Both patients had delayed hematopoietic reconstitution requiring prolonged support with blood and platelet transfusions as well as growth factors (G-CSF and eltrombopag). One patient had intercurrent parvovirus. Both events were ongoing at least 18 months after Skysona infusion.

Infusion-related reactions

Vomiting occurred in two patients on the day of infusion, potentially related to the cryopreservation agent. Premedication may be utilized at physician discretion.

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 must not be mixed with other medicinal products.