WASKYRA Dispersion for infusion Ref.[116230] Active ingredients: Etuvetidigene 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

Waskyra is intended solely for autologous use and must not, under any circumstances, be administered to other patients. Waskyra must not be administered if the information on the product labels and Lot Information Sheet (LIS) do not match the patient's identity.

Age related adverse reactions

It is advisable to administer gene therapy at younger age. The risk of autoimmunity pre-GT, as well as the risk of incomplete reversal of clinical autoimmunity after gene therapy appeared higher in the age group >5 years. Also, older patients may need to be carefully screened for conditions which may imply a higher risk for adverse reactions to conditioning.

Mobilisation, rituximab and conditioning medicinal products

Warnings and precautions of the mobilisation, rituximab and conditioning medicinal products must be considered before planning cell collection for manufacturing.

Central venous catheter (CVC) complications

Infections and bleeding related to the use of CVCs have been reported in clinical trials (see section 4.8). Patients should be closely monitored for potential infections and catheter-related complications.

Hypersensitivity and infusion-related reactions

Dimethylsulfoxide (DMSO), one of the excipients of Waskyra, is known to possibly cause serious hypersensitivity reactions, including anaphylaxis. Patients should be observed closely during and after infusion. Vital signs (blood pressure, heart rate, and oxygen saturation) and the occurrence of any symptom should be monitored prior to the start of the infusion, approximately every ten minutes during the infusion and every hour, for 3 hours, after the infusion.

It should be ensured prior to infusion that the total volume of DMSO administered should remain <1% of the patient's estimated plasma volume. The maximum volume of Waskyra to be administered should therefore remain <20% of the patient's estimated plasma volume (see section 6.6).

Prolonged cytopenia and engraftment failure

Patients may exhibit severe cytopenias, including severe neutropenia, defined as Absolute Neutrophil Count (ANC) <500/μL, for several weeks following reduced intensity conditioning and Waskyra infusion. Patients should be monitored frequently by complete blood count for at least 6 weeks after infusion or until recovery of hematopoiesis and infections managed according to standard guidelines and medical judgement. Supportive transfusion of irradiated packed red blood cells and platelets should be given according to medical judgement and institutional practice.

Failure of engraftment is a potentially important risk defined as not achieving an absolute neutrophil count (ANC) >500 cells/μL, associated with no evidence of bone marrow recovery (i.e., hypocellular marrow), by day 60 after Waskyra infusion. In case of persisting neutropenia, G-CSF should be started to stimulate bone marrow recovery or earlier based on medical judgement. If failure of engraftment and neutropenia persist despite the use of granulocyte colony–stimulating factor, administration of the non-transduced back up autologous stem cells is recommended.

Transmission of an infectious agent

Although Waskyra is tested for sterility and mycoplasma, a risk of transmission of infectious agents exists. Healthcare professionals administering Waskyra must, therefore, monitor patients for signs and symptoms of infections after treatment and treat appropriately, if needed.

Serological testing

All patients should be tested for HIV-1/2, HTLV-1/2, HBV, HCV and mycoplasma prior to mobilisation to ensure acceptance of the cellular source material for Waskyra manufacturing.

Interference with HIV testing

Due to limited and short spans of identical genetic information between the lentiviral vector used to created Waskyra and HIV, some HIV nucleic acid tests (NAT) may give a false positive result.

Patients who have received Waskyra are therefore likely to test positive by polymerase chain reaction (PCR) assays for HIV due to lentiviral vector provirus insertion, resulting in a false positive test for HIV. Therefore, patients who have received Waskyra should not be screened for HIV infection using a PCR-based assay.

Anti-retroviral use

Patients should not take anti-retroviral medicinal products from at least one month prior to mobilisation until at least 7 days after Waskyra infusion (see section 4.5). If a patient requires anti-retroviral treatment following exposure to HIV/HTLV, initiation of Waskyra treatment should be delayed until an HIV/HTLV western blot and viral load assay have been performed at 6 months post-exposure.

Risk of insertional oncogenesis

There is a theoretical risk of leukaemia or lymphoma after treatment with Waskyra. In the event a malignancy is suspected or confirmed, the marketing authorisation holder must be contacted for detailed instructions on sample collection for vector integration‑site analysis (ISA) and clonal proliferation testing (see the malignancy work up checklist and the contact details of the marketing authorisation holder in the Educational/safety advice tools).

Blood, organ, tissue and cell donation

Patients treated with Waskyra should not donate plasma, blood, organs, tissues and cells for transplantation at any time in the future. This information is provided in the Patient Card which should be given to the patient after treatment.

After Waskyra administration

After the infusion, standard procedures for patient management after HSPC transplantation should be followed.

The viral load for cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus-6 (HSV6) and adenovirus will be determined weekly by polymerase chain reaction (PCR) on peripheral blood until Day +90. If repeatedly negative, the testing interval could be prolonged after Day +90. If the subject is positive for CMV, preemptive therapy with ganciclovir, valganciclovir or foscarnet will be administered, according to local standards.

Pre-emptive therapy with rituximab will be administered if the subject is EBV-positive before or after gene therapy in case of repeated increase of EBV viral load, according to local standards.

Immunoglobulin G serum level should be maintained above 5 g/L to prevent potential infections associated with severe hypogammaglobinaemia, resulting from disease-related immune deficiency, rituximab administration and conditioning.

Any blood products required after Waskyra infusion should be irradiated.

Long-term follow-up

Patients who receive Waskyra are expected to be enrolled in a post-authorisation study and should be actively followed for up to 15 years after infusion. Treating physicians should schedule yearly clinical assessments (including haematology, biochemistry, and malignancy surveillance) in accordance with the agreed post-authorisation safety study.

Educational/safety advice tools

Educational/safety advice tools will be provided to healthcare professionals involved in Waskyra treatment of a patient with WAS, to the patients and/or their parents/carers with the aim to facilitate informed decision-making by healthcare professionals and patients, parents/carers based on the known benefits and risks of Waskyra and to minimise the risks to the patients.

Sodium content

This medicinal product contains 3.5 mg sodium per ml.

In adults this may range between 35–560 mg sodium per dose, depending on the volume of the medicinal product. This is equivalent to 2 to 28% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

The theoretical content of sodium in the medicinal product in a pediatric population may vary between 2.3 to 56% of the WHO recommended maximum daily intake for children, however this percentage may vary depending on their weight, age and medicinal product volume.

No interaction studies have been performed.

The drug-drug interaction of mobilisation and myeloablative conditioning medicinal products must be considered.

Patients should not take anti-retroviral medicinal products from at least one month prior to mobilisation until at least 7 days after Waskyra infusion (see section 4.4).

Live vaccines

The safety of immunisation with live viral vaccines during or following Waskyra treatment has not been studied. Vaccination is not recommended with live virus vaccines for 6 weeks before being given the conditioning medicine to prepare for Waskyra treatment, nor after treatment until immune reconstitution is completed following treatment with Waskyra.

Pregnancy

There are no clinical data from the use of Waskyra in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with etuvetidigene autotemcel.

A negative serum pregnancy test must be confirmed prior to the start of each mobilisation cycle and re-confirmed prior to myeloablative conditioning.

Women of childbearing potential and men capable of fathering a child must use effective method of contraception from start of mobilisation through at least 6 months after administration of myeloablative conditioning. Please also refer to the Summary of Product Characteristics for the mobilization, pre-treatment, and myeloablative conditioning medicinal products.

Breast-feeding

It is unknown whether Waskyra is excreted in human milk or transferred to the breast-feeding child. There are no data available.

Breast-feeding should be discontinued during conditioning and Waskyra administration because of the potential risks associated with conditioning.

The decision to breast-feed after Waskyra treatment should be discussed with the treating physician, taking into account the benefit of breast-feeding for the child versus any potential adverse events from Waskyra or from the underlying condition.

Fertility

There are no data on the effects of Waskyra 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 myeloablative conditioning. It is therefore advised to consider fertility preservation options such as cryopreservation of semen or ova before treatment if possible.

Waskyra has no influence on the ability to drive and use machines. The effect of the mobilisation agents and the conditioning agents on the ability to drive or use machines must be considered.

Summary of the safety profile

Treatment with Waskyra is preceded by medical interventions, namely haematopoietic stem cell collection through peripheral blood mobilisation with G-CSF with plerixafor followed by apheresis, pre-treatment with rituximab (anti-CD20 monoclonal antibody) and reduced intensity conditioning, which carry their own risks. When assessing the safety of a treatment with Waskyra, the safety profile and product information of the medicinal products used for peripheral blood mobilisation, pre-treatment and reduced intensity conditioning should be considered, in addition to the risks linked to the gene therapy

Adverse reactions were attributed to pre-treatment (including mobilisation/leukapheresis) conditioning regimen and administration site conditions (device related infection, catheter site haemorrhage very commonly reported).

Tabulated list of adverse reactions

The safety of Waskyra was evaluated in 28 patients with WAS. The median duration of the follow up was 5.67 years (range: 0.37–13.26 years).

Given the small patient population, adverse reactions in the table below do not provide a complete perspective on the nature and frequency of these events.

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).

Table 1. Adverse reactions attributed to mobilisation/apheresis and pre-treatment (G-CSF ± plerixafor, rituximab):

Table 2. Adverse reactions attributed to reduced intensity conditioning regimen (busulfan and fludarabine):

Administration site conditions very commonly reported were: device related infections and catheter site haemorrhage.

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.