ZYNTEGLO Dispersion for infusion Ref.[50056] Active ingredients: Betibeglogene 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.

General

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

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

Zynteglo is intended solely for autologous use and must not be administered to other patients. Confirm that the patient’s identity matches the unique patient identification information on the Zynteglo infusion bag(s) and metal cassette(s). Do not infuse Zynteglo if the information on the patient specific label on the infusion bag(s) or metal cassette(s) do not match the intended patient.

Risks associated with TDT and iron overload

Patients with TDT experience iron overload due to chronic red blood cell (RBC) transfusions that can lead to end organ damage. HSC transplantation with myeloablative conditioning is not appropriate for patients with TDT who have evidence of severely elevated iron in the heart i.e., patients with cardiac T2* <10 msec by magnetic resonance imaging (MRI). MRI of the liver should be performed on all patients prior to myeloablative conditioning. It is recommended that patients with MRI results demonstrating liver iron content ≥15 mg/g undergo liver biopsy for further evaluation. If the liver biopsy demonstrates bridging fibrosis, cirrhosis, or active hepatitis, HSC transplantation with myeloablative conditioning is not appropriate.

Risk of insertional oncogenesis

No cases of myelodysplasia, leukaemia, or lymphoma have been reported in clinical studies with Zynteglo in patients with TDT. There are no reports of LVV-mediated insertional mutagenesis resulting in oncogenesis after treatment with Zynteglo. Nevertheless, there is a theoretical risk of myelodysplasia, leukaemia, or lymphoma after treatment with Zynteglo.

Patients should be monitored at least annually for myelodysplasia, leukaemia, or lymphoma (including with a complete blood count) for 15 years post treatment with Zynteglo. If myelodysplasia, leukaemia, or lymphoma is detected in any patient who received Zynteglo, 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 Zynteglo manufacturing (see section 4.2).

Interference with serology testing

It is important to note that patients who have received Zynteglo 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 Zynteglo should not be screened for HIV infection using a PCR-based assay.

Engraftment failure as measured by neutrophil engraftment

Treatment with Zynteglo involves the infusion and engraftment of CD34+ HSCs that have been genetically modified ex vivo with a LVV. In clinical trials, no patients failed to engraft bone marrow, as measured by neutrophil engraftment (N=45). Neutrophil engraftment occurred on median (min, max) Day 21.0 (13, 38) after medicinal product infusion. 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 Zynteglo. Patients who experience neutrophil engraftment failure should receive rescue treatment with the back-up collection (see section 4.2).

Delayed platelet engraftment

Platelet engraftment is defined as 3 consecutive platelet values ≥20 × 10⁹/L obtained on different days after Zynteglo infusion, with no platelet transfusions administered for 7 days immediately preceding and during the evaluation period. Patients with TDT treated with Zynteglo who achieved platelet engraftment had a median (min, max) platelet engraftment on Day 42.0 (19, 191) in clinical trials (N=45). No correlation was observed between incidence of bleeding and delayed platelet engraftment. Patients should be made aware of the risk of bleeding until platelet recovery has been achieved. Patients should be monitored for thrombocytopenia and bleeding according to standard guidelines. Platelet counts should be monitored according to medical judgment until platelet engraftment and platelet recovery are achieved. Blood cell count determination and other appropriate testing should be promptly considered whenever clinical symptoms suggestive of bleeding arise.

Anti-retroviral and hydroxyurea use

Patients should not take anti-retroviral medications or hydroxyurea from at least one month prior to mobilisation until at least 7 days after Zynteglo infusion (see section 4.5). If a patient requires anti-retrovirals for HIV prophylaxis, Zynteglo treatment, including mobilisation and apheresis of CD34+ cells through Zynteglo infusion, should be delayed until an HIV infection could be adequately ruled out according to local guidance for HIV testing.

Sodium content

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

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

Drug-drug interactions between iron chelators and the myeloablative conditioning agent must be considered. Iron chelators should be discontinued 7 days prior to initiation of conditioning. The Summary of Product Characteristics (SmPC) for the iron chelator and the myeloablative conditioning agent must be consulted for the recommendations regarding co-administration with CYP3A substrates.

Some iron chelators are myelosuppressive. After Zynteglo infusion, avoid use of these iron chelators for 6 months. If iron chelation is needed, consider administration of non-myelosuppressive iron chelators (see sections 4.2 and 5.1).

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

There is no clinical experience with the use of erythropoiesis-stimulating agents in patients treated with Zynteglo.

The safety of immunisation with live viral vaccines during or following Zynteglo treatment has not been studied.

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 Zynteglo. Women of childbearing potential and men capable of fathering a child must use a reliable method of contraception (intra-uterine device or combination of hormonal and barrier contraception) from start of mobilisation through at least 6 months after administration of Zynteglo. Consult the SmPC of the myeloablative conditioning agent for information on the need for effective contraception in patients who undergo conditioning.

Pregnancy

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

No clinical data on exposed pregnancies are available.

Reproductive and developmental toxicity studies with Zynteglo were not performed. Zynteglo must not be used during pregnancy because of myeloablative conditioning (see section 4.3). It is unknown whether Zynteglo transduced cells have the potential to be transferred in utero to a foetus.

There is no opportunity for germline transmission of the β^A-T87Q-globin gene after treatment with Zynteglo, therefore the likelihood that an offspring would have general somatic expression of the β^A-T87Q-globin gene is considered negligible.

Breast-feeding

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

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

Fertility

There are no data on the effects of Zynteglo 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 cryopreserve semen or ova before treatment if possible.

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

The effect of the mobilisation agents and the myeloablative conditioning agent on the ability to drive or use machines must be considered.

Summary of the safety profile

The safety of Zynteglo was evaluated in 45 patients with TDT. The only serious adverse reaction attributed to Zynteglo was thrombocytopenia (2.2%). 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.

Tabulated list of adverse reactions

Adverse reactions are listed by MedDRA body system organ class and by frequency convention. Frequencies are defined as: very common (≥1/10), and common (≥1/100 to <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, myeloablative conditioning, and Zynteglo, respectively, experienced by patients with TDT in clinical trials with Zynteglo.

Table 1. Adverse reactions attributed to mobilisation/apheresis:

Table 2. Adverse reactions attributed to myeloablative conditioning:

Table 3. Adverse reactions attributed to Zynteglo:

Description of selected adverse reactions

Bleeding

Bleeding is a potential complication of thrombocytopenia subsequent to myeloablative conditioning and treatment with Zynteglo. The majority of all reported bleeding events were nonserious. A risk of bleeding exists before platelet engraftment and may continue after platelet engraftment in patients who have continued thrombocytopenia.

Following platelet engraftment, all patients maintained platelet levels of ≥20 × 10⁹/L. Median (min, max) times to unsupported platelet counts of ≥50 × 10⁹/L and ≥100 × 10⁹/L were 51 (20, 268) days (N=45) and 63.5 (20, 1231) days (N=42), respectively (see section 4.4 for guidance on platelet monitoring and management).

Hepatic veno-occlusive disease

Serious events of hepatic VOD occurred in 11.1% of patients following myeloablative conditioning; 80% of these patients did not receive prophylaxis for VOD. All patients who experienced VOD received treatment with defibrotide and recovered. Patients with TDT may be at an increased risk of VOD following myeloablative conditioning compared with other patient populations.

Infusion related reactions to Zynteglo

Pre-medication for infusion reactions was managed at physician discretion. Infusion related reactions to Zynteglo were observed in 13.3% of patients and occurred on the day of Zynteglo infusion. All reactions resolved and the majority were mild. Events included abdominal pain, dyspnoea, hot flush, and non-cardiac chest pain in 11.1%, 2.2%, 2.2%, and 2.2% of patients, respectively.

Paediatric population

According to available data, the frequency, type, and severity of adverse reactions in adolescents 12-17 years of age are similar to adults with the exception that VOD and pyrexia occurred more frequently in adolescents.

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.