Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Orchard Therapeutics (Netherlands) B.V., Basisweg 10, 1043 AP Amsterdam, The Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Previous treatment with haematopoietic stem cells gene therapy.
Contraindications to the mobilisation and the myeloablative medicinal products must be considered.
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 must be kept for a period of 30 years after expiry date of the product.
Libmeldy is intended solely for autologous use and must not, under any circumstances, be administered to other patients. Libmeldy must not be administered if the information on the product labels and Lot Information Sheet (LIS) do not match the patient’s identity.
Treatment with Libmeldy should be performed before the disease enters its rapidly progressive phase.
Eligibility to treatment with Libmeldy should initially be assessed by the treating physician via full neurological examination, motor function assessment and neurocognitive assessment, as appropriate for the patients' age.
Prior to the commencement of cellular harvest, the treating physician should ensure that the patient has not clinically deteriorated. Thereafter, prior to the commencement of conditioning, the treating physician should his medicinal product contains 35-560 mg sodium per dose, which is equivalent to 2 to 28% of the WHO recommended maximum daily intake of 2 g sodium for an adult.ensure that autologous HSPC gene therapy administration remains clinically appropriate for the patient, and that treatment with Libmeldy is still indicated.
Warnings and precautions of the mobilisation and myeloablative conditioning medicinal products must be considered.
Infections related to the use of CVCs have been reported in clinical studies and there is a risk of thrombosis associated with the CVC. Patients should be closely monitored for potential infections and catheter-related events.
Although Libmeldy is tested for sterility and mycoplasma, a risk of transmission of infectious agents exists. Healthcare professionals administering Libmeldy should therefore monitor patients for signs and symptoms of infections after treatment and treat appropriately, if needed.
Due to limited and short spans of identical genetic information between the lentiviral vector used to create Libmeldy and HIV, some HIV nucleic acid tests (NAT) may give a false positive result. Patients who have received Libmeldy should not be screened for HIV infection using a PCR-based assay.
Patients treated with Libmeldy must not donate blood, organs, tissues and cells for transplantation. This information is provided in the Patient Alert Card which must be given to the patient after treatment.
Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethylsulfoxide (DMSO) in Libmeldy. Patients not previously exposed to DMSO should be observed closely. 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.
When more than one bag of Libmeldy is needed, it should be ensured prior to infusion that the volume of medicinal product to be infused is compatible with the recommended limit of DMSO, i.e. the total volume of DMSO administered should remain <1% of the patient’s estimated plasma volume. The maximum volume of Libmeldy to be administered should therefore remain <20% of the patient’s estimated plasma volume (see section 6.6).
Also, when more than one bag of Libmeldy is needed, only one bag of medicinal product should be infused per hour.
In clinical studies, no patients failed to engraft bone marrow, as measured by neutrophil count in peripheral blood. Failure of neutrophil engraftment is a short-term but potentially important risk, defined as failure to reach an absolute neutrophil count (ANC) >500 cells/μL associated with no evidence of bone marrow recovery (i.e. hypocellular marrow) by day 60 after Libmeldy infusion. In case of engraftment failure, the non-transduced back-up stem cells should be infused according to local standards (see section 4.2).
Patients may exhibit severe cytopenias, including severe neutropenia [defined as Absolute Neutrophil Count (ANC) <500/μL] and prolonged thrombocytopenia, for several weeks following myeloablative conditioning and Libmeldy infusion. In clinical studies, haematological recovery after conditioning with busulfan was typically seen four to five weeks from the day of infusion of Libmeldy. In the clinical study with the cryopreserved (commercial) formulation, neutrophil engraftment occurred after a median (min, max) of 36.5 (31-40) days after gene-therapy. Patients should, therefore, be monitored for signs and symptoms of cytopenia for at least 6 weeks after infusion.
Red blood cells should be monitored according to medical judgment until engraftment of these cells and recovery are achieved. Supportive transfusion of red cells and platelets should be given according to medical judgement and institutional practice. Blood cell count determination and other appropriate testing should be promptly considered whenever clinical symptoms suggestive of anaemia arise. If cytopenia persists beyond six to seven weeks, despite the use of granulocyte mobilising medicinal products, the non-transduced back up stem cells should be infused. If cytopenia persists despite infusion of non-transduced back-up stem cells, alternative treatments should be considered.
Platelet engraftment is defined as the first of 3 consecutive days with platelet values ≥20 × 109/L obtained on different days after Libmeldy infusion, with no platelet transfusion administered for 7 days immediately preceding and during the evaluation period (up to 60 days post gene therapy). During the clinical development, 4/35 patients (11.4%) reported delayed platelet engraftment (median: 73.5 days, range 65-109 days) which was not correlated with an increased incidence of bleeding. As part of the standard of care/prophylaxis, all patients in the integrated safety set (N=29) received transfusion support with platelets. Platelets counts should be monitored according to medical judgment until engraftment of these cells and recovery is achieved. Supportive transfusion of platelets should be given according to medical judgement and institutional practice.
Prior to a treatment with Libmeldy, the presence of renal tubular acidosis should be evaluated alongside risks of the conditioning medicinal product and risks of the gene therapy procedure, which may contribute to the development of metabolic acidosis. Acid-base status should be monitored throughout conditioning and until the patient is no longer under metabolic stress. The treating physician should consider sodium bicarbonate replacement alongside any other required treatment and should aim to correct any concurrent adverse reaction(s) that might contribute to metabolic acidosis.
Transient increases in thyroid stimulating hormone (TSH), free T4 (FT4; thyroxine) and free T3 (FT3; tri-iodothyronine) were observed in some patients during clinical studies. Considering that thyroid disorders could potentially be masked by critical illness or induced by concomitant medication, patients should be assessed for thyroid function and structure prior to treatment with Libmeldy. Thyroid function and structure should also be monitored in the short term after treatment, and as necessary thereafter.
There is a theoretical risk of leukaemia or lymphoma after treatment with Libmeldy. In the event that leukaemia or lymphoma is detected in any patient who received Libmeldy, blood samples should be collected for integration site analysis.
During clinical development, anti-ARSA antibodies (AAA) were reported in 5 patients. Titers were generally low and resolved spontaneously or after treatment with rituximab (see section 4.8). No impacts on the clinical efficacy or safety outcomes were observed.
Monitoring of AAA is recommended prior to treatment, between 1 and 2 months after gene therapy, and then at 6 months, 1 year, 3 years, 5 years, 7 years, 9 years, 12 years, 15 years post treatment. In a case of disease onset or significant disease progression, additional AAA monitoring is recommended.
Libmeldy has not been studied in patients with HIV-1, HIV-2, HTLV-1, HTLV-2, HBV, HCV or mycoplasma infection.
All patients should be tested for HIV-1/2, HTLV-1/2, HBV, HCV and mycoplasma prior to mobilisation or bone marrow harvest to ensure acceptance of the cellular source material for Libmeldy manufacturing.
Patients should not take anti-retroviral medicinal products from at least one month prior to mobilisation until at least 7 days after Libmeldy infusion (see section 4.5). If a patient requires anti-retrovirals following exposure to HIV/HTLV, initiation of Libmeldy treatment should be delayed until an HIV/HTLV western blot and viral load assay have been performed at 6 months post-exposure.
Patients who have received Libmeldy 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 Libmeldy should not be screened for HIV infection using a PCR-based assay.
Patients treated with Libmeldy should not donate blood, organs, tissues and cells for transplantation at any time in the future. This information is provided in the Patient Alert Card which should be given to the patient after treatment.
After the infusion, standard procedures for patient management after HSPC transplantation should be followed.
Immunoglobulin G should be maintained above 5 g/L to prevent potential late infections (occurring later than 100 days post therapy) associated with severe hypogammaglobinaemia, resulting from apheresis and conditioning.
Any blood products required within the first 3 months after Libmeldy infusion should be irradiated.
Patients are expected to be enrolled in a long-term follow-up scheme in order to better understand the long-term safety and efficacy of Libmeldy.
This medicinal product contains 35–560 mg sodium per dose, which is equivalent to 2 to 28% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
No interaction studies have been performed.
The nature of Libmeldy is such that no pharmacokinetic interactions are expected with other medicinal products.
Patients should not take anti-retroviral medicinal products from at least one month prior to mobilisation until at least 7 days after Libmeldy infusion (see section 4.4).
The safety of immunisation with live viral vaccines during or following treatment with Libmeldy has not been studied. As a precautionary measure, vaccination with live vaccines is not recommended for at least 6 weeks prior to the start of myeloablative conditioning, during Libmeldy treatment, and until haematological recovery following treatment.
As Libmeldy is not intended for use in adults, human data on use during pregnancy or lactation and animal reproduction studies are not available.
With regard to fertility, consult the SmPC of the myeloablative conditioning medicinal product. It should be noted that the treating physician should inform the patient’s parents/carers about options for cryopreservation of spermatogonial stem cells or ovarian tissue.
Not relevant.
The safety of Libmeldy was evaluated in 35 patients with MLD.
The median duration of follow-up in the integrated safety data set, which included 29 patients treated with the fresh (investigational) formulation was 4.51 years (range: 0.64 to 8.85 years). Three patients died and a total of 26 patients remained in the follow-up phase.
The median duration of follow-up in the 6 patients treated with the cryopreserved (commercial) formulation was 0.87 years (range: 0.0 to 1.47 years). All of them remained in the follow-up phase (see section 5.1).
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.
Treatment with Libmeldy is preceded by medical interventions, namely haematopoietic stem cell collection through peripheral blood mobilisation with G-CSF with or without plerixafor followed by apheresis, and myeloablative conditioning (preferably using busulfan), which carry their own risks. When assessing the safety of a treatment with Libmeldy, the safety profile and product information of the medicinal products used for peripheral blood mobilisation and myeloablative conditioning should be considered, in addition to the risks linked to the gene therapy.
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 Libmeldy:
| System Organ Class | Very Common | Common |
|---|---|---|
| Immune system disorders | Antibody Test Positive (Anti ARSA Antibody) |
Table 2. Adverse reactions potentially attributed to myeloablative conditioning*:
| System Organ Class | Very Common | Common |
|---|---|---|
| Infections and infestations | Cytomegalovirus viraemia, Pneumonia, Staphylococcal infection, Urinary tract infection, Viral infection | |
| Blood and lymphatic system disorders | Febrile neutropenia, Neutropenia | Anaemia, Thrombocytopenia |
| Metabolism and nutrition disorders | Metabolic acidosis | Fluid overload |
| Psychiatric disorders | Insomnia | |
| Nervous system disorders | Headache | |
| Respiratory, thoracic and mediastinal disorders | Epistaxis, Oropharyngeal pain | |
| Gastrointestinal disorders | Stomatitis, Vomiting | Ascites, Diarrhoea, Gastrointestinal haemorrhage, Nausea |
| Hepatobiliary disorders | Hepatomegaly, Veno-occlusive liver disease | Hypertransaminasaemia |
| Skin and subcutaneous tissue disorders | Skin exfoliation | |
| Musculoskeletal and connective tissue disorders | Back pain, Bone pain | |
| Renal and urinary disorders | Oliguria | |
| Reproductive system and breast disorders | Ovarian failure | |
| General disorders and administration site conditions | Pyrexia | |
| Investigations | Alanine aminotransferase increased, Aspartate aminotransferase increased, Aspergillus test positive |
* Based on 29 patients who have undergone myeloablative conditioning by busulfan in the integrated data set.
Five out of 35 patients tested positive for anti-ARSA antibodies (AAA) at various post-treatment time points and had the event “Antibody test positive / Presence of antibodies against arylsulfatase A” reported by the Investigator. Antibody titres were generally low and resolved either spontaneously or after a short course of rituximab.
In all patients with positive AAA test results, no negative effects were observed in the post-treatment ARSA activity of peripheral blood or bone marrow cellular subpopulations nor in the ARSA activity within the cerebrospinal fluid.
Patients treated with Libmeldy should be regularly monitored for AAA (see section 4.4).
During the clinical studies, haematopoietic stem cell collection was performed either through bone marrow (BM) harvest or peripheral blood mobilisation. The safety profile of BM harvest and mobilisation/apheresis were consistent with the known safety and tolerability of both procedures and the SmPC of mobilisation agents (G-CSF and plerixafor).
No serious adverse events were reported as potentially attributable to BM harvest within the range of BM volumes harvested (median volume was 35.5 mL/kg; range: 15.1-56.4 mL/kg). In the Integrated Safety Set (n=29), one patient experienced bone pain, which was qualified as a grade 2 adverse event and deemed related to the BM harvest procedure, but unrelated to the volume harvested.
No serious adverse events were reported as potentially attributable to mobilisation and apheresis and none of the patients who underwent mobilisation experienced any adverse events in the pre-treatment phase which could have been attributed to the mobilising agents.
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.
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