4.1. Therapeutic indications

Libmeldy is indicated for the treatment of metachromatic leukodystrophy (MLD) characterized by biallelic mutations in the arylsulfatase A (ARSA) gene leading to a reduction of the ARSA enzymatic activity:

- in children with late infantile or early juvenile forms, without clinical manifestations of the disease,

- in children with the early juvenile form, with early clinical manifestations of the disease, who still have the ability to walk independently and before the onset of cognitive decline (see section 5.1).

4.2. Posology and method of administration

Libmeldy must be administered in a qualified treatment centre by a physician with experience in Haematopoietic Stem Cell Transplantation (HSCT) and trained for administration and management of patients treated with the medicinal product.

Posology

Libmeldy is intended for autologous use (see section 4.4) and should only be administered once.

The dose of Libmeldy must be determined based on the patient's body weight at the time of infusion.

Treatment consists of a single dose for infusion containing a dispersion of viable CD34+ cells in one or more infusion bags.

The minimum recommended dose of Libmeldy is 3 × 106 CD34+ cells/kg of body weight. In clinical studies, doses up to 30 × 106 CD34+ cells/kg have been administered.

The maximum volume of Libmeldy to be administered should remain < 20% of the patient's estimated plasma volume (see section 4.4 and section 6.6).

See the accompanying Lot Information Sheet (LIS) for additional information pertaining to dose.

Peripheral blood mobilisation and apheresis

The autologous CD34+ cells are isolated from mobilised peripheral blood (mPB). This is achieved by apheresis procedure(s) following peripheral blood mobilisation.

For manufacture of Libmeldy, the patient must be able to donate a minimum of 8-10 ×106 CD34+ cells/kg, considering that the optimal range is between 20-30 × 106 CD34+ cells/kg.

The minimum CD34+ cell quantity may be achieved using one or more cycles of apheresis.

If, after medicinal product manufacturing, the minimum dose of Libmeldy of 3 × 106 CD34+ cells/kg is not achieved, the patient may undergo a further mobilisation protocol with one or more cycles of apheresis, in order to obtain more cells for additional manufacture (see Mobilisation and apheresis in section 5.1).

A back-up collection of HSPC containing at least 2 x 106 CD34+ cells/kg is also required for use as rescue treatment should the quality of Libmeldy be compromised after initiation of myeloablative conditioning and before Libmeldy infusion, failure of primary engraftment, or prolonged bone marrow aplasia after treatment with Libmeldy (see section 4.4).

These cells must be collected from the patient and be cryopreserved according to institutional procedures prior to myeloablative conditioning. The back-up cells may be harvested either through mPB apheresis or bone marrow harvest.

Peripheral blood mobilisation

Patients are required to undergo HSPC mobilisation with Granulocyte colony-stimulating factor (G-CSF) with or without plerixafor followed by apheresis to obtain CD34+ stem cells for medicinal product manufacturing (see section 5.1 for a description of the mobilisation regimen used in clinical studies).

Pre-treatment conditioning

The treating physician should confirm that autologous HSPC gene therapy administration is clinically appropriate for the patient before myeloablative conditioning is initiated (see section 4.4).

A myeloablative conditioning is required before infusion of Libmeldy to promote efficient engraftment of the genetically modified autologous CD34+ cells (see section 5.1 for a description of the myeloablative regimen used in clinical studies).

Busulfan is the recommended conditioning medicinal product.

Myeloablative conditioning should not begin until the complete set of infusion bag(s) constituting the dose of Libmeldy has been received and stored at the qualified treatment centre, and the availability of the back-up collection is confirmed.

Concurrently with the conditioning regimen, and prior to treatment with Libmeldy, it is recommended that patients receive prophylaxis for veno-occlusive disease (VOD) and related endothelial injury complications i.e. transplant-associated thrombotic microangiopathy (TA-TMA) or atypical haemolytic uremic syndrome (aHUS), in line with local guidelines.

Depending on the myeloablative conditioning regimen administered, prophylaxis for seizures should also be considered. Phenytoin is not recommended as it may increase busulfan clearance.

Prophylactic and empiric use of anti-infectives (bacterial, fungal, viral) should be considered for the prevention and management of infections especially during the neutropenic period following conditioning. Routine monitoring of most common viruses subject to re-activation is recommended as per local guidelines. Infection control measures and isolation procedures should be employed during the hospitalization according to local standards.

Pre-medication

It is recommended that pre-medication with intravenous chlorpheniramine (0.25 mg/kg, max. dose 10 mg), or equivalent medicinal products, be administered 15-30 minutes before the infusion of Libmeldy to reduce the possibility of an infusion reaction.

Special populations

Elderly

Libmeldy has not been studied in patients >65 years of age.

Renal impairment

Libmeldy has not been studied in patients with renal impairment. Patients should be assessed for renal impairment to ensure autologous HSPC gene therapy administration is appropriate. No dose adjustment is required.

Hepatic impairment

Libmeldy has not been studied in patients with hepatic impairment. Patients should be assessed for hepatic impairment to ensure autologous HSPC gene therapy administration is appropriate. No dose adjustment is required.

Paediatric population

The safety and efficacy of Libmeldy have not yet been established in patients with the late juvenile form of the disease (i.e. with a typical onset after 7 years of age). No data are available.

Method of administration

Libmeldy is for intravenous infusion only.

Precautions to be taken before handling or administering the medicinal product

This medicinal product contains genetically modified human cells. Healthcare professionals should therefore take appropriate precautions (wearing gloves and glasses) to avoid potential transmission of infectious diseases when handling the product.

For instructions on preparation, accidental exposure and disposal of Libmeldy, see section 6.6.

Preparation for infusion

Before administration, it must be confirmed that the patient's identity matches the unique patient information on the Libmeldy infusion bag(s) and accompanying documentation. The total number of infusion bags to be administered must also be confirmed with the patient specific information on the Lot Information Sheet (LIS) (see section 4.4).

The timing of thaw and infusion of Libmeldy should be coordinated. The infusion start time should be confirmed in advance and adjusted for thaw so that Libmeldy is available for infusion when the patient is ready. To maintain product viability, as soon as thawing is complete, it is recommended that Libmeldy be administered immediately. Administration must be completed within 2 hours from the time of thawing.

Administration

Administer the product as an intravenous infusion via a central venous catheter. When more than one bag of Libmeldy is needed, only one bag of medicinal product should be infused per hour. Each bag should be infused at an infusion rate which does not exceed 5 mL/kg/h, within approximately 30 minutes. The recommended administration set consists of a blood transfusion set equipped with a 200µm filter (see section 6.6).

For detailed instructions on preparation, administration, accidental exposure and disposal of Libmeldy, see section 6.6.

4.3. Contraindications

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.

4.4. Special warnings and precautions for use

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 must be kept for a period of 30 years after expiry date of the product.

Autologous use

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.

Rapidly progressive phase of the disease

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 ensure that autologous HSPC gene therapy administration remains clinically appropriate for the patient, and that treatment with Libmeldy is still indicated.

Mobilisation and myeloablative conditioning medicinal products

Warnings and precautions of the mobilisation and myeloablative conditioning medicinal products must be considered.

Central venous catheter (CVC) complications including infections and thromboses

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.

Transmission of an infectious agent

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.

Interference with virology testing

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.

Blood, organ, tissue and cell donation

Patients treated with Libmeldy should 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.

Hypersensitivity and infusion-related reactions

Serious hypersensitivity reactions, including anaphylaxismay 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.

Engraftment failure

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).

Prolonged cytopenia

Patients may exhibit severe cytopenias, including severe neutropenia [defined as Absolute Neutrophil Count (ANC) <500 cells/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.

Delayed platelet engraftment

Platelet engraftment is defined as the first of 3 consecutive days with platelet values ≥ 20 x 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.

Metabolic acidosis

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.

Thyroid monitoring

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.

Risk of insertional oncogenesis

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.

Anti-ARSA antibodies

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.

Serological testing

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 to ensure acceptance of the cellular source material for Libmeldy manufacturing.

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 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.

After Libmeldy administration

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

Immunoglobulin G should be maintained above 5g/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.

Long-term follow-up

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.

Sodium content

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.

4.5. Interaction with other medicinal products and other forms of interaction

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).

Live vaccines

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.

4.6. Fertility, pregnancy and lactation

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.

4.7. Effects on ability to drive and use machines

Not relevant.

4.8. Undesirable effects

Summary of the safety profile

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 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.

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).

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.

Description of selected adverse reactions

Presence of Anti ARSA Antibodies

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).

Peripheral blood mobilisation and apheresis

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 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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

No data from clinical studies are available regarding overdose of Libmeldy.