LIBMELDY Dispersion for infusion Ref.[27971] Active ingredients: Atidarsagene autotemcel

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.

The minimum recommended dose of Libmeldy is 3 × 10⁶ CD34+ cells/kg. 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 × 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 × 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 200 µm filter (see section 6.6).

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

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

6 months.

Once thawed: maximum 2 hours at room temperature (20°C-25°C).

Keep the infusion bag(s) in the metal cassette(s).

Libmeldy must be stored in the vapour phase of liquid nitrogen (< -130°C) and must remain frozen until the patient is ready for treatment to ensure viable cells are available for patient administration. Thawed medicinal product should not be refrozen.

For storage conditions after thawing of the medicinal product, see section 6.3.

50 mL ethylene vinyl acetate (EVA) infusion bag(s) with two available spike ports, packed in an EVA overwrap bag placed inside a metal cassette.

Libmeldy is shipped from the manufacturing facility to the treatment centre storage facility in a cryoshipper, which may contain multiple metal cassettes intended for a single patient. Each metal cassette contains one infusion bag of Libmeldy.

Precautions to be taken before handling or administering the medicinal product:

• This medicinal product contains human blood cells. Healthcare professionals handling Libmeldy must take appropriate precautions (wearing gloves, protective clothing and eye protection) to avoid potential transmission of infectious diseases.
• Libmeldy must remain at < -130°C at all times, until the content of the bag is thawed for infusion.

Definition of the dose to be administered

• Considering the posology information provided in section 4.2, the dose to be infused and number of infusion bags to be used should be defined based on the total number of CD34+ cells supplied indicated on the Lot Information Sheet (i.e. the ‘supplied dose’, calculated based on patient’s weight at time of cell harvest). The dose of Libmeldy to be administered should also take into account the patient’s weight at the time of treatment, and the fact that any bag used should be administered in its entirety.
• Careful consideration must be given to the volume of infusion in relation to age and weight of the patient. When the dose of Libmeldy to be infused represents more than one bag, 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. Therefore, the maximum volume of Libmeldy to be administered should remain <20% of the patient’s estimated plasma volume.
• The following graph is provided as a reference in order to determine the maximum volume of Libmeldy which can be infused to a patient based on their estimated plasma volume.

Figure 2. Guidance on DMSO safety limit: the maximum volume of Libmeldy to be administered should remain <20% of the patient’s estimated plasma volume:

Preparation for the infusion:

• A patient may have multiple infusion bags. Each infusion bag is provided inside an overwrap bag, which is contained in a metal cassette.
• The overwrapped infusion bag(s) must be kept inside the metal cassette(s) in the vapour phase of liquid nitrogen at < -130°C until ready to thaw and infuse.
• Account for all infusion bags and confirm each infusion bag is within the expiry date using the accompanying Lot Information Sheet.
• Sterile sodium chloride 9 mg/mL (0.9%) solution for injection should be available to prime the tubing prior to infusion, and to flush the infusion bag and tubing after infusion.

Checking prior to thawing:

• Do not remove the metal cassette from cryogenic storage or thaw Libmeldy until the patient is ready to be infused. The timing of thaw of the infusion bag(s) containing Libmeldy and of the infusion should be coordinated. Confirm the infusion time in advance and adjust the start time for thaw so that the treatment is available for infusion when the patient is ready.
• Open the metal cassette and inspect the overwrap bag and infusion bag for any breaches of integrity before thawing. If an infusion bag is compromised, follow the local guidelines for handling of waste of human-derived material and contact Orchard Therapeutics immediately.
• Prior to thawing Libmeldy, it must be verified that the patient identity matches the unique patient information reported on the packaging labels and on the accompanying Lot Information Sheet. Libmeldy is intended solely for autologous use. Do not thaw or infuse Libmeldy if the information on the patient-specific label on the infusion bag does not match the intended patient.

Thawing:

• After careful removal from the metal cassette, thaw the infusion bag in its sealed overwrap bag at 37°C in a controlled thawing device until there is no visible ice in the infusion bag.
• Once thawing is complete, the bag should be removed immediately from the thawing device.
• The overwrap bag should be carefully opened to remove the infusion bag which should be kept at room temperature (20°C-25°C) until infusion.
• Gently massage the infusion bag to resuspend the cells. The content of the infusion bag should be inspected for any remaining visible cellular aggregates. Small clumps of cellular material should disperse with gentle manual mixing. Do not shake the bag.
• The infusion bag should not be washed, spun down, sampled and/or resuspended in new media prior to infusion.
• Libmeldy should not be irradiated as irradiation could lead to inactivation of the product.
• If more than one infusion bag is provided for the patient treatment dose, the next bag should only be thawed after the content of the preceding bag has been fully infused.

Administration:

• Libmeldy should be administered as an intravenous infusion via a central venous catheter, per the administration site’s standard procedures for cell therapy products.
• The recommended administration set consists of a blood transfusion set equipped with a 200µm filter.
• Each bag should be infused by gravity within 2 hours of thaw, including any interruption during the infusion, to maintain maximum product viability.
• The maximum infusion rate is 5 mL/kg/h, and the content of each bag should be infused within approximately 30 minutes.
• When more than one bag of Libmeldy is needed, only one bag of product should be infused per hour.
• 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 for up to 3 hours following the infusion.
• At the end of the infusion, flush all Libmeldy remaining in the infusion bag and any associated tubing with sodium chloride 9 mg/mL (0.9%) solution for injection to ensure that as many cells as possible are infused into the patient. Careful consideration must be given to the volume of infusion in relation to the age and weight of the patient.

Measures to take in case of accidental exposure:

• In case of accidental local guidelines on handling of human-derived material must be followed. Work surfaces and materials which have potentially been in contact with Libmeldy must be decontaminated with appropriate disinfectant.

Precautions to be taken for the disposal of the medicinal product:

• Unused medicinal product and all material that has been in contact with Libmeldy (solid and liquid waste) should be handled and disposed of as potentially infectious waste in accordance with local guidelines on handling human-derived material.