Libmeldy

Package leaflet: Information for the patient or caregiver

Libmeldy 2-10 x 10 cells/mL dispersion for infusion

atidarsagene autotemcel (CD34 cells)
This medicinal product is subject to additional monitoring. This will allow for rapid identification of new safety information. You can help by reporting any side effects you notice in the child while receiving this medicine. See the end of section 4 for information on how to report side effects.
Please read this leaflet carefully before this medicine is administered to the child
as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, contact the child’s doctor or nurse.
• The child’s doctor or nurse will provide you with a patient alert card. Read it carefully and follow the instructions contained therein.
• Always show the patient alert card to the doctor or nurse during medical visits or if the child is admitted to hospital.
• If the child experiences any side effects, including those not listed in this leaflet, contact the doctor or nurse. See section 4.

Contents of this leaflet

1. What Libmeldy is and what it is used for
2. What you need to know before Libmeldy is given to the child
3. How Libmeldy is administered
4. Possible side effects
5. How to store Libmeldy
6. Contents of the pack and other information

1. What Libmeldy is and what it is used for

What Libmeldy is
Libmeldy (atidarsagene autotemcel) is a type of medicine called a gene therapy. It is specially manufactured for the child using their own blood cells.

What Libmeldy is used for
Libmeldy is used to treat a severe disease called metachromatic leukodystrophy (MLD):

• in children with the "late infantile" or "early juvenile" forms of the disease who have not yet developed signs or symptoms;
• in children with the "early juvenile" form of the disease who have begun to show symptoms, but whose symptoms are not yet rapidly worsening.

People affected by MLD have a defect in the gene responsible for producing an enzyme called arylsulfatase A (ARSA). This leads to an accumulation of substances called sulfatides in the brain and nervous system, causing damage to the nervous system and progressive loss of physical abilities, followed by mental decline, ultimately leading to death.

How Libmeldy works
Stem cells are collected from the child's blood. These cells are then modified in the laboratory to introduce a functional gene for the production of ARSA. When the child receives Libmeldy, which consists of these modified cells, the cells will begin producing ARSA to break down the accumulated sulfatides in nerve cells and other cells in the child's body. This should slow down disease progression and improve the child's quality of life.

Libmeldy is administered through an intravenous infusion (infusion). For more information about what happens before and during treatment, see section 3, How Libmeldy is administered.

If you have questions about how Libmeldy works or why this medicine has been prescribed for the child, please consult the doctor.

2. What you should know before your child is given Libmeldy

Your child must not be given Libmeldy:

• if they are allergic to atidarsagene autotemcel or to any of the ingredients of this medicine (listed in section 6). If you think your child may be allergic, consult your doctor;
• if they have previously received gene therapy using their own blood stem cells;
• if they are allergic to any of the ingredients of the medicines that will be administered before treatment with Libmeldy, or if the doctor thinks your child may experience unacceptable side effects from these medicines (see section 3).

Warnings and precautions
Please consult your doctor before your child is given Libmeldy.

• Information about cell-based medicines such as Libmeldy must be kept in the hospital for 30 years. The information stored about your child will include the name and batch number of Libmeldy administered.
• Libmeldy is manufactured from your child’s own stem cells and must only be given to them.

Before treatment with Libmeldy

• Your child will be evaluated by the doctor to confirm the diagnosis of MLD and to assess the symptoms and effects of the disease before deciding whether to proceed with Libmeldy. Your child may not show any symptoms at the time of initial evaluation. If the MLD has progressed and worsened before treatment begins, the doctor may determine that the disease has reached a "rapidly progressing phase." In such cases, your child may not benefit from treatment, and the doctor may decide not to administer Libmeldy.
• Central venous catheters are thin, flexible tubes inserted by the doctor into a large vein to access your child’s bloodstream. Risks associated with these catheters include infections and blood clots. The doctor and nurses will monitor your child for any complications related to the central venous catheter.
• Libmeldy is tested to exclude the presence of infectious microorganisms before administration. There remains a small risk of infection. Doctors and nurses will monitor your child during infusion for signs of infection and will intervene if necessary.
• The doctor will check your child’s thyroid gland. The thyroid is located in the neck and produces hormones important for normal body function. It will also be monitored after treatment, if needed.

After treatment with Libmeldy

• After treatment, you may be asked to enroll your child in a follow-up study for up to 15 years to better understand the long-term effects of Libmeldy.
• If your child requires a blood transfusion within the first 3 months after receiving Libmeldy, blood-derived products must be irradiated before administration. This process reduces white blood cells, called lymphocytes, to minimize the risk of transfusion reactions. The doctor will monitor your child for possible transfusion reactions.
• After treatment with Libmeldy, your child’s blood cell counts will be low for a period of time. This particularly affects neutrophils, the blood cells that fight infections, which can be measured with a simple blood test. If your child’s neutrophil count remains low after 60 days, this may be referred to as "failure to engraft." In such cases, the doctor may decide to reinfuse the previously collected reserve cells (see section 3). The reserve cells do not contain the functional ARSA gene and will not produce the ARSA enzyme.
• After receiving the conditioning medicine, your child may have a low platelet count. This means their blood may not clot normally, and they may be at risk of bleeding for some time after treatment. The doctor will monitor your child’s platelet count through routine blood tests and, if necessary, provide appropriate treatment. This may include a platelet transfusion to help increase the platelet count.
• Metabolic acidosis, a condition in which blood acidity increases, may occur. It can be caused by various factors and is more common in patients with MLD. Symptoms of metabolic acidosis include shortness of breath and rapid breathing, nausea, and vomiting. The doctor will monitor your child for signs and symptoms of metabolic acidosis.
• Insertion of a new gene into stem cells could theoretically lead to blood cancers (leukaemia and lymphoma). After treatment, the doctor will monitor your child for any signs of leukaemia or lymphoma.
• During clinical studies, some patients developed antibodies against the ARSA enzyme, known as anti-ARSA antibodies (see section 4, Undesirable effects of Libmeldy). These resolved spontaneously or after treatment with appropriate medicines. The doctor will check your child’s blood for anti-ARSA antibodies and, if necessary, administer appropriate treatment.
• After receiving Libmeldy, your child will be monitored with regular blood tests, including measurement of antibodies known as immunoglobulins. If levels are low, your child may require immunoglobulin replacement therapy. The doctor will discuss this with you if needed.
• Libmeldy is manufactured using parts of the human immunodeficiency virus (HIV), which have been modified so they cannot cause infection. The modified virus is used to insert the ARSA gene into your child’s stem cells. Although this medicine will not cause HIV infection, the presence of Libmeldy in the blood may lead to a false positive result in certain commercial HIV tests (so-called "PCR-based tests") that detect a fragment of HIV used in the production of Libmeldy. If your child tests positive for HIV after treatment with Libmeldy, contact your doctor or nurse.
• After treatment with Libmeldy, your child will no longer be able to donate blood, organs, tissues, or cells, as Libmeldy is a gene therapy product.

Before your child is given Libmeldy, the doctor will:

• check your child’s lungs, heart, kidneys, liver, and blood pressure;
• look for any signs of infection; any infection will be treated before Libmeldy is administered;
• perform tests for hepatitis B, hepatitis C, human T-cell leukaemia virus (HTLV), HIV, or mycoplasma infection;
• check whether your child has been vaccinated within the previous 6 weeks or if vaccination is planned in the coming months.

When treatment with Libmeldy cannot be completed
Before receiving Libmeldy, your child will be given a conditioning medicine to clear cells from the bone marrow.
If Libmeldy cannot be administered after your child has received the conditioning medicine, or if the modified stem cells fail to engraft in your child’s body, the doctor may decide to reinfuse the previously collected reserve cells (see also section 3, How Libmeldy is administered). The reserve cells do not contain the functional ARSA gene and will not produce the ARSA enzyme. For further details, consult your doctor.

Other medicines and Libmeldy
Inform the doctor if your child is taking, has recently taken, or might take any other medicines.

• Your child must not take any HIV infection medicines for at least one month before administration of the mobilization medicines, up to at least 7 days after Libmeldy infusion (see also section 3, What Libmeldy contains and how it is administered).
• Your child must not receive live vaccines within 6 weeks before administration of the conditioning medicine for Libmeldy treatment, or after treatment while their immune system (the body’s defence system) is recovering.

Libmeldy contains sodium and dimethyl sulfoxide (DMSO)
This medicine contains 35–560 mg of sodium (a main component of table salt) per dose, equivalent to 2–28% of the maximum recommended daily dietary intake for an adult.
If your child has not previously been exposed to DMSO (a substance used to preserve frozen cells), the doctor or nurse must closely monitor them for possible reactions during and after infusion of each bag.

3. How Libmeldy is administered

Libmeldy will always be administered to the child by a physician at a qualified treatment centre
and will be administered only once.

Other medicines that will be given to the child before Libmeldy
The child may be given so-called mobilisation and conditioning medicines (for further information on possible side effects of these medicines, see section 4).
Since Libmeldy is made from the child's own stem cells, their blood will be drawn from a vein and collected to prepare the medicine approximately 2 months before treatment.

• First, the child will be given a mobilisation medicine to move blood stem cells from the bone marrow into the bloodstream.
• Blood stem cells can then be collected using a machine that separates blood components (apheresis machine). More than one day may be needed to collect enough blood stem cells to produce Libmeldy.

The blood stem cells collected will be divided into:

• Treatment cells, which will be used to produce Libmeldy by inserting a functioning copy of the ARSA gene into the stem cells of the sample.

• Backup cells, which will be frozen and stored to be given to the child as replacement stem cells if Libmeldy cannot be administered or does not work (see "When treatment with Libmeldy cannot be completed" in section 2). Please note that backup cells may alternatively be collected from the child's bone marrow. In this case, the child will be given medicines to relax, prevent pain, or induce unconsciousness before the procedure. The doctor will collect the child's bone marrow using a special syringe.
  How Libmeldy is given to the child

• Libmeldy will be administered to the child at a qualified treatment centre and by doctors trained in the use of this type of medicine.

• Doctors will verify that all Libmeldy infusion bags are correctly labelled as being produced from the child's own cells.

• Libmeldy is a one-time treatment and will not be administered again to the child.

If you have any doubts about the use of this medicine, please consult the doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone experiences them.
Some side effects are related to the conditioning medicine used to prepare the child's bone marrow for treatment with Libmeldy.
Talk to the child’s doctor about the side effects of the conditioning medicine. You may also read the package leaflet of that medicine.
Side effects of the conditioning medicine
➔ Tell the doctor or nurse immediately if the child experiences any of the following side effects after administration of the conditioning medicine. These usually occur within the first days to several weeks after administration of the conditioning medicine, but they may also develop much later.
Very common side effects (may affect more than 1 in 10 people)

• blood tests showing a low level of white blood cells, with or without fever
• mouth ulcers and inflammation of the mouth
• vomiting
• enlarged liver
• loss of function or reduced function of the ovaries

Common side effects (may affect up to 1 in 10 people)

• viral and bacterial infections
• chest infection (pneumonia)
• runny nose
• extreme response to an infection
• low level of red blood cells (anaemia)
• or of white blood cells
• unusual bleeding or bruising: may be caused by a low platelet count, reducing the blood’s ability to clot
• metabolic acidosis, a condition in which acid levels in the blood are high
• fluid overload in the body
• difficulty sleeping
• headache
• infection of organs involved in urine excretion (such as the bladder and urinary tract)
• nosebleeds
• pain in the mouth and throat
• fluid accumulation in the abdomen
• diarrhoea
• bleeding from the gastrointestinal tract
• nausea
• constipation
• indigestion
• increased liver enzymes (transaminases and aminotransferases) observed in blood tests
• decreased albumin observed in blood tests
• pain in the upper right part of the abdomen (belly) under the ribs, yellowing of the eyes or skin, rapid weight gain, swelling of the arms, legs and abdomen, and difficulty breathing. These may be signs of a serious liver disease called veno-occlusive disease
• skin peeling
• nappy rash
• skin itching
• skin inflammation
• back pain
• bone pain
• joint pain
• reduced urine production
• fever
• inflammation of the gastrointestinal tract
• positive test for Aspergillus (a fungus that may cause lung disease)

Side effects of Libmeldy
The following side effects have been reported with the use of Libmeldy.
Very common side effects (may affect more than 1 in 10 people)

• positive test for antibodies against ARSA. Antibodies are the body’s natural defence against anything the body perceives as foreign.

Reporting of side effects
If the child experiences any side effects, including those not listed in this leaflet, consult the doctor or nurse. You may also report side effects directly through the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Libmeldy

The following information is intended for healthcare professionals only.
Since this medicinal product will be administered in a hospital setting, the hospital is responsible for the proper storage of the medicinal product before and during use, as well as for its proper disposal.
Keep this medicinal product out of the sight and reach of children.
Do not use this medicinal product after the expiry date stated on the labels of the outer container and infusion bag.
Do not use this medicinal product if the infusion bag is damaged or if the contents are leaking.
Store at < -130 °C for up to 6 months. Do not thaw the product until it is ready for use. Once thawed, store at room temperature (20-25 °C) and use within 2 hours. Do not re-freeze.
This medicinal product contains genetically modified human cells. Unused medicinal product and waste material arising from this medicinal product must be disposed of in accordance with local guidelines for the handling of human-derived materials.

6. Package contents and other information

What Libmeldy contains

• The active substance consists of the child's stem cells containing functional copies of the ARSA gene. The concentration per bag is 2–10 x 10 cells per milliliter.
• The other ingredients are a solution used to preserve the frozen cells and sodium chloride (see section 2, Libmeldy contains sodium).

This medicinal product contains genetically modified human blood cells.
Description of the appearance of Libmeldy and package contents
Libmeldy is a dispersion ranging from clear to slightly cloudy, colourless to yellow or pink, supplied in one or more transparent infusion bags, each enclosed in a pouch inside a sealed metal container.
The child's name and date of birth, as well as coded information identifying the child as the patient, are printed on each infusion bag and on each metal container.
Marketing Authorization Holder
Orchard Therapeutics (Netherlands) B.V.
Bargelaan 200,
2333 CW Leiden,
The Netherlands
Manufacturer
AGC Biologics S.p.A.
Zambon Scientific Park
Via Meucci 3
20091 Bresso (MI)
Italy
AGC Biologics S.p.A.
Via Olgettina 58
20132 Milano
Italy
Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: https://www.ema.europa.eu.
This leaflet is available in all languages of the European Union/European Economic Area on the European Medicines Agency website.
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The following information is intended for healthcare professionals only:

It is important to read the entire content of this procedure before administering 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 (wear gloves, protective clothing, and protective eyewear) to avoid potential transmission of infectious diseases.
• Libmeldy must always be kept at a temperature < -130 °C until the bag contents are thawed for infusion.

Defining the dose to be administered

• The dose to be administered and the number of infusion bags of Libmeldy to be used must be determined based on the total number of CD34 cells provided, as indicated on the batch information sheet (i.e., the “provided dose,” calculated according to the patient’s weight at the time of cell collection). The dose of Libmeldy to be administered must also take into account the patient’s weight at the time of treatment, and each bag used must be administered in its entirety.

Preparation prior to administration

• A patient may be allocated multiple infusion bags. Each infusion bag is supplied within a sealed pouch, contained in a metal canister.
• Each wrapped infusion bag must be stored within its metal canister in liquid nitrogen vapor at < -130 °C until ready for thawing and infusion.
• Verify that all infusion bags are present and that no infusion bag has exceeded its expiration date by referring to the attached batch information sheet.
• A sterile 9 mg/mL (0.9%) sodium chloride injection solution must be available to prime the tubing before infusion and to flush the infusion bag and tubing after infusion.

Check before thawing

• Do not remove the metal canister from cryogenic storage or begin thawing Libmeldy until the patient is ready for infusion. The thawing times for each infusion bag containing Libmeldy and the infusion itself must be coordinated. Confirm the infusion time in advance and adjust the thawing start time so that Libmeldy is available for infusion when the recipient is ready.
• Open the metal canister and inspect the pouch and infusion bag for integrity before thawing. If an infusion bag is damaged, follow local guidelines for handling waste from human-derived material and contact Orchard Therapeutics immediately.
• Before thawing Libmeldy, verify that the patient’s identity matches the unique patient information on the packaging labels and the attached batch information sheet. Libmeldy is intended for autologous use only. Do not thaw or administer Libmeldy if the patient-specific label information on the infusion bag does not match the intended patient.

Thawing

• After carefully removing from the metal canister, thaw the infusion bag in its sealed pouch at 37 °C using a controlled-rate thawing device until no ice is visible in the infusion bag.
• Once thawing is complete, the bag must be removed immediately from the thawing device.
• Carefully open the pouch to remove the infusion bag, which should then be kept at room temperature (20–25 °C) until the time of infusion.
• Gently massage the infusion bag to resuspend the cells. The contents of the infusion bag should be inspected to ensure there are no visible cellular aggregates. Small clumps of cellular material should be dispersed by gentle manual mixing. Do not shake the bag.
• The infusion bag must not be washed, centrifuged, sampled, and/or resuspended in new media prior to infusion.
• Libmeldy must not be irradiated, as irradiation may result in product inactivation.
• If more than one infusion bag is provided for the patient’s treatment dose, the next bag should only be thawed after the entire contents of the previous bag have been completely infused.

Administration

• Libmeldy must be administered as an intravenous infusion via a central venous catheter, in accordance with standard procedures at the qualified cellular therapy treatment center.
• The recommended administration set consists of a blood transfusion set equipped with a 200 µm filter.
• Each bag must be infused by gravity within 2 hours of thawing, including any interruptions during infusion, to maintain maximum product viability.
• The maximum infusion rate is 5 mL/kg/h, and the contents of each bag should be infused over approximately 30 minutes.
• When more than one Libmeldy bag is required, only one bag of product should be administered per hour.
• Patients who have not been previously exposed to DMSO should be closely monitored. Vital signs (blood pressure, heart rate, and oxygen saturation) and the occurrence of any symptoms should be monitored before the start of infusion, during infusion, and after infusion of each Libmeldy bag, according to the institution’s clinical protocols.

After infusion, flush any remaining Libmeldy in the infusion bag and associated tubing with a 9 mg/mL (0.9%) sodium chloride injection solution to ensure that the maximum possible number of cells are infused into the patient. The infusion volume should be carefully assessed in relation to the patient’s age and weight.

Measures to be taken in case of accidental exposure

• In case of accidental exposure, follow local guidelines for handling human-derived material. Work surfaces and materials that may have come into contact with Libmeldy must be decontaminated with an appropriate disinfectant.

Precautions for disposal of the medicinal product

• Unused medicinal product and all materials that have come into contact with Libmeldy (solid and liquid waste) must be handled and disposed of as potentially infectious waste in compliance with local guidelines for handling human-derived material.