Libmeldy 2-10 x 10^6 cells/ml dispersion for infusion

Patient Leaflet: Information for the Patient or Caregiver

Introduction

Patient Information Leaflet

Libmeldy 2-10 x 10⁶ cells/ml dispersion for infusion

atidarsagene autotemcel

This medicinal product is subject to additional monitoring, which will enable rapid identification of new safety information. You can help by reporting any side effects your child may experience. Information on how to report side effects is provided at the end of section 4.

Read this entire leaflet carefully before this medicine is administered to your child, as it contains important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, consult your child's doctor or nurse.
• Your child's doctor or nurse will provide you with a patient information card. Read this card carefully and follow the instructions it contains.
• Always show the patient information card to your child's doctor or nurse when your child visits them, or if your child is admitted to a hospital.
• If your child experiences any side effects, consult your child's doctor or nurse, even if they are side effects not listed in this leaflet. See section 4.

Leaflet Contents

1. What Libmeldy is and what it is used for
2. What you need to know before Libmeldy is administered to your child
3. How Libmeldy is administered
4. Possible side effects
5. How to store Libmeldy
6. Package contents and additional 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 made for your child using their own blood cells.

What Libmeldy is used for

Libmeldy is used to treat a serious disease called metachromatic leukodystrophy (MLD):

• in children with the “late infantile” or “early juvenile” forms of the disease who have not yet developed any signs or symptoms;
• in children with the “early juvenile” form of the disease who have started to develop symptoms, but whose symptoms are not yet rapidly worsening.

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

How Libmeldy works

Stem cells are taken from your child’s blood. These cells are then modified in the laboratory to introduce a functional gene for producing ARSA. When Libmeldy, which consists of these modified cells, is given to your child, the cells will start producing ARSA to break down sulfatides in nerve cells and other cells in your child’s body. This process is expected to slow the progression of the disease and improve your child’s quality of life.

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

If you have any questions about how Libmeldy works or why it has been prescribed for your child, please ask your child’s doctor.

2. What you need to know before your child is given Libmeldy

Do not give Libmeldy to your child:

• If your child is allergic to atidarsagene autotemcel or to any of the components of this medicine (listed in section 6). If you think your child may be allergic, please consult your doctor.
• If your child has previously received gene therapy using their own blood stem cells.
• If your child is allergic or if your doctor thinks your child might experience unacceptable adverse effects from any of the components of the medicines your child will receive before treatment with Libmeldy (see section 3).

Warnings and precautions

Talk to your doctor before your child starts receiving Libmeldy.

• Information about cell-based medicines such as Libmeldy must be kept for 30 years at the hospital. The information stored will include your child's name and the batch number of Libmeldy they received.

• Libmeldy is made from your child’s own stem cells and should only be given to your child.

Before treatment with Libmeldy

• Your child will be evaluated by their doctor to confirm they have MLD and to assess the symptoms and effects of their disease before deciding whether to use Libmeldy. Your child may not show any physical signs of the disease at the time of initial evaluation.

If your child’s MLD has progressed and worsened before treatment begins, your doctor may determine that the disease has reached a "rapidly progressive phase." If this occurs, your child may not benefit from treatment, and their 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 lines include infections and blood clots. The medical team will monitor your child for any catheter-related complications.

• Libmeldy has been tested for infectious microorganisms before administration to your child. There remains a small risk of infection. Your child’s doctors and nurses will monitor them throughout the infusion for signs of infection and provide treatment if needed.

• Your child’s doctor will examine their thyroid gland. The thyroid gland is located in the neck and produces hormones important for normal body function. Follow-up monitoring may also be performed after treatment if required.

After treatment with Libmeldy

• After treatment, your child may be asked to enroll 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 three months after receiving Libmeldy, blood products must be irradiated. This means white blood cells, called lymphocytes, have been reduced to minimize the risk of transfusion reactions. The doctor will monitor your child for any transfusion-related complications.

• Your child’s red blood cell count may remain low for some time after treatment with Libmeldy. This also affects blood cells that fight infections, called neutrophils, 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 "graft failure." In such a case, your child’s doctor may decide to infuse previously collected rescue cells (see section 3). The rescue cells have not been modified with the functional ARSA gene and will not produce this enzyme.

• After receiving the conditioning medicine, your child may have a low platelet count. This means their blood may not clot normally, making them prone to bleeding for some time after treatment. The doctor will monitor your child’s platelet count through blood tests and provide treatment if needed. This may include a platelet transfusion to help increase their platelet count.

• Metabolic acidosis may occur. This is a condition in which the level of acid in the blood increases. There can be many different reasons for this, and it is more common in patients with MLD. Symptoms of metabolic acidosis include feeling short of breath, rapid breathing, nausea (feeling unwell), 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 cause blood cancers (leukemia and lymphoma). After treatment, your child’s doctor will monitor them for any signs of leukemia or lymphoma.

• During clinical studies, some patients developed antibodies against the ARSA enzyme, called anti-ARSA antibodies (see adverse effects of Libmeldy in section 4). This resolved either spontaneously or after treatment with an appropriate medicine. Your child’s doctor will test their blood for anti-ARSA antibodies and provide treatment if needed.

• After your child has received Libmeldy, they will be monitored with regular blood tests. This includes measuring antibodies, known as immunoglobulins, in their blood. If levels are low, your child may require immunoglobulin replacement therapy. Your child’s doctor will discuss this with you if necessary.

• Libmeldy is produced 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 infect your child with HIV, having Libmeldy in their blood may cause a false positive HIV test result with some commercial tests (so-called "PCR-based tests") that detect a part of HIV used in making Libmeldy. If your child’s HIV test result is positive after treatment with Libmeldy, contact your child’s doctor or nurse.

• After treatment with Libmeldy, your child will not be able to donate blood, organs, tissues, or cells. This is because Libmeldy is a gene therapy product.

Before Libmeldy is given to your child, the doctor will:

• Examine your child’s lungs, heart, kidneys, liver, and blood pressure.
• Look for signs of infection; any infection will be treated before your child receives Libmeldy.
• Test for hepatitis B, hepatitis C, human T-cell leukemia virus (HTLV), HIV, or mycoplasma infection.
• Check whether your child has been vaccinated within the past six weeks or if vaccination is planned in the coming months.

When Libmeldy treatment cannot be completed

Before Libmeldy is administered, your child will receive a conditioning medicine to eliminate their bone marrow cells.

If Libmeldy cannot be administered after your child has received the conditioning medicine, or if the modified stem cells do not engraft (take hold) in your child’s body, the doctor may decide to reinfuse the previously collected rescue cells via an infusion (see also section 3, How Libmeldy is made and administered). The rescue cells have not been modified with the functional ARSA gene and will not produce this enzyme. For more information, please contact your child’s doctor.

Other medicines and Libmeldy

Tell your doctor if your child is taking, has recently taken, or might need to take any other medicines.

• Your child must not take any HIV infection medicines starting at least one month before administration of the medicines, up to at least seven days after infusion with Libmeldy (see also section 3, How Libmeldy is made and administered).
• Your child must not receive live attenuated virus vaccines during the six weeks before administration of the conditioning medicine to prepare for Libmeldy treatment, or after treatment while your child’s immune system (the body’s defense system) is recovering.

Libmeldy contains sodium and dimethyl sulfoxide

This medicine contains 35–560 mg of sodium (main component of common/table salt) per dose. This corresponds to 2–28% of the maximum daily recommended sodium intake for an adult.

If your child has not previously been exposed to dimethyl sulfoxide (a substance used to preserve frozen cells), the doctor or nurse should monitor your child for any reactions during and after the infusion of each bag.

3. How Libmeldy is administered

Libmeldy will always be given to your child at a specialized treatment center by a doctor and can only be administered once.

Other medicines that will be given to your child before Libmeldy

Your child may receive medicines known as mobilization medicines and conditioning medicines (see section 4 for more information about the possible side effects of these medicines).

Since Libmeldy is made from your child's own stem cells, your child's blood will be drawn from a vein and collected to prepare the medicine approximately two months before treatment.

• First, your child will be given a mobilization medicine to move blood stem cells from the bone marrow into the bloodstream.
• Then, the blood stem cells can be collected using a machine that separates the blood components (apheresis machine). It may take more than one day to collect enough stem cells from the blood to produce Libmeldy.

The stem cells collected from the blood will be divided into:

• The treatment sample, which will be sent for preparation of Libmeldy by inserting a functional copy of the ARSA gene into the stem cells in the sample.
• The back-up sample, which will be frozen and stored so that it can be given to your child as replacement stem cells if Libmeldy cannot be administered or does not work (see "When Libmeldy treatment cannot be completed" in section 2). It should be noted that alternatively, back-up cells may be obtained from your child's bone marrow. In this case, your child will receive medicines to relax, prevent pain, or induce unconsciousness before the procedure. The doctor will extract the bone marrow from your child using a special needle.

How Libmeldy is administered to your child

• Libmeldy will be administered to your child at a specialized treatment center and by doctors experienced in using this type of medicine.
• Doctors will verify that the Libmeldy infusion bags are labeled as being manufactured from your child's own sample.
• Libmeldy is a single-use treatment. It cannot be administered again to your child in the future.

If you have any further questions about the use of this medicine, ask your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

Some side effects are related to the conditioning medicine used to prepare your child's bone marrow for treatment with Libmeldy.

Talk to your 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 your doctor or nurse immediately if your child experiences any of the following side effects after receiving the conditioning medicine. These usually occur within the first few days to several weeks after receiving 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, mouth inflammation
• feeling unwell (vomiting)
• hepatomegaly
• loss or reduced function of the ovaries

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

• bacterial and viral infections
• chest infection (pneumonia)
• runny nose
• extreme response to an infection
• low number of red blood cells (anaemia) or white blood cells
• bleeding or bruising: may be caused by a low platelet count, which reduces the blood’s ability to clot
• metabolic acidosis, a condition in which acid levels in the blood are high
• excess fluid in the body
• trouble sleeping
• headache
• infection of the 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 in the intestinal tract
• feeling of illness (nausea)
• constipation
• indigestion
• increased liver enzymes (transaminases and aminotransferases) observed in blood tests
• decreased liver enzymes (albumin) observed in blood tests
• pain in the upper right part of the abdomen (belly) below 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 condition called veno-occlusive disease
• skin peeling
• diaper dermatitis
• skin itching
• skin inflammation
• back pain
• bone pain
• joint pain
• reduced urine production
• fever
• inflammation of the intestinal tract
• positive Aspergillus test (a fungus that may cause lung disease)

Side effects of Libmeldy

The following side effects have been reported with 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 any substance the body considers foreign.

Reporting of side effects

If your child experiences any type of side effect, speak to your child’s doctor or nurse, even if it is a side effect not listed in this leaflet. You may also report them directly through the national reporting system included in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of 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 medicine before and during use, as well as for its proper disposal.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date stated on the outer packaging and infusion bag labels.

Do not use this medicine if the infusion bag is damaged or shows signs of leakage.

Store at <-130 °C for up to six months. Do not thaw the medicine until it is ready to be used. After thawing, store at room temperature (20 °C–25 °C) and use within two hours. Do not refreeze.

This medicine contains genetically modified human cells. Any unused medicine or waste material must be disposed of in accordance with local guidelines for handling materials of human origin.

6. Package contents and other information

Composition of Libmeldy

• The active substance consists of your child's own stem cells containing functional copies of the ARSA gene. The concentration per bag is 2–10 × 10⁶ cells per millilitre.

• The other components 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.

Appearance of Libmeldy and contents of the container

Libmeldy is a dispersion of cells ranging from transparent to slightly turbid, colourless to yellow or pinkish, supplied in one or more transparent infusion bags, each individually enclosed in a sealed pouch within a closed container.

Your child's name, date of birth, and coded information identifying your child as the patient are printed on each infusion bag and on each container.

Marketing Authorisation 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

Date of latest revision of this leaflet:

Other sources of information

Detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu.

This package leaflet is available on the European Medicines Agency website in all languages of the European Union/European Economic Area.

This information is intended for healthcare professionals only:

It is important to read all of this procedure before administering Libmeldy.

Precautions to be taken before handling or administering the medicine

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

Definition of the administered dose

• The dose to be infused and the number of Libmeldy infusion bags to be used must be determined based on the total number of CD34+ cells supplied, as indicated on the batch information label (i.e., the "supplied dose", calculated according to the patient's weight at the time of cell collection). The dose of Libmeldy administered must also take into account the patient's weight at the time of treatment, and any bag used must be administered in its entirety.

Preparation prior to administration

• Multiple infusion bags may be used for each patient. Each infusion bag is provided within a sealed overwrap pouch contained in a metal cartridge.
• The overwrap pouch(es) containing the infusion bag(s) must remain inside the metal cartridge(s) and stored in the vapour phase of liquid nitrogen at < -130 °C until ready for thawing and infusion.
• Count all infusion bags and confirm that each infusion bag is within the expiry date indicated on the attached batch information label.
• 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.

Checks before thawing

• Do not remove the metal cartridge from cryogenic storage or begin thawing Libmeldy until the patient is ready for infusion. The timing of thawing the Libmeldy infusion bag(s) and the infusion itself must be coordinated. Confirm the infusion time in advance and adjust the start time accordingly so that Libmeldy is available when the recipient is ready.
• Open the metal cartridge and inspect the sealed overwrap pouch and infusion bag for any loss of integrity before thawing. If an infusion bag is compromised, follow local guidelines for handling human-origin waste materials and contact Orchard Therapeutics immediately.
• Before thawing Libmeldy, verify that the patient's identity matches the unique patient information on the container labels and the batch information label provided. Libmeldy is intended for autologous use only. Do not thaw or infuse Libmeldy if the patient-specific label information on the infusion bag does not match the patient.

Thawing

• After carefully removing it from the metal cartridge, thaw the infusion bag in its sealed overwrap pouch at 37 °C using a controlled thawing device until no visible ice remains in the infusion bag.
• Once thawing is complete, immediately remove the bag from the thawing device.
• Carefully open the sealed overwrap pouch to remove the infusion bag, which should then be kept at room temperature (20 °C–25 °C) until infusion.
• Gently massage the infusion bag to resuspend the cells. Inspect the bag contents for any remaining visible cellular aggregates. Small clumps of cellular material should be dispersed with gentle manual mixing. Do not shake the bag.
• The infusion bag must not be washed, centrifuged, sampled, or resuspended in other media prior to infusion.
• Libmeldy must not be irradiated, as irradiation may lead to product inactivation.
• If more than one infusion bag is provided for the patient's treatment dose, the next bag must only be thawed after the previous bag has been completely infused.

Administration

• Libmeldy must be administered as an intravenous infusion via a central venous catheter, in accordance with standard procedures at the specialised treatment centre for cellular therapy products.
• The recommended administration set consists of a blood transfusion set equipped with a 200 µm filter.
• Each bag must be infused by gravity within two 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 should be infused per hour.
• Patients who have not been previously exposed to dimethyl sulfoxide (DMSO) must be closely monitored. Vital signs (blood pressure, heart rate, and oxygen saturation) and the emergence of any symptoms must be monitored before starting infusion, during infusion, and after infusion of each Libmeldy bag, according to institutional guidelines.
• At the end of the infusion, flush residual Libmeldy remaining in the infusion bag and any tubing used with 9 mg/ml (0.9%) sodium chloride injection solution to ensure that the maximum number of cells is delivered to the patient. Special consideration must be given to the infusion volume in relation to the patient's age and weight.

Measures to be taken in case of accidental exposure

• In the event of accidental exposure, local guidelines for handling human-origin materials must be followed. Work surfaces and materials that may have come into contact with Libmeldy must be decontaminated using an appropriate disinfectant.

Precautions for disposal of the medicine

• Unused medicine 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 accordance with local guidelines for handling human-origin materials.