2.1 Dose

LENMELDY is provided as a single dose for infusion containing a suspension of CD34 +cells in one to eight infusion bags. Table 1 provides the minimum and maximum recommended dose of LENMELDY based on MLD disease subtype:

The dose administered is calculated based on the child’s weight at time of LENMELDY infusion using the information provided on the Lot Information Sheet. See the Lot Information Sheet provided with the product shipment for additional information pertaining to dose.

2.2 Preparation before LENMELDY Infusion

Mobilization, apheresis, and myeloablative conditioning are required prior to LENMELDY infusion. Before initiating these procedures, confirm that hematopoietic stem cell (HSC) gene therapy is appropriate for the child.

Screen children for hepatitis B virus (HBV), hepatitis C virus (HCV), human T-lymphotrophic virus 1 & 2 (HTLV-1/HTLV-2), human immunodeficiency virus 1 & 2 (HIV-1/HIV-2), cytomegalovirus (CMV), and mycoplasma infection in accordance with clinical guidelines before collection of cells for manufacturing.

Mobilization and Apheresis

Children are required to undergo HSC mobilization followed by apheresis to obtain CD34 +cells for LENMELDY manufacturing. In clinical trials of LENMELDY, granulocyte-colony stimulating factor (G-CSF) with or without plerixafor was used for mobilization.

For the manufacture of LENMELDY, a collection of a minimum of 8.0 × 10 6CD34 +cells/kg of autologous cells is required based on a weight at time of apheresis collection. Collection of the minimum number of CD34 +cells required for manufacture may be achieved using one or more cycles of mobilization.

A collection of unmanipulated back-up CD34 +cells of at least 2.0 × 10 6CD34 +cells/kg is required. These cells must be collected from the child and be cryopreserved prior to myeloablative conditioning. The back-up collection may be needed for rescue treatment if there is: 1) compromise of LENMELDY after initiation of conditioning but before infusion, 2) primary engraftment failure, or 3) loss of engraftment after infusion with LENMELDY. The back-up cells may be collected either through mobilized peripheral blood (mPB) apheresis or bone marrow collection.

Myeloablative Conditioning

Myeloablative conditioning must be administered before infusion of LENMELDY. In clinical trials of LENMELDY, busulfan was used for myeloablative conditioning. There is no data available supporting the use of alternative conditioning agents with LENMELDY.

Do not begin myeloablative conditioning until LENMELDY has been received and stored at the treatment center and the availability of the back-up collection of CD34 +cells has also been confirmed. After completion of the myeloablative conditioning, allow a minimum of 24 hours of washout before LENMELDY infusion.

Receipt and Storage of LENMELDY

• LENMELDY is shipped to the treatment center in the vapor phase of liquid nitrogen at less than -130°C (-202°F) along with the corresponding Lot Information Sheet. Two shippers would be used in the event that 5-8 bags are manufactured.
  
  
• Confirm patient identifiers on the product labels and the Lot Information Sheet.
  
  
• If there are any concerns about the product or packaging upon receipt, contact Orchard Therapeutics at 1-888-878-0185.
  
  
• Keep the infusion bag(s) in the metal cassette(s) and transfer LENMELDY from the transport vapor phase of liquid nitrogen shipper to the treatment center’s own vapor phase of liquid nitrogen storage at less than -130°C (-202°F). Store in the vapor phase of liquid nitrogen at less than -130°C (-202°F) until ready for thaw and administration.
  

Preparation of LENMELDY for Infusion

Coordinate the timing of LENMELDY thaw and infusion. Confirm the infusion time in advance and adjust the start time of LENMELDY thaw such that it will be available for infusion when the child and healthcare providers are ready to initiate LENMELDY administration as soon as possible after thaw. Each bag of LENMELDY should be infused via a central venous catheter and must be infused within 2 hours, post-thawing.

LENMELDY contains human blood cells that are genetically modified with replication-incompetent, self-inactivating lentiviral vector (LVV). Follow universal precautions and local biosafety guidelines for handling and disposal of LENMELDY to avoid potential transmission of infectious diseases.

Ensure the correct number of infusion bags are present. Use the corresponding Lot Information Sheet to confirm the number of LENMELDY bags shipped to the treatment center. A maximum of eight bags may be provided per child, which would take a maximum of approximately 16 hours to complete the infusion process. If more than one infusion bag is provided, thaw and administer each infusion bag completely before proceeding to thaw the next infusion bag. The following steps must be repeated for each LENMELDY infusion bag immediately prior to thaw.

1. Remove the metal cassette from the vapor phase of liquid nitrogen storage.
   
   
2. Confirm that "LENMELDY" is printed on the infusion bag label.
   
   
3. Confirm that the child's identity matches the unique patient identifiers located on the LENMELDY infusion bag. Do not infuse LENMELDY if the information on the patient-specific label on the infusion bag does not match the intended patient, and contact Orchard Therapeutics at 1-888-878-0185.
   
   
4. Use the accompanying Lot Information Sheet to confirm that the infusion bag is within the expiration date.
   
   
5. Inspect the infusion bag for any breaches of integrity before thawing and infusion. If an infusion bag is compromised, follow the local guidelines and contact Orchard Therapeutics immediately at 1-888-878-0185.
   
   
6. Thaw LENMELDY in the overwrap bag at 37°C (98.6°F) in a controlled thawing device. 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 until infusion.
   
   
7. After thawing, mix the contents gently by massaging the infusion bag to homogenize the cell suspension  and disperse any remaining cell aggregates. If visible cell aggregates remain, continue to gently mix the contents of the bag. Most cell aggregates should disperse with gentle manual mixing. Do not shake the bag. Do not wash, spin down and/or resuspend LENMELDY in new media prior to infusion.
   

• Do not sample, alter, irradiate, or refreeze LENMELDY.
  

2.3 Administration

LENMELDY is for autologous use only. The child’s identity must match the patient identifiers on the LENMELDY cassette(s) and infusion bag(s). Do not infuse LENMELDY if the information on the patient-specific label does not match the intended patient. LENMELDY must not be irradiated or infused using a leukodepleting filter.

1. Before infusion, confirm that the child’s identity matches the unique patient identifiers on the LENMELDY infusion bag.Use the Lot Information Sheet to confirm the total number of infusion bags to be administered.
   
   
2. Prime the tubing of the infusion set with 0.9% sodium chloride solution prior to infusion.
   
   
3. Expose the sterile port on the infusion bag by tearing off the protective wrap covering the port.
   
   
4. Access the infusion bag and infuse LENMELDY as soon as possible after thawing and complete the infusion within 2 hours after thawing.
   
   
5. Administer each infusion bag of LENMELDY as an intravenous infusion via a central venous catheter within 30 minutes via gravity or infusion pump. An infusion flow rate should be calculated based on the volume in each infusion bag.
   
   
6. After the entire content of the infusion bag is infused, flush all LENMELDY remaining in the infusion bag and any associated tubing with 0.9% sodium chloride solution using a rinse volume that is equal to or greater than the priming volume of any intravenous infusion set used to ensure that as many cells as possible are infused into the child.
   
   
7. If more than one infusion bag is provided, administer the content of each infusion bag completely before proceeding to thaw (following Section 2.2steps 1-7) and infuse (following Section 2.3steps 1-6) the content of the next infusion bag. If more than one infusion bag is necessary, do not administer more than one bag of product per hour.
   

After LENMELDY Administration

Standard procedures for patient management after HSC transplantation should be followed after LENMELDY infusion.

• Irradiate any blood products required within the first 3 months after LENMELDY infusion.
  
  
• Children treated with LENMELDY should not donate blood, organs, tissues, or cells at any time in the future.

5.1 Thrombosis and Thromboembolic Events

Treatment with LENMELDY may increase the risk of thrombosis and thromboembolic events. A child with PSEJ MLD died after experiencing a left hemisphere cerebral infarction secondary to a thrombotic event in a large blood vessel approximately one year after treatment with LENMELDY. Prior to the cerebral infarction, the child’s D-dimer was elevated (82 nmol/L, normal range: 1.5 - 4.2). Additional clinical findings included a minor elevation of liver enzymes. The etiology of the cerebral infarction was unclear but attribution to LENMELDY cannot be ruled out. No other events related to cerebral infarction have been reported during the clinical development of LENMELDY.

Some children received anti-thrombotic prophylaxis [ see Clinical Trials Experience (6.1)]. Evaluate the risk factors for thrombosis prior to and after LENMELDY infusion according to best clinical practice.

5.2 Encephalitis

Treatment with LENMELDY may increase the risk of encephalitis. A child with ESEJ MLD developed a serious event of encephalitis after treatment with LENMELDY. At the time of treatment, GMFC-MLD was Level 1 (able to walk independently with impaired gait). One month after treatment, the child experienced subacute neurological deterioration, with asthenia, hypotonia, cognitive and behavioral problems, vomiting, and swallowing disturbance. The child was afebrile, blood and CSF cultures were negative for bacterial infection, a large viral panel was negative and all routine laboratory tests were normal. The child was treated with plasmapheresis, immunoglobulin and rituximab leading to clinical improvement. Five months after onset of symptoms the child had reached GMFC-MLD Level 4 (walking not possible; able to sit without support and locomotion possible, or unable to sit without support but locomotion is possible). The child was subsequently treated with eculizumab and tocilizumab.

The etiology of this event is unclear but attribution to LENMELDY cannot be ruled out. Treatment with LENMELDY may trigger a relapsing-remitting pattern of disease progression. No other events related to encephalitis have been reported during the clinical development of LENMELDY.

Monitor children for signs or symptoms of encephalitis after LENMELDY treatment.

5.3 Serious Infection

In the period between start of conditioning and within one year after LENMELDY treatment, severe Grade 3 infections occurred in 39% of all children (21% bacterial, 5% viral, 5% bacterial and viral or bacterial and fungal, and 8% unspecified). The most common Grade 3 infections were device related infections (18%) (including two events of sepsis), respiratory tract infections (including 1 Grade 3 event of pneumonia) (8%), and gastroenteritis/enteritis (8%).

Grade 3 febrile neutropenia developed within 1 month after LENMELDY infusion in 82% of children. In the event of febrile neutropenia, monitor for signs and symptoms of infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated.

Monitor children for signs and symptoms of infection after myeloablative conditioning and LENMELDY infusion and treat appropriately. Administer prophylactic antimicrobials according to best clinical practice.

5.4 Veno-occlusive Disease

Three children (8%) treated in clinical trials of LENMELDY developed veno-occlusive disease (VOD), with one Grade 4 SAE and two Grade 3 AEs. None of these three events met Hy’s Law criteria.

Monitor children for signs and symptoms of VOD including liver function tests in all children during the first month after LENMELDY infusion. Consider prophylaxis for VOD with anti-thrombotic agents based on risk factors for VOD and best clinical practice.

5.5 Delayed Platelet Engraftment

Delayed platelet engraftment has been observed with LENMELDY treatment [ see Adverse Reactions (6.1)].  Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in children with prolonged thrombocytopenia. In clinical trials of LENMELDY, 4 (10%) children had delayed platelet engraftment after day 60 (range day 67-109), with 3 children requiring platelet transfusions until engraftment occurred. All children treated with LENMELDY received transfusion support with platelets according to best clinical practice.

Inform children of the risk of bleeding until platelet recovery has been achieved. Monitor children for thrombocytopenia and bleeding.

5.6 Neutrophil Engraftment Failure 

There is a potential risk of neutrophil engraftment failure after treatment with LENMELDY. In clinical trials of LENMELDY, no cases of neutrophil engraftment failure have been reported. Neutrophil engraftment failure is defined as failure to achieve three consecutive absolute neutrophil counts (ANC) ≥ 500 cells/microliter obtained on different days by Day 60 after infusion of LENMELDY.

Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a child treated with LENMELDY, provide rescue treatment with the unmanipulated back-up collection of CD34 +cells [ see Preparation before LENMELDY Infusion (2.2)].

5.7  Insertional Oncogenesis

There is a potential risk of LVV-mediated insertional oncogenesis after treatment with LENMELDY. In clinical trials of LENMELDY, no cases of insertional oncogenesis have been reported. Children treated with LENMELDY may develop hematologic malignancies and should be monitored lifelong. Monitor for hematologic malignancies with a complete blood count (with differential) annually and integration site analysis as warranted for at least 15 years after treatment with LENMELDY.

In the event that a malignancy occurs, contact Orchard Therapeutics at 1-888-878-0185 for reporting and to obtain instructions on collection of samples for testing.

5.8 Hypersensitivity Reactions

There is a potential risk of allergic reactions in children treated with LENMELDY. The dimethyl sulfoxide (DMSO) in LENMELDY may cause hypersensitivity reactions, including anaphylaxis which is potentially life-threatening and requires immediate intervention. Hypersensitivity including anaphylaxis can occur in children with and without prior exposure to DSMO.  In clinical trials of LENMELDY, no cases of hypersensitivity reactions have been reported.

5.9 Anti-retroviral Use 

Children should not take prophylactic HIV anti-retroviral medications for at least one month prior to mobilization, or for the expected duration of time needed for the elimination of the medications. Anti-retroviral medications may interfere with the manufacturing of LENMELDY. [ see Drug Interactions (7.2)].

If a child requires anti-retrovirals for HIV prophylaxis, initiation of LENMELDY treatment should be delayed until confirmation of a negative test for HIV.

5.10 Interference with Serology Testing

Children who have received LENMELDY 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, children who have received LENMELDY should not be screened for HIV infection using a PCR-based assay.

6.1  Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety data reflect experience from 39 children with MLD treated in clinical trials of LENMELDY: PSLI (n=20), PSEJ (n=7), ESEJ (n=10), and 2 children with advanced disease at the time of treatment [ see Clinical Studies (14)]. The median (min, max) years of follow-up for the safety population was 6.8 (0.6, 12.2).

Table 2 presents the non-laboratory treatment emergent adverse reactions occurring in ≥10% of all children with onset reported on or after the date of conditioning up to 1 year follow-up post-treatment.

In clinical trials of LENMELDY, 11 children (28%) developed an adverse event of neutropenia following conditioning, 8 of which (21%) reported a Grade 3 event. Despite best clinical practices including transfusion to prevent severe anemia, three children (8%) developed an adverse event of anemia, 1 of which reported a Grade 3 event. Nine children (23%) developed elevated liver enzymes, including three children (8%) who developed a Grade 3 event. Elevated levels of D-dimer (greater than 4.2 nmol/L) have been reported in 26/39 (67%) children during clinical trials of LENMELDY. Abnormal values up to 109.5 nmol/L were identified at timepoints from Day 21 to Year 7 after LENMELDY infusion, with no pattern identified.

Other clinically important events that occurred in < 10% of the population included the following:

One child reported Grade 3 adverse reactions of elevated alanine- and aspartate transaminases which met the definition of Hy’s Law at day 14 after LENMELDY infusion and resolved without treatment by 9 months after initial onset. Two children reported Grade 3 elevations in liver enzymes, and 1 child reported Grade 1 elevations in liver enzymes. All events resolved without treatment and are considered related to conditioning.

7.1 Vaccines

The safety and effectiveness of vaccination during or following LENMELDY treatment have not been studied. Vaccination is not recommended during the 6 weeks preceding the start of myeloablative conditioning, and until hematological recovery following treatment with LENMELDY. Where feasible, administer childhood vaccinations prior to myeloablative conditioning for LENMELDY.

7.2 Anti-retrovirals

Children should not take anti-retroviral medications for at least one month prior to mobilization or the expected duration for elimination of the medications [ see Warnings and Precautions (5.5)]. Anti-retroviral medications may interfere with the manufacturing of LENMELDY.

8.1 Pregnancy

Risk Summary

There are no clinical data from the use of LENMELDY in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with LENMELDY to assess whether it can cause fetal harm when administered to a pregnant woman. LENMELDY must not be administered during pregnancy because of the risk associated with myeloablative conditioning. Pregnancy after LENMELDY infusion should be discussed with the treating physician.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

8.2 Lactation

Risk Summary

There are no data on the presence of LENMELDY in human or animal milk, the effects on the breastfed child, or the effects on milk production. Because of the potential risks associated with myeloablative conditioning, breast-feeding should be discontinued during conditioning. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LENMELDY and any potential adverse effects on the breastfed child from LENMELDY or from the underlying maternal condition. Breast-feeding after LENMELDY infusion should be discussed with the treating physician.  Children receiving breast milk may continue to do so throughout their treatment under the advice of their treating physician.

8.3  Females and Males of Reproductive Potential

Pregnancy Testing

As a precautionary measure, a negative serum pregnancy test must be confirmed prior to the start of mobilization and re-confirmed prior to conditioning procedures and before administration of LENMELDY in females of childbearing potential.

Contraception

Males capable of fathering a child and females of childbearing age should use an effective method of contraception from start of mobilization through at least 6 months after administration of LENMELDY.

Infertility

There are no data on the effects of LENMELDY on fertility.

Data are available on the risk of infertility with myeloablative conditioning. In clinical trials of LENMELDY, seven children (50% of females) developed ovarian failure. Advise children of the option to cryopreserve semen or ova before treatment, if appropriate.

8.4  Pediatric Use

The safety and efficacy of LENMELDY has been established in children with PSLI, PSEJ and ESEJ MLD. The clinical trials of LENMELDY treated 20 PSLI, 7 PSEJ, and 10 ESEJ MLD children who received LENMELDY between ages 8 – 19 months (median age of 12 months), 11 months – 5.56 years (median age of 2.57 years), and 2.54 – 11.64 years (median age of 5.84 years), respectively. The safety and efficacy of LENMELDY have not yet been established in children with the late juvenile form of the disease [ see Clinical Studies (14)].

8.6 Patients Seropositive for Human Immunodeficiency Virus (HIV) or other infectious diseases

LENMELDY has not been studied in children with HIV-1, HIV-2, HTLV-1, HTLV-2, HBV, HVC, or mycoplasma infection. Negative serology tests for HIV-1/2, HTLV-1/2, HBV, HCV, and mycoplasma are necessary to ensure acceptance of apheresis material for LENMELDY manufacturing.

8.7 Renal Impairment

LENMELDY has not been studied in children with renal impairment. Children should be assessed for renal impairment to ensure HSC transplantation is appropriate.

8.8 Hepatic Impairment

LENMELDY has not been studied in children with hepatic impairment. Children should be assessed for hepatic impairment to ensure HSC transplantation is appropriate.

12.1 Mechanism of Action

LENMELDY inserts one or more functional copies of the human ARSA complementary deoxyribonucleic acid (cDNA) into the patients’ HSCs, through transduction of autologous CD34 +cells with ARSA LVV. After LENMELDY infusion, transduced CD34 +HSCs engraft in bone marrow, repopulate the hematopoietic compartment and their progeny produce ARSA enzyme. Functional ARSA enzyme can breakdown or prevent the harmful accumulation of sulfatides.

12.2 Pharmacodynamics

Deficiency of ARSA is known to be the cause of MLD; therefore, ARSA activity in peripheral blood mononuclear cells of the hematopoietic lineage (i.e. ARSA in PBMC) was evaluated to provide evidence of pharmacodynamic activity of LENMELDY. 

Median ARSA activity in PBMCs was at supranormal levels by 3 months post-treatment in the PSLI and PSEJ populations (normal range for ARSA activity is 31-198 nmol/mg/h) and supranormal median levels were sustained throughout the duration of follow-up (Table 3). In ESEJ median ARSA activity was within normal range from Month 3 to Year 2 and supranormal activity was achieved at Year 3 and 5 (Table 3).

12.3 Pharmacokinetics

LENMELDY is an autologous gene therapy which includes hematopoietic stem cells (HSCs) that have been genetically modified ex vivo. The nature of LENMELDY is such that conventional pharmacokinetic studies on absorption, distribution, metabolism, and excretion are not applicable.

12.6 Immunogenicity

During the clinical development program, anti-ARSA antibodies (AAA) were reported in 6/39 children (5 PSLI and 1 PSEJ) with titers between 1:80 and 1:6400. Five events resolved between Days 45 and 368, of which two resolved spontaneously. One event was reported as ongoing. One child reported declining ARSA levels in the setting of AAA but the impact on clinical efficacy is unknown as the child is still in the pre-symptomatic phase of the disease. Four children received treatment with rituximab. There is insufficient information to characterize the impact of AAA on ARSA activity in PBMC, clinical efficacy, or safety.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity studies have been performed with LENMELDY. No studies have been conducted to evaluate the effects of LENMELDY on fertility.