LENMELDY

1 INDICATIONS AND USAGE LENMELDY is indicated for the treatment of children with pre-symptomatic late infantile (PSLI), pre-symptomatic early juvenile (PSEJ) or early symptomatic early juvenile (ESEJ) metachromatic leukodystrophy (MLD). LENMELDY is an autologous hematopoietic stem cell-based gene therapyindicated for the treatment of children with pre-symptomatic late infantile (PSLI), pre-symptomatic early juvenile (PSEJ) or early symptomatic early juvenile (ESEJ) metachromatic leukodystrophy (MLD).

2 DOSAGE AND ADMINISTRATION For autologous use only. For one-time single-dose intravenous use only. For autologous use only. For one-time single-dose intravenous use only. Children are required to undergo hematopoietic stem cell (HSC) mobilization followed by apheresis to obtain CD34+ cells for LENMELDY manufacturing. ( 2.2 ) Dosing of LENMELDY is based on the number of CD34+ cells in the infusion bag(s) per kg of body weight. ( 2.1 ) The minimum recommended dose is based on the MLD disease subtype. ( 2.1 ) Myeloablative conditioning must be administered before infusion of LENMELDY. ( 2.2 ) Confirm that the child’s identity matches the unique patient identification information on the LENMELDY infusion bag(s) prior to infusion. ( 2.2 ) Do not sample, alter, irradiate, or refreeze LENMELDY. ( 2.2 ) Do not use a leukodepleting filter. ( 2.3 ) 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: Table 1: Minimum and Maximum Recommended Dose of LENMELDY MLD Subtype Minimum Recommended Dose (CD34 + cells/kg) Maximum Recommended Dose (CD34 + cells/kg) Pre-symptomatic late infantile 4.2 x 10 6 30 x 10 6 Pre-symptomatic early juvenile 9 x 10 6 30 x 10 6 Early symptomatic early juvenile 6.6 x 10 6 30 x 10 6 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 6 CD34 + 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 6 CD34 + 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. Remove the metal cassette from the vapor phase of liquid nitrogen storage. Confirm that "LENMELDY" is printed on the infusion bag label. 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. Use the accompanying Lot Information Sheet to confirm that the infusion bag is within the expiration date. 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. 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. 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. 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. Prime the tubing of the infusion set with 0.9% sodium chloride solution prior to infusion. Expose the sterile port on the infusion bag by tearing off the protective wrap covering the port. Access the infusion bag and infuse LENMELDY as soon as possible after thawing and complete the infusion within 2 hours after thawing . 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. 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. If more than one infusion bag is provided, administer the content of each infusion bag completely before proceeding to thaw (following Section 2.2 steps 1-7) and infuse (following Section 2.3 steps 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.

4 CONTRAINDICATIONS None. None ( 4 )

5 WARNINGS AND PRECAUTIONS Thrombosis and Thromboembolic Events : Evaluate the risk factors for thrombosis prior to and after LENMEDLY infusion. Consider prophylaxis with anti-thrombotic agents prior to treatment with LENMELDY. ( 5.1 ) Encephalitis : Monitor children for signs or symptoms of encephalitis after treatment with LENMELDY. ( 5.2 ) Serious Infection : Monitor children for serious infection after myeloablative conditioning and LENMELDY infusion. ( 5.3 ) Veno-occlusive Disease : Monitor children for signs and symptoms of VOD including liver function tests in all patients during the first month after LENMELDY infusion. Consider prophylaxis for VOD. ( 5.4 ) Delayed Platelet Engraftment : Monitor children for thrombocytopenia and bleeding until platelet recovery is achieved. ( 5.5 ) Risk of Neutrophil Engraftment Failure : Monitor absolute neutrophil counts (ANC) after LENMELDY infusion. If neutrophil engraftment does not occur, administer rescue cells. ( 5.6 ) Risk of Insertional Oncogenesis: Monitor children for hematologic malignancies annually after treatment with LENMELDY. ( 5.7 ) Risk of Hypersensitivity Reactions : Monitor for hypersensitivity reactions during infusion. ( 5.8 ) 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.

7 DRUG INTERACTIONS No formal drug interaction studies have been performed. LENMELDY is not expected to interact with the hepatic cytochrome P-450 family of enzymes or drug transporters. Anti-retrovirals : Do not take anti-retroviral medications for at least one month prior to initiating medications for stem cell mobilization and for the expected duration of time needed for the elimination of the medications. ( 7.2 ) 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.

6 ADVERSE REACTIONS The most common non-laboratory adverse reactions (occurring in ≥10% of all children within Year 1 of treatment) were: febrile neutropenia (85%), stomatitis (77%), respiratory tract infections (54%), rash (33%), device related infections (31%), other viral infections (28%), pyrexia (21%), gastroenteritis (21%), and hepatomegaly (18%). The following clinically significant adverse reactions are described elsewhere in the labeling: Thrombosis and Thrombotic Events [ see Warnings and Precautions (5.1) ] Encephalitis [ see Warnings and Precautions (5.2) ] Serious Infection [ see Warnings and Precautions (5.3) ] Veno-occlusive Disease [ see Warnings and Precautions (5.4) ] Delayed Platelet Engraftment [ see Warnings and Precautions (5.5) ] Neutrophil Engraftment Failure [ see Warnings and Precautions (5.6) ] Insertional Oncogenesis [ see Warnings and Precautions (5.7) ] Hypersensitivity Reactions [ see Warnings and Precautions (5.8) ] The most common non-laboratory adverse reactions (incidence ≥ 10%) were: febrile neutropenia (85%), stomatitis (77%), respiratory tract infections (54%), rash (33%), device related infections (31%), other viral infections (28%), pyrexia (21%), gastroenteritis (21%), and hepatomegaly (18%). ( 6.1 ) The most common laboratory abnormalities were: elevated D-dimer (67%), neutropenia (28%), and elevated liver enzymes (23%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Orchard Therapeutics at toll-free phone 1-888-878-0185 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Table 2: Summary of Non-Laboratory Treatment Emergent Adverse Reactions Reported in at Least 10% of Patients Within Year 1 Following Treatment with LENMELDY (N = 39) Includes adverse events potentially related to busulfan myeloablative conditioning. Adverse reaction System Organ Class/Preferred Term Any Grade n (%) patients Grade 3 or higher n (%) patents Blood and lymphatic system disorders -- -- Febrile neutropenia 33 (85) 32 (82) Gastrointestinal disorders -- -- Stomatitis 30 (77) 29 (74) General disorders and administration site conditions -- -- Pyrexia 8 (21) 1 (3) Hepatobiliary disorders -- -- Hepatomegaly 7 (18) 0 Infections and infestations -- -- Respiratory tract infections Includes events with PTs of Bronchitis, Nasopharyngitis, Pharyngitis, Pneumonia, Respiratory tract infection, Rhinitis, Tonsillitis, Upper respiratory fungal infection and Upper respiratory tract infection. 21 (54) 3 (8) Device related infection Includes events of Bacterial sepsis, Catheter site cellulitis, Catheter site infection, Device related infection, Sepsis, and Vascular device infection. 12 (31) 7 (18) Gastroenteritis Includes events with PTs of Enteritis, Gastroenteritis, Gastroenteritis Aeromonas and Gastroenteritis rotavirus. 8 (21) 3 (8) Other viral infections Includes events with PTs of Adenovirus infection, Cytomegalovirus infection, Cytomegalovirus test positive, Cytomegalovirus viremia, Enterovirus infection, Hand-foot-and-mouth disease, Herpes zoster, SARSCov-2-test positive, and Viral infection (excluding PT of Gastroenteritis rotavirus). 11 (28) 2 (5) Skin and subcutaneous tissue disorders -- -- Rash Includes events with PTs of Dermatitis, Dermatitis bullous, Rash, Rash erythematous, Drug eruption and Rash maculopapular. 13 (33) 3 (8) 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.

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.