Atidarsagene Autotemcel

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).

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.

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 LENMEL

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 eve

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 n

4 CONTRAINDICATIONS None. None ( 4 )