Elivaldogene Autotemcel

1 INDICATIONS AND USAGE SKYSONA is indicated to slow the progression of neurologic dysfunction in boys 4-17 years of age with early, active cerebral adrenoleukodystrophy (CALD) without an available human leukocyte antigen (HLA)-matched donor for allogeneic hematopoietic stem cell transplant. Early, active cerebral adrenoleukodystrophy refers to asymptomatic or mildly symptomatic (neurologic function score, NFS ≤ 1) boys who have gadolinium enhancement on brain magnetic resonance imaging (MRI) and Loes scores of 0.5-9. This indication is approved under accelerated approval based on 24-month Major Functional Disability (MFD)-free survival [see Clinical Studies (14) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). SKYSONA is an autologous hematopoietic stem cell-based gene therapy indicated to slow the progression of neurologic dysfunction in boys 4-17 years of age with early, active cerebral adrenoleukodystrophy (CALD) without an available human leukocyte antigen (HLA)-matched donor for allogeneic hematopoietic stem cell transplant. Early, active CALD refers to asymptomatic or mildly symptomatic (neurologic function score, NFS ≤ 1) boys who have gadolinium enhancement on brain magnetic resonance imaging (MRI) and Loes scores of 0.5-9. This indication is approved under accelerated approval based on 24-month Major Functional Disability (MFD)-free survival. [see Clinical Studies (14) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). ( 1 ) Limitations of Use SKYSONA does not treat or prevent adrenal insufficiency. ( 1 ) An immune response to SKYSONA may cause rapid loss of efficacy of SKYSONA in patients with full deletions of the human adenosine triphosphate binding cassette, sub family D, member 1 ( ABCD1) gene. ( 1 ) SKYSONA has not been studied in CALD secondary to head trauma. ( 1 ) Given the risk of hematologic malignancy with SKYSONA, and unclear long-term durability of SKYSONA and human adrenoleukodystrophy protein (ALDP) expression, careful consideration should be given to the timing of treatment for each boy and treatment of boys with isolated pyramidal tract disease as clinical manifestations do not usually occur until adulthood. ( 1 ) Limitations of Use SKYSONA does not prevent the development of or treat adrenal insufficiency due to adrenoleukodystrophy. An immune response to SKYSONA may limit the persistence of descendent cells of SKYSONA, causing rapid loss of efficacy of SKYSONA in patients with full deletions of the human adenosine triphosphate binding cassette, sub family D, member 1 ( ABCD1) gene. SKYSONA has not been studied in patients with CALD secondary to head trauma. Given the risk of hematologic malignancy with SKYSONA, and unclear long-term durability of SKYSONA and human adrenoleukodystrophy protein (ALDP) expression, careful consideration should be given to the appropriateness and timing of treatment for each boy, especially for boys with isolated pyramidal tract disease since their clinical symptoms do not usually occur until adulthood.

12.1 Mechanism of Action SKYSONA adds functional copies of the ABCD1 cDNA into patients' hematopoietic stem cells (HSCs) through transduction of autologous CD34+ cells with Lenti-D LVV. After SKYSONA infusion, transduced CD34+ HSCs engraft in the bone marrow and differentiate into various cell types, including monocytes (CD14 + ) capable of producing functional ALDP. Functional ALDP can then participate in the local degradation of very long chain fatty acids (VLCFAs), which is believed to slow or possibly prevent further inflammation and demyelination.

2 DOSAGE AND ADMINISTRATION For autologous use only. For intravenous use only. For autologous use only. For intravenous use only. Patients must undergo hematopoietic stem cell (HSC) mobilization and apheresis to obtain CD34+ cells for SKYSONA manufacturing. ( 2.2 ) Dosing of SKYSONA 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 5.0 × 10 6 CD34+ cells/kg. ( 2.1 ) Full myeloablative and lymphodepleting conditioning must be administered before infusion of SKYSONA. ( 2.2 ) Verify the patient's identity matches the unique patient identification information on the SKYSONA infusion bag(s) prior to infusion. ( 2.2 ) Do not sample, alter, or irradiate SKYSONA. ( 2.2 ) Do not use an in-line blood filter or an infusion pump. ( 2.3 ) 2.1 Dose SKYSONA is provided as a single dose for infusion containing a suspension of CD34+ cells in one or two infusion bags. The minimum recommended dose of SKYSONA is 5.0 × 10 6 CD34+ cells/kg. The dose is calculated based on the patient's weight prior to first apheresis. See the Lot Information Sheet provided with the product shipment for additional information pertaining to dose. 2.2 Preparation Before SKYSONA Infusion Before mobilization, apheresis, and conditioning are initiated, confirm that hematopoietic stem cell (HSC) transplantation is appropriate for the patient. Perform screening for hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus 1 & 2 (HIV-1/HIV-2) and Human T-lymphotropic virus 1 & 2 (HTLV-1/HTLV-2) in accordance with clinical guidelines before collection of cells for manufacturing. Mobilization and Apheresis Patients are required to undergo HSC mobilization followed by apheresis to obtain CD34+ cells for product manufacturing. Weigh the patient prior to the first apheresis collection. Collect a minimum number of CD34+ cells of 12 × 10 6 CD34+ cells/kg. A back-up collection of CD34+ cells of ≥ 1.5 × 10 6 CD34+ cells/kg (if collected by apheresis) or ≥ 1.0 × 10 8 TNC/kg (Total Nucleated Cells, if collected by bone marrow harvest) is required. Collect and cryopreserve these cells prior to initiating conditioning and infusion with SKYSONA. The back-up collection may be needed for rescue treatment if there is: 1) compromise of SKYSONA after initiation of conditioning and before SKYSONA infusion, 2) primary engraftment failure, or 3) loss of engraftment after infusion with SKYSONA. Myeloablative and Lymphodepleting Conditioning Full myeloablative and lymphodepleting conditioning must be administered before infusion of SKYSONA. Consult prescribing information for the conditioning agents prior to treatment. Do not begin conditioning until SKYSONA has been received and stored at the treatment center and the availability of the back-up collection of CD34+ cells is confirmed. After completion of conditioning, allow a minimum of 48 hours of washout before SKYSONA infusion. Receipt and Storage of SKYSONA Ensure the availability of vapor phase of liquid nitrogen storage at less than or equal to -140°C (-220°F) at the treatment center. SKYSONA is shipped to the treatment center in the vapor phase of liquid nitrogen shipper. Confirm Patient Identifiers on the product labels and Lot Information Sheet within the shipper. If there are any concerns about the product or packaging upon receipt, contact Genetix Biotherapeutics at 1-833-999-6378. Keep the infusion bag(s) in the metal cassette(s) and transfer SKYSONA from the vapor phase of liquid nitrogen shipper to the treatment center vapor phase of liquid nitrogen storage at less than or equal to -140°C (-220°F) until ready for thaw and administration. Preparation of SKYSONA for Infusion Coordinate the timing of SKYSONA thaw and infusion. Confirm the infusion time in advance and adjust the start time of SKYSONA thaw such that it will be available for infusion when the patient and healthcare providers are ready. SKYSONA contains human blood cells that are

6 ADVERSE REACTIONS Most common non-laboratory adverse reactions (≥ 20%): mucositis, nausea, vomiting, febrile neutropenia, alopecia, decreased appetite, abdominal pain, constipation, pyrexia, diarrhea, headache, rash. ( 6.1 ) Most common Grade 3 or 4 laboratory abnormalities (≥ 40%): leukopenia, lymphopenia, thrombocytopenia, neutropenia, anemia, hypokalemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genetix Biotherapeutics at 1-833-999-6378 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 described in this section reflect exposure to a single dose of SKYSONA in 67 patients with CALD. Data were obtained from two single-arm trials and, for 36 patients, from a long-term follow-up study [see Clinical Studies (14) ] . The median (min, max) age across studies was 6 (4, 14) years; 100% were male; 54% were White/Caucasian, 4% were Black or African American, 1% were Asian, 10% were of other races including mixed race, and 30% did not report race; 25% were of Hispanic ethnicity. The median (min, max) duration of follow-up at time of initial approval was 24 (1, 88) months. In the two trials, serious adverse reactions from Day 1 (SKYSONA infusion) to last follow-up occurred in 54% of patients. The most common non-laboratory, serious adverse reactions (≥ 3% incidence) that occurred after treatment with SKYSONA were febrile neutropenia (18%), pyrexia (fever) (18%), seizure (7%), myelodysplastic syndrome (4%), pseudomonal bacteremia (3%), pancytopenia (3%), vascular device infection (3%), mucositis (3%), and vomiting (3%). Most common non-laboratory adverse reactions by time of onset follow: During mobilization and conditioning and occurring in ≥ 20% of patients: nausea (79%), vomiting (72%), decreased appetite (42%), catheter site pain (39%), constipation (30%), headache (24%), abdominal pain (21%), rash (13%) In the first 60 days after treatment with SKYSONA in ≥ 15% of patients: mucositis (88%), febrile neutropenia (73%), alopecia (72%), abdominal pain (33%), vomiting (31%), decreased appetite (31%), pyrexia (27%), nausea (27%), constipation (21%), diarrhea (21%), epistaxis (19%), pruritus (18%), headache (16%), oropharyngeal pain (16%), skin hyperpigmentation (16%), anxiety (15%) Between 60 days and 1 year after treatment with SKYSONA in ≥ 5% of patients: pyrexia (fever) (9%) and vomiting (6%) Table 1 presents non-laboratory adverse reactions reported in at least 10% of patients between the start of conditioning and 24 months after SKYSONA administration. Table 2 presents Grade 3 or 4 laboratory abnormalities that occurred in at least 40% of patients between the start of conditioning and 24 months after SKYSONA administration. Table 1: Non-Laboratory Adverse Reactions Reported in ≥ 10% of Patients Between the Start of Conditioning and 24 Months Following Treatment with SKYSONA Includes adverse events associated with conditioning. Adverse Reaction Any Grade n (%) Grade 3 or Higher n (%) Blood and lymphatic system disorders -- -- Febrile neutropenia Febrile neutropenia includes febrile bone marrow aplasia and febrile neutropenia. 49 (73%) 49 (73%) Cardiac disorders -- -- Tachycardia Tachycardia includes sinus tachycardia and tachycardia. 10 (15%) 0 Eye disorders -- -- Vision blurred 7 (10%) 0 Gastrointestinal disorders -- -- Mucositis Mucositis includes anal inflammation, colitis, gastrointestinal inflammation, mucosal inflammation, proctitis, and stomatitis. Encompasses more than one system organ class. 62 (92%) 34 (51%) Nausea 56 (84%) 17 (25%) Vomiting 51 (76%) 12 (18%) Abdominal pain Abdominal pain includes abdominal discomfort, abdominal pain, and abdominal pain upper. 30 (45%) 2 (3%) Constipation 28 (42%) 0 Diarr

5 WARNINGS AND PRECAUTIONS Serious Infections: Life-threatening bacterial and viral infections may occur. Monitor patients for signs and symptoms of infection. ( 5.2 ) Prolonged Cytopenias: Patients may exhibit cytopenias >1 year after treatment. Monitor patients for bleeding and infection. ( 5.3 ) Delayed Platelet Engraftment: Monitor patients for thrombocytopenia and bleeding until platelet engraftment and count recovery. ( 5.4 ) Risk of Neutrophil Engraftment Failure: Monitor absolute neutrophil counts and if neutrophil engraftment does not occur, give rescue cells. ( 5.5 ) 5.1 Hematologic Malignancy Hematologic malignancies, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), have developed in patients treated with SKYSONA in clinical studies between 14 months and 10 years after SKYSONA administration [see Adverse Reactions (6.1) ] . Malignancies are life-threatening. Death related to treatment for malignancy and relapse of malignancy have occurred . SKYSONA Lenti-D lentiviral vector genomic integration, including into the proto-oncogene MECOM , appears to have mediated the cases of hematologic malignancy. All patients treated with SKYSONA in clinical studies have integrations into MECOM ; however, it is unknown which integrations into MECOM or other genes are likely to lead to malignancy. Consider consultation with hematology experts prior to SKYSONA treatment to inform benefit-risk treatment decision and to ensure adequate monitoring for hematologic malignancy. Consider performing the following baseline hematologic assessments: complete blood count with differential, hematopathology review of peripheral blood smear, and bone marrow biopsy (core and aspirate) with flow cytometry, conventional karyotyping, and next generation sequencing (NGS) with a molecular panel appropriate for age and including coverage for gene mutations expected in myeloid and lymphoid malignancies; and testing for germline mutations that are associated with hematologic malignancy. Early diagnosis of hematologic malignancy can be critically important, therefore, monitor patients treated with SKYSONA lifelong for hematologic malignancy. For at least the first fifteen years after treatment with SKYSONA, monitor via complete blood count (with differential) at least every 3 months and via integration site analysis or other testing for evidence of clonal expansion and predominance at least twice in the first year and then annually. Consider appropriate expert consultation and additional testing such as more frequent complete blood count (with differential) and integration site analysis, bone marrow studies, and gene expression studies in the following settings after treatment with SKYSONA: Delayed or failed engraftment of platelets or other cell lines (while all patients are at risk for hematologic malignancy, patients who do not achieve unsupported platelet counts of ≥ 20 × 10 9 /L on or after Day 60 appear to be at higher risk); or New or prolonged cytopenias; or, Presence of clonal expansion or predominance (e.g., increasing relative frequency of an integration site, especially if ≥ 10% and present in MECOM or another proto-oncogene known to be involved in hematologic malignancy). If hematologic malignancy is detected in a patient who received SKYSONA, contact Genetix Biotherapeutics at 1-833-999-6378 for reporting and to obtain instructions on collection of samples for further testing. Post-Marketing Long Term Follow-Up Study Patients who intend to receive treatment with SKYSONA are encouraged to enroll in the study, as available, to assess the long-term safety of SKYSONA and the risk of malignancies occurring after treatment with SKYSONA by calling Genetix Biotherapeutics, Inc. at 1-833-999-6378. The study includes monitoring (at pre-specified intervals) for clonal expansion. 5.2 Serious Infections Severe infections, including life-threatening and fatal infections, have occurred in patients after SKYSONA infusion. Febrile neutr

4 CONTRAINDICATIONS None. None. ( 4 )