Betibeglogene Autotemcel

1 INDICATIONS AND USAGE ZYNTEGLO is indicated for the treatment of adult and pediatric patients with β-thalassemia who require regular red blood cell (RBC) transfusions. ZYNTEGLO is an autologous hematopoietic stem cell-based gene therapy indicated for the treatment of adult and pediatric patients with β-thalassemia who require regular red blood cell (RBC) transfusions. ( 1 )

12.1 Mechanism of Action ZYNTEGLO adds functional copies of a modified β-globin gene into patients' hematopoietic stem cells (HSCs) through transduction of autologous CD34+ cells with BB305 LVV. After ZYNTEGLO infusion, transduced CD34+ HSCs engraft in the bone marrow and differentiate to produce RBCs containing biologically active β A-T87Q -globin (a modified β-globin protein) that will combine with α-globin to produce functional adult Hb containing β A-T87Q -globin (HbA T87Q ). β A-T87Q -globin can be quantified relative to other globin species in peripheral blood using high-performance liquid chromatography. β A-T87Q -globin expression is designed to correct the β/α-globin imbalance in erythroid cells of patients with β-thalassemia and has the potential to increase functional adult HbA and total Hb to normal levels and eliminate dependence on regular pRBC transfusions.

2 DOSAGE AND ADMINISTRATION For autologous use only. For one-time single-dose intravenous use only. For autologous use only. For intravenous use only. Patients are required to undergo hematopoietic stem cell (HSC) mobilization followed by apheresis to obtain CD34+ cells for ZYNTEGLO manufacturing. ( 2.2 ) Dosing of ZYNTEGLO 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 conditioning must be administered before infusion of ZYNTEGLO. ( 2.2 ) Prophylaxis for hepatic veno-occlusive disease (VOD) is recommended. Prophylaxis for seizures should be considered. ( 2.2 ) Verify that the patient's identity matches the unique patient identification information on the ZYNTEGLO infusion bag(s) prior to infusion. ( 2.2 ) Do not sample, alter, or irradiate ZYNTEGLO. ( 2.2 ) Do not use an in-line blood filter or an infusion pump. ( 2.3 ) Administer each infusion bag of ZYNTEGLO via intravenous infusion over a period of less than 30 minutes. ( 2.3 ) 2.1 Dose ZYNTEGLO is provided as a single dose for infusion containing a suspension of CD34+ cells in one or more infusion bags. The minimum recommended dose of ZYNTEGLO is 5.0 × 10 6 CD34+ cells/kg. See the Lot Information Sheet provided with the product shipment for additional information pertaining to dose. 2.2 Preparation Before ZYNTEGLO Infusion Before mobilization, apheresis, and myeloablative conditioning are initiated, confirm that hematopoietic stem cell (HSC) transplantation is appropriate for the patient. It is recommended that patients be maintained at a hemoglobin (Hb) ≥ 11 g/dL for at least 30 days prior to mobilization and 30 days prior to myeloablative conditioning. Granulocyte-colony stimulating factor (G-CSF) and plerixafor were used for mobilization and busulfan was used for myeloablative conditioning. Refer to the prescribing information for the mobilization agent(s) and the myeloablative conditioning agent(s) prior to treatment. Perform screening for hepatitis B virus (HBV), hepatitis C virus (HCV), human T-lymphotrophic virus 1 & 2 (HTLV-1/HTLV-2), and human immunodeficiency virus 1 & 2 (HIV-1/HIV-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. The target number of CD34+ cells to be collected is ≥ 12 × 10 6 CD34+ cells/kg. If the minimum dose of 5.0 × 10 6 CD34+ cells/kg is not met, the patient may undergo additional cycles of mobilization and apheresis, separated by at least 14 days, in order to obtain more cells for additional manufacture. Up to two drug product lots may be administered to meet the target dose. 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. These cells must be collected from the patient and be cryopreserved prior to myeloablative conditioning. The back-up collection may be needed for rescue treatment if there is: 1) compromise of hematopoietic stem cells or ZYNTEGLO before infusion, 2) primary engraftment failure, or 3) loss of engraftment after infusion with ZYNTEGLO. Myeloablative Conditioning Full myeloablative conditioning must be administered before infusion of ZYNTEGLO. Consult prescribing information for the myeloablative conditioning agent(s) prior to treatment. Stop iron chelation at least 7 days prior to myeloablative conditioning. Prophylaxis for hepatic veno-occlusive disease (VOD) is recommended [see Clinical Studies (14) ] . Prophylaxis for seizures should be considered, as appropriate. Do not begin myeloablative conditioning until the complete set of infusion bag(s) constituting the dose of ZYNTEGLO has been received and stored at the treatment center and the availability of the back-up co

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the labeling: Delayed Platelet Engraftment [see Warnings and Precautions (5.1) ] Risk of Neutrophil Engraftment Failure [see Warnings and Precautions (5.2) ] Risk of Insertional Oncogenesis [see Warnings and Precautions (5.3) ] Hypersensitivity Reactions [see Warnings and Precautions (5.4) ] The most common non-laboratory adverse reactions (incidence ≥ 20%) were mucositis, febrile neutropenia, vomiting, pyrexia (fever), alopecia (hair loss), epistaxis (nose bleed), abdominal pain, musculoskeletal pain, cough, headache, diarrhea, rash, constipation, nausea, decreased appetite, pigmentation disorder, and pruritus (itch). ( 6.1 ) The most common Grade 3 or 4 laboratory abnormalities (> 50%) include neutropenia, thrombocytopenia, leukopenia, anemia, and lymphopenia. ( 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 ZYNTEGLO in two open-label, single-arm clinical trials and one long-term follow-up study, in which 41 patients with β-thalassemia requiring regular transfusions were treated with ZYNTEGLO [see Clinical Studies (14) ]. The median (min, max) age across the trials was 13 (4, 34) years; 49% were females; 49% were Asian, 44% White, 5% Other, 2% Not Reported. The median (min, max) duration of follow-up was 27.2 (4.1, 48.2) months. In the two trials, serious adverse reactions occurred in 37% of patients as of last follow-up. The most common serious adverse reactions (> 3%) were pyrexia (fever), thrombocytopenia, liver veno-occlusive disease, febrile neutropenia, neutropenia, and stomatitis. There were no deaths. The most common adverse reactions (≥ 20%) were mucositis, febrile neutropenia, vomiting, pyrexia (fever), alopecia (hair loss), epistaxis (nose bleed), abdominal pain, musculoskeletal pain, cough, headache, diarrhea, rash, constipation, nausea, decreased appetite, pigmentation disorder, and pruritus (itch). Table 1 presents the non-laboratory treatment emergent adverse reactions reported in at least 10% of patients and Table 2 describes the laboratory abnormalities of Grade 3 or 4 that occurred in at least 10% of patients. Table 1: Summary of Non-Laboratory Treatment Emergent Adverse Reactions in at Least 10% of Patients; Day 1 – Month 24 After ZYNTEGLO Administration Includes adverse events associated with busulfan myeloablative conditioning. (N = 41) Adverse Reaction % Any Grade % Grade 3 or Higher Blood and lymphatic system disorders Febrile neutropenia 51 51 Gastrointestinal disorders Mucositis Mucositis includes anal inflammation, mucosal inflammation, oral mucosal exfoliation, oral mucosal roughening, pharyngeal inflammation, stomatitis. Encompasses more than one system organ class. 95 63 Vomiting 49 0 Abdominal pain Abdominal pain includes abdominal pain, abdominal pain lower, abdominal discomfort, abdominal pain upper. 39 2 Diarrhea 27 0 Nausea 24 2 Constipation 24 0 Dyspepsia 10 5 Gingival bleeding 10 2 General disorders and administration site conditions Pyrexia 49 12 Fatigue 12 0 Hepatobiliary disorders Venoocclusive liver disease 10 7 Infections and infestations Viral infection Viral infection includes BK virus infection, human rhinovirus test positive, influenza, influenza like illness, parainfluenza virus infection, rhinovirus infection, SARS-CoV-2 test positive, viral infection. 17 2 Upper respiratory tract infections Upper respiratory tract infections include upper airway cough syndrome, upper respiratory tract infection, viral upper respiratory tract infection, pharyngitis, phary

5 WARNINGS AND PRECAUTIONS Delayed Platelet Engraftment: Monitor platelet counts until platelet engraftment and recovery are achieved. Patients should be monitored for thrombocytopenia and bleeding. ( 5.1 ) Risk of Neutrophil Engraftment Failure: Monitor absolute neutrophil counts (ANC) after ZYNTEGLO infusion. If neutrophil engraftment does not occur administer rescue cells. ( 5.2 ) Risk of Insertional Oncogenesis: Monitor patients at least annually for hematologic malignancies for at least 15 years after ZYNTEGLO infusion. ( 5.3 ) Hypersensitivity Reactions: Monitor for hypersensitivity reactions during infusion. ( 5.4 ) 5.1 Delayed Platelet Engraftment Delayed platelet engraftment has been observed with ZYNTEGLO treatment. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia; 15% of patients had ≥ Grade 3 decreased platelets on or after Day 100. Patients should be made aware of the risk of bleeding until platelet recovery has been achieved. Monitor patients for thrombocytopenia and bleeding according to standard guidelines. Conduct frequent platelet counts until platelet engraftment and platelet recovery are achieved. Perform blood cell count determination and other appropriate testing whenever clinical symptoms suggestive of bleeding arise. 5.2 Risk of Neutrophil Engraftment Failure There is a potential risk of neutrophil engraftment failure after treatment with ZYNTEGLO. Neutrophil engraftment failure is defined as failure to achieve three consecutive absolute neutrophil counts (ANC) ≥ 500 cells/microliter obtained on different days by Day 43 after infusion of ZYNTEGLO. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a patient treated with ZYNTEGLO, provide rescue treatment with the back-up collection of CD34+ cells. 5.3 Risk of Insertional Oncogenesis There is a potential risk of lentiviral vector (LVV)-mediated insertional oncogenesis after treatment with ZYNTEGLO. Patients treated with ZYNTEGLO may develop hematologic malignancies and should be monitored lifelong. Monitor for hematologic malignancies with a complete blood count (with differential) at Month 6 and Month 12 and then at least annually for at least 15 years after treatment with ZYNTEGLO, and integration site analysis at Months 6, 12, and as warranted. In the event that a malignancy occurs, contact Genetix Biotherapeutics at 1-833-999-6378 for reporting and to obtain instructions on collection of samples for testing. 5.4 Hypersensitivity Reactions Allergic reactions may occur with the infusion of ZYNTEGLO. The dimethyl sulfoxide (DMSO) in ZYNTEGLO may cause hypersensitivity reactions, including anaphylaxis. 5.5 Anti-retroviral and Hydroxyurea Use Patients should not take prophylactic HIV anti-retroviral medications or hydroxyurea for at least one month prior to mobilization, or for the expected duration for elimination of the medications, and until all cycles of apheresis are completed [see Drug Interactions (7.2) ] . If a patient requires anti-retrovirals for HIV prophylaxis, then confirm a negative test for HIV before beginning mobilization and apheresis of CD34+ cells. 5.6 Interference with Serology Testing Patients who have received ZYNTEGLO are likely to test positive by polymerase chain reaction (PCR) assays for HIV due to integrated BB305 LVV proviral DNA, resulting in a false-positive test for HIV. Therefore, patients who have received ZYNTEGLO should not be screened for HIV infection using a PCR-based assay.

4 CONTRAINDICATIONS None. None. ( 4 )