Zynteglo

betibeglogene autotemcel · Suspension · Intravenous

Prescription (Rx)

Uses

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 )

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 collection is confirmed. After completion of the myeloablative conditioning, allow a minimum of 48 hours of washout before ZYNTEGLO infusion. Receipt and Storage of ZYNTEGLO ZYNTEGLO is shipped to the treatment center in the vapor phase of liquid nitrogen shipper. Confirm patient identifiers on the product label(s) 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 ZYNTEGLO from the vapor phase of liquid nitrogen shipper to the treatment center vapor phase of liquid nitrogen storage at ≤ -140°C (≤ -220°F). Store in the vapor phase of liquid nitrogen at ≤ -140°C (≤ -220°F) until ready for thaw and administration. Preparation of ZYNTEGLO for Infusion Coordinate the timing of ZYNTEGLO thaw and infusion. Confirm the infusion time in advance and adjust the start time of ZYNTEGLO thaw such that it will be available for infusion when the patient and healthcare providers are ready. 1. Remove each metal cassette from liquid nitrogen storage and remove each infusion bag from the metal cassette. 2. Confirm that ZYNTEGLO is printed on the infusion bag(s). 3. Confirm that patient identity matches the unique patient identifiers located on the ZYNTEGLO infusion bag(s). Do not infuse ZYNTEGLO if the information on the patient-specific label on the infusion bag does not match the intended patient, and contact Genetix Biotherapeutics at 1-833-999-6378. 4. Ensure the correct number of infusion bags are present. Use the accompanying Lot Information Sheet to confirm that each infusion bag is within the expiration date. 5. Inspect each infusion bag for any breaches of integrity before thawing and infusion. If an infusion bag is compromised, follow the local guidelines and contact Genetix Biotherapeutics immediately at 1-833-999-6378. 6.

Dosage forms and strengths

3 DOSAGE FORMS AND STRENGTHS ZYNTEGLO is a cell suspension for intravenous infusion. ZYNTEGLO is composed of up to four infusion bags which contain 2.0 to 20 × 10 6 cells/mL suspended in cryopreservation solution [see How Supplied/Storage and Handling (16) ] . Each infusion bag contains approximately 20 mL of ZYNTEGLO. A single dose of ZYNTEGLO contains a minimum of 5.0 × 10 6 CD34+ cells per kg of body weight, suspended in cryopreservation solution . See the Lot Information Sheet for actual dose. ZYNTEGLO is a cell suspension for intravenous infusion. ( 3 ) A single dose of ZYNTEGLO contains a minimum of 5.0 × 10 6 CD34+ cells/kg of body weight, in one or more infusion bags. ( 3 )

Contraindications

None. None. ( 4 )

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.

Side effects

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, pharyngitis streptococcal. 15 0 Nasopharyngitis 12 0 Sepsis Sepsis includes bacterial sepsis, neutropenic sepsis, fungal sepsis, sepsis. 10 10 Injury, poisoning and procedural complications Procedural pain 15 0 Transfusion reaction 15 0 Metabolism and nutrition disorders Decreased appetite 24 15 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain includes musculoskeletal pain, musculoskeletal chest pain, bone pain, musculoskeletal discomfort, chest pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, spinal pain, tendon pain, back pain. 37 0 Nervous system disorders Headache Headache includes headache, migraine. 29 0 Respiratory, thoracic and mediastinal disorders Epistaxis 42 20 Cough Cough includes cough, upper-airway cough syndrome, productive cough. 34 0 Oropharyngeal pain Oropharyngeal pain includes oropharyngeal pain, oral pain, oropharyngeal discomfort, jaw pain. 15 0 Dyspnea 12 0 Hypoxia 12 7 Rhinitis Rhinitis includes rhinitis, rhinorrhea, rhinitis allergic. 12 0 Skin and subcutaneous tissue disorders Alopecia 44 0 Rash Rash includes acne, dermatitis acneiform, dermatitis atopic, macule, petechiae, rash, rash follicular, rash macular, rash maculo-papular, rash pruritic, rash pustular, rash vesicular. 27 0 Pigmentation disorder Pigmentation disorder includes oral pigmentation, pigmentation disorder, skin hyperpigmentation, skin hypopigmentation. 24 0 Pruritus 22 0 Vascular disorders Hypertension 10 0 Other clinically important adverse reactions that occurred in less than 10% of patients include the following: Cardiac disorders: congestive heart failure (2%) Hepatobiliary disorders: Serious hepatic veno-occlusive disease (VOD) occurred in 3 (7%) patients; of these three, two had not received prophylaxis for VOD. All patients who experienced serious VOD received treatment with defibrotide and recovered.

Drug interactions

No formal drug interaction studies have been performed. ZYNTEGLO is not expected to interact with the hepatic cytochrome P-450 family of enzymes or drug transporters. Anti-retrovirals and Hydroxyurea : Do not take anti-retroviral medications or hydroxyurea for one month prior to mobilization, or for the expected duration for elimination of the medications, and until all cycles of apheresis are completed ( 7.2 ) Iron Chelation: Discontinue iron chelators 7 days prior to initiation of myeloablative conditioning. Avoid use of myelosuppressive iron chelators for 6 months after ZYNTEGLO infusion. ( 7.3 ) 7.1 Live Vaccines Follow institutional guidelines for vaccine administration. The safety of immunization with live viral vaccines during or following ZYNTEGLO treatment has not been studied. 7.2 Anti-retrovirals and Hydroxyurea Patients should not take anti-retroviral medications or hydroxyurea for at least one month prior to mobilization or the expected duration for elimination of the medications, and until all cycles of apheresis are completed [see Warnings and Precautions (5.5) ] . Anti-retroviral medications may interfere with manufacturing of the apheresed cells. 7.3 Iron Chelation Drug-drug interactions between iron chelators and the myeloablative conditioning agent must be considered. Iron chelators should be discontinued at least 7 days prior to initiation of conditioning. The prescribing information for the iron chelator(s) and the myeloablative conditioning agent should be consulted for the recommendations regarding co-administration with CYP3A substrates. Some iron chelators are myelosuppressive. After ZYNTEGLO infusion, avoid use of these iron chelators for 6 months. If iron chelation is needed, consider administration of non-myelosuppressive iron chelators . Phlebotomy can be used in lieu of iron chelation, when appropriate [see Clinical Studies (14) ] . 7.4 Erythropoiesis-Stimulating Agents There is no clinical experience with the use of erythropoiesis-stimulating agents in patients treated with ZYNTEGLO.

Use in specific populations

8.1 Pregnancy Risk Summary There are no available data with ZYNTEGLO administration in pregnant women. Consider the risks associated with myeloablative conditioning agents on pregnancy and fertility. No reproductive and developmental toxicity studies in animals have been conducted with ZYNTEGLO to assess whether it can cause fetal harm when administered to a pregnant woman. It is not known whether ZYNTEGLO has the potential to be transferred to the fetus. Therefore, ZYNTEGLO should not be administered to women who are pregnant, and pregnancy after ZYNTEGLO infusion should be discussed with the treating physician. No nonclinical germline transmission studies have been conducted with ZYNTEGLO. 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 is no information regarding the presence of ZYNTEGLO in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ZYNTEGLO and any potential adverse effects on the breastfed child from ZYNTEGLO. Therefore, ZYNTEGLO is not recommended for women who are breastfeeding, and breastfeeding after ZYNTEGLO infusion should be discussed with the treating physician. 8.3 Females and Males of Reproductive Potential Pregnancy Testing A negative serum pregnancy test must be confirmed prior to the start of mobilization and re-confirmed prior to conditioning procedures and before ZYNTEGLO administration. Contraception There are insufficient exposure data to provide a precise recommendation on duration of contraception following treatment with ZYNTEGLO. Women of childbearing potential and men capable of fathering a child should use an effective method of contraception (intra-uterine device or combination of hormonal and barrier contraception) from start of mobilization through at least 6 months after administration of ZYNTEGLO. Advise patients of the risks associated with conditioning agents. Infertility There are no data on the effects of ZYNTEGLO on fertility. Data are available on the risk of infertility with myeloablative conditioning. Advise patients of the option to cryopreserve semen or ova before treatment, if appropriate. 8.4 Pediatric Use The safety and efficacy of ZYNTEGLO have been established in pediatric patients with β-thalassemia requiring regular transfusions. Use of ZYNTEGLO is supported by two Phase 3 studies [see Clinical Studies (14) ] that included 27 pediatric patients in the following age groups: 16 children (less than 12 years) and 11 adolescents (age 12 years to less than 18 years). No differences in efficacy or clinical safety were observed between the adult and pediatric subgroups. Engraftment times were longer in pediatric patients, but not associated with increases in infections or bleeding events. The median (min, max) time to neutrophil engraftment for patients less than 18 years was 26 (16, 39) days versus 21 (13, 27) days for patients 18 years or older. The median (min, max) time to platelet engraftment for patients less than 18 years was 50 (20, 94) days versus 43 (21, 58) days for patients 18 years or older. Longer engraftment time was associated with intact spleens. The safety and efficacy of ZYNTEGLO in children less than 4 years of age have not been established. No data are available. 8.5 Geriatric Use ZYNTEGLO has not been studied in patients > 65 years of age. Hematopoietic stem cell (HSC) transplantation must be appropriate for a patient to be treated with ZYNTEGLO. 8.6 Patients Seropositive for Human Immunodeficiency Virus (HIV) ZYNTEGLO has not been studied in patients with HIV-1, HIV-2, HTLV-1, or HTLV-2. A negative serology test for HIV is necessary to ensure acceptance of apheresis material for ZYNTEGLO manufacturing. Apheresis material from patients with a positive test for HIV will not be accepted for ZYNTEGLO manufacturing. 8.7 Renal Impairment ZYNTEGLO has not been studied in patients with renal impairment. Patients should be assessed for renal impairment, defined as creatinine clearance ≤ 70 mL/min/1.73 m 2 , to ensure HSC transplantation is appropriate. 8.8 Hepatic Impairment ZYNTEGLO has not been studied in patients with hepatic impairment. Patients should be assessed for hepatic impairment to ensure HSC transplantation is appropriate.

Pregnancy

Pediatric use

8.4 Pediatric Use The safety and efficacy of ZYNTEGLO have been established in pediatric patients with β-thalassemia requiring regular transfusions. Use of ZYNTEGLO is supported by two Phase 3 studies [see Clinical Studies (14) ] that included 27 pediatric patients in the following age groups: 16 children (less than 12 years) and 11 adolescents (age 12 years to less than 18 years). No differences in efficacy or clinical safety were observed between the adult and pediatric subgroups. Engraftment times were longer in pediatric patients, but not associated with increases in infections or bleeding events. The median (min, max) time to neutrophil engraftment for patients less than 18 years was 26 (16, 39) days versus 21 (13, 27) days for patients 18 years or older. The median (min, max) time to platelet engraftment for patients less than 18 years was 50 (20, 94) days versus 43 (21, 58) days for patients 18 years or older. Longer engraftment time was associated with intact spleens. The safety and efficacy of ZYNTEGLO in children less than 4 years of age have not been established. No data are available.

Geriatric use

8.5 Geriatric Use ZYNTEGLO has not been studied in patients > 65 years of age. Hematopoietic stem cell (HSC) transplantation must be appropriate for a patient to be treated with ZYNTEGLO.

Description

(betibeglogene autotemcel) is a β A-T87Q -globin gene therapy consisting of autologous CD34+ cells, containing hematopoietic stem cells (HSCs), transduced with BB305 LVV encoding β A-T87Q -globin, suspended in cryopreservation solution. ZYNTEGLO is intended for one-time administration to add functional copies of a modified form of the β-globin gene (β A-T87Q -globin gene) into the patient's own HSCs. ZYNTEGLO is prepared from the patient's own HSCs, which are collected via apheresis procedure(s). The autologous cells are enriched for CD34+ cells, then transduced ex vivo with BB305 LVV, a self-inactivating LVV. The promoter, a regulatory element of the LVV that controls the expression of the transgene selected for BB305 LVV, is a cellular (non-viral) promoter that controls gene expression specific to the erythroid lineage cells (red blood cells and their precursors). BB305 LVV encodes β A-T87Q -globin. The transduced CD34+ cells are washed, formulated into a suspension, and then cryopreserved. ZYNTEGLO is frozen in a patient-specific infusion bag(s) and is thawed prior to administration [see Dosage and Administration (2.2) , How Supplied/Storage and Handling (16) ] . The thawed product is colorless to white to red, including shades of white or pink, light yellow, and orange, and may contain small proteinaceous particles. Due to the presence of cells, the solution may be clear to slightly cloudy and may contain visible cell aggregates. The formulation contains 5% dimethyl sulfoxide (DMSO).

Mechanism of action

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.

How supplied

16 HOW SUPPLIED/STORAGE AND HANDLING ZYNTEGLO is supplied in up to four infusion bags containing a frozen suspension of genetically modified autologous cells, enriched for CD34+ cells. Each bag contains approximately 20 mL. Each infusion bag is individually packed within an overwrap in a metal cassette. ZYNTEGLO is shipped from the manufacturing facility to the treatment center storage facility in a cryoshipper, which may contain multiple metal cassettes intended for a single patient. A Lot Information Sheet is affixed inside the shipper. 20 mL infusion bag, overwrap, and metal cassette (NDC 73554-3111-1) Match the identity of the patient with the patient identifiers on the metal cassette(s), infusion bag(s), and Lot Information Sheet upon receipt. Keep the infusion bag(s) in the metal cassette(s) and store in the vapor phase of liquid nitrogen at less than or equal to -140°C (≤ -220°F) until ready for thaw and administration. Thaw ZYNTEGLO prior to infusion [see Dosage and Administration (2.2) ]. Do not re-freeze after thawing. Do not irradiate ZYNTEGLO, as this could lead to inactivation.

Storage

Match the identity of the patient with the patient identifiers on the metal cassette(s), infusion bag(s), and Lot Information Sheet upon receipt. Keep the infusion bag(s) in the metal cassette(s) and store in the vapor phase of liquid nitrogen at less than or equal to -140°C (≤ -220°F) until ready for thaw and administration. Thaw ZYNTEGLO prior to infusion [see Dosage and Administration (2.2) ]. Do not re-freeze after thawing. Do not irradiate ZYNTEGLO, as this could lead to inactivation.

Patient information

Advise the patient to read the FDA-approved patient labeling (Patient Information). Ensure that patients understand the risk of manufacturing failure. In case of manufacturing failure or the need for additional cells, additional cell collection and manufacturing of ZYNTEGLO would be needed [see Dosage and Administration (2.2) ] . Prior to treatment, advise patients of the following: Risks associated with mobilization and myeloablative conditioning agents [see Dosage and Administration (2.2) , Use in Specific Populations (8.1 , 8.3) ] . Delayed platelet engraftment – A risk of bleeding exists after myeloablative conditioning and before platelet engraftment and may continue after engraftment in patients who have continued thrombocytopenia [see Warnings and Precautions (5.1) ] . Risk of neutrophil engraftment failure –Patients who experience neutrophil engraftment failure will receive rescue treatment with their back-up collection of CD34+ cells [see Warnings and Precautions (5.2) ] . Risk of insertional oncogenesis – There is a potential risk of insertional oncogenesis after treatment with ZYNTEGLO. Patients should be monitored lifelong. Monitoring will include assessment for hematologic malignancies with a complete blood count at Month 6 and Month 12 and then at least annually for at least 15 years after treatment with ZYNTEGLO. This will include integration site analysis at Months 6, 12, and as warranted [see Warnings and Precautions (5.3) ] . Advise patients to seek immediate attention for the following: New or worsening bleeding or bruising. Platelet recovery following ZYNTEGLO infusion could be delayed, potentially resulting in an increased risk of bruising or bleeding until platelet recovery has been achieved [see Warnings and Precautions (5.1) , Adverse Reactions (6.1) ] . Advise patients to: Monitor for signs and symptoms of bleeding and have frequent blood draws for platelet counts, until platelet recovery has been achieved [see Warnings and Precautions (5.1) ] . Have their treating physician contact Genetix Biotherapeutics at 1-833-999-6378 if they are diagnosed with a malignancy [see Warnings and Precautions (5.3) ] . Advise patients that they should not donate blood, organs, tissues, or cells at any time in the future [see Dosage and Administration (2.3) ] . Advise patients that they may test positive for HIV if tested using a PCR assay after being treated with ZYNTEGLO [see Warnings and Precautions (5.6) ] .

Label text from the FDA structured product label by Genetix Biotherapeutics Inc. (revised Jul 21, 2026). Long sections are shortened; the complete label is on DailyMed.

Active ingredients

Betibeglogene Autotemcel in 1 product

Zynteglo NDC products (1)

NDC	Strength & form	Labeler	Type
73554-3111	Betibeglogene Autotemcel 20000000 1/1 Suspension	Genetix Biotherapeutics Inc.	BLA

Frequently asked questions

What is Zynteglo used for?

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Who makes Zynteglo?

Zynteglo is listed by 1 labeler in the FDA NDC directory, including Genetix Biotherapeutics Inc..