BETIBEGLOGENE AUTOTEMCEL: 35 Adverse Event Reports & Safety Profile

ZYNTEGLO (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).

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 )

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 bluebird bio 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 bluebird bio 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 bluebird bio immediately at 1-833-999-6378. 6. If more than one infusion bag is provided, thaw and administer each infusion bag completely before proceeding to thaw the next infusion bag. 7. Thaw ZYNTEGLO at 37°C (98.6°F) in a water bath or dry bath. Thawing of each infusion bag takes approximately 2 to 4 minutes. Do not leave ZYNTEGLO unattended. Do not submerge the infusion ports in a water bath. 8. After thaw, mix the contents gently by massaging the infusion bag to disperse clumps of cellular material until all of the contents are uniform. If visible cell clumps remain, continue to gently mix the contents of the bag. Most small clumps of cellular material should disperse with gentle manual mixing. Do not filter, wash, spin down and/or resuspend ZYNTEGLO in new media prior to infusion. 9. Do not sample, alter, irradiate or refreeze ZYNTEGLO.

2.3 Administration ZYNTEGLO is for autologous use only. The patient&apos;s identity must match the patient identifiers on the ZYNTEGLO cassette(s) and infusion bag(s). Do not infuse ZYNTEGLO if the information on the patient-specific label does not match the intended patient. Product must be administered within 4 hours after thawing. Do not use an in-line blood filter or an infusion pump. 1. Before infusion, confirm that the patient&apos;s identity matches the unique patient identifiers on the ZYNTEGLO infusion bag(s). Use the Lot Information Sheet to confirm the total number of infusion bags to be administered. 2. Expose the sterile port on the infusion bag by tearing off the protective wrap covering the port. 3. Access the infusion bag and infuse ZYNTEGLO as soon as possible after thawing and complete the infusion within 4 hours. 4. Administer each infusion bag of ZYNTEGLO via intravenous infusion over a period of less than 30 minutes. If more than one infusion bag is provided, administer each infusion bag completely before proceeding to thaw and infuse the next infusion bag. 5. Flush all ZYNTEGLO remaining in the infusion bag(s) and any associated tubing with at least 50 mL of 0.9% sodium chloride solution to ensure that as many cells as possible are infused into the patient. After ZYNTEGLO Administration Standard procedures for patient management after HSC transplantation should be followed after ZYNTEGLO infusion. Irradiate any blood products required within the first 3 months after ZYNTEGLO infusion. Granulocyte-colony stimulating factor (G-CSF) is not recommended for 21 days after ZYNTEGLO infusion. Restarting iron chelation after ZYNTEGLO infusion may be necessary and should be based on clinical practice <span class="opacity-50 text-xs">[see Drug Interactions (7.3) and Clinical Studies (14) ]</span> . Phlebotomy can be used in lieu of iron chelation, when appropriate. Patients should not donate blood, organs, tissues, or cells at any time in the future. ZYNTEGLO contains human blood cells that are genetically modified with replication-incompetent, self-inactivating lentiviral vector. Follow universal precautions and biosafety guidelines (Biosafety Level 2) for handling and disposal of ZYNTEGLO to avoid potential transmission of infectious diseases.

None. None. ( 4 )

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 bluebird bio 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 <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span>. 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 (&gt; 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. Patients with β-thalassemia requiring regular transfusions may be at an increased risk of VOD following myeloablative conditioning. 1 Infections and infestations : pneumonia (7%) Infusion-related reaction including abdominal pain (7%) and tachycardia (2%).

Table

2: Grade 3 or 4 Treatment Emergent Laboratory Abnormalities Occurring in ≥ 10% of Patients Following Treatment with ZYNTEGLO Includes lab abnormalities associated with busulfan myeloablative conditioning. from Day 1 to Month 24 (N = 41) The denominator is 36 for hyperglycemia, due to missing data.

Laboratory Abnormality

Baseline lab values were assessed prior to apheresis.

Grade

3 or 4 (%) Abbreviations: ALT: alanine aminotransferase Neutropenia 100 Thrombocytopenia 100 Leukopenia 100 Anemia 95 Lymphopenia 61 ALT Increased 24 Hypophosphatemia 20 Hyperglycemia 14 Hypokalemia 12 Hyperbilirubinemia 10 Hyponatremia 10 Platelet Engraftment Delay Platelet engraftment was defined as three consecutive platelet values ≥ 20,000 cells/microliter, obtained on different days after ZYNTEGLO infusion, with no platelet transfusions administered for 7 days immediately preceding and during the evaluation period. Forty-one patients treated with ZYNTEGLO achieved platelet engraftment by a median of Day 46 (range 20 - 94) in clinical studies. Patients without a spleen reached the criterion for platelet engraftment earlier as compared to patients with an intact spleen: median Day 42 (range, 21 - 53 days) vs. median Day 50 (range, 20 - 94 days), respectively. Patients achieving platelet engraftment at ≥ Day 46 did not have an increased incidence of bleeding compared with patients with platelet engraftment at < Day 46.

Neutrophil Engraftment

While all subjects achieved neutrophil engraftment after ZYNTEGLO in the clinical studies, 7% of patients remained dependent on G-CSF beyond Day 43, one through Day 77. G-CSF discontinuation was followed by transient decreases in neutrophil counts to < 500 cells/microliter after Day 43 in six (15%) patients.

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 bluebird bio 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 <span class="opacity-50 text-xs">[see Drug Interactions (7.2) ]</span> . 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.

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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.5) ]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span> .

7.4 Erythropoiesis-Stimulating Agents There is no clinical experience with the use of erythropoiesis-stimulating agents in patients treated with ZYNTEGLO.