Zynteglo
Generic: BETIBEGLOGENE AUTOTEMCEL
Basic Information
Manufacturer
Genetix Biotherapeutics Inc.
Product Type
CELLULAR THERAPY
Route of Administration
INTRAVENOUS
FDA Set ID
86931613-c262-47f5-8202-bc31fa69ad3d
Indications & Usage
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 )
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 )
Adverse Reactions
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, 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.
( 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.
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.