Zynteglo

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.

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.

<table width="90%"><caption>Table 1: Summary of Non-Laboratory Treatment Emergent Adverse Reactions in at Least 10% of Patients; Day 1 &#x2013; Month 24 After ZYNTEGLO Administration<footnote>Includes adverse events associated with busulfan myeloablative conditioning.</footnote> (N = 41)</caption><col width="50%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule">Adverse Reaction</th><th styleCode="Rrule">% Any Grade</th><th styleCode="Rrule">% Grade 3 or Higher</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Blood and lymphatic system disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Febrile neutropenia</td><td styleCode="Rrule">51</td><td styleCode="Rrule">51</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Gastrointestinal disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Mucositis<footnote>Mucositis includes anal inflammation, mucosal inflammation, oral mucosal exfoliation, oral mucosal roughening, pharyngeal inflammation, stomatitis.</footnote><footnote ID="t1f1">Encompasses more than one system organ class.</footnote></td><td styleCode="Rrule">95</td><td styleCode="Rrule">63</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">49</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal pain<footnote>Abdominal pain includes abdominal pain, abdominal pain lower, abdominal discomfort, abdominal pain upper.</footnote></td><td styleCode="Rrule">39</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">27</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">24</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Constipation</td><td styleCode="Rrule">24</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dyspepsia</td><td styleCode="Rrule">10</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Gingival bleeding</td><td styleCode="Rrule">10</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">General disorders and administration site conditions</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pyrexia</td><td styleCode="Rrule">49</td><td styleCode="Rrule">12</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue</td><td styleCode="Rrule">12</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Hepatobiliary disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Venoocclusive liver disease</td><td styleCode="Rrule">10</td><td styleCode="Rrule">7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Infections and infestations</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Viral infection<footnote>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.</footnote></td><td styleCode="Rrule">17</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Upper respiratory tract infections<footnote>Upper respiratory tract infections include upper airway cough syndrome, upper respiratory tract infection, viral upper respiratory tract infection, pharyngitis, pharyngitis streptococcal.</footnote><footnoteRef IDREF="t1f1"/></td><td styleCode="Rrule">15</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nasopharyngitis</td><td styleCode="Rrule">12</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Sepsis<footnote>Sepsis includes bacterial sepsis, neutropenic sepsis, fungal sepsis, sepsis.</footnote></td><td styleCode="Rrule">10</td><td styleCode="Rrule">10</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Injury, poisoning and procedural complications</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Procedural pain</td><td styleCode="Rrule">15</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Transfusion reaction</td><td styleCode="Rrule">15</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Metabolism and nutrition disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased appetite</td><td styleCode="Rrule">24</td><td styleCode="Rrule">15</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Musculoskeletal and connective tissue disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Musculoskeletal pain<footnote>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.</footnote><footnoteRef IDREF="t1f1"/></td><td styleCode="Rrule">37</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Nervous system disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache<footnote>Headache includes headache, migraine. </footnote></td><td styleCode="Rrule">29</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Epistaxis</td><td styleCode="Rrule">42</td><td styleCode="Rrule">20</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Cough<footnote>Cough includes cough, upper-airway cough syndrome, productive cough.</footnote></td><td styleCode="Rrule">34</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Oropharyngeal pain<footnote>Oropharyngeal pain includes oropharyngeal pain, oral pain, oropharyngeal discomfort, jaw pain.</footnote><footnoteRef IDREF="t1f1"/></td><td styleCode="Rrule">15</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dyspnea</td><td styleCode="Rrule">12</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypoxia</td><td styleCode="Rrule">12</td><td styleCode="Rrule">7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Rhinitis<footnote>Rhinitis includes rhinitis, rhinorrhea, rhinitis allergic.</footnote></td><td styleCode="Rrule">12</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Skin and subcutaneous tissue disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Alopecia</td><td styleCode="Rrule">44</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Rash<footnote>Rash includes acne, dermatitis acneiform, dermatitis atopic, macule, petechiae, rash, rash follicular, rash macular, rash maculo-papular, rash pruritic, rash pustular, rash vesicular.</footnote><footnoteRef IDREF="t1f1"/></td><td styleCode="Rrule">27</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pigmentation disorder<footnote>Pigmentation disorder includes oral pigmentation, pigmentation disorder, skin hyperpigmentation, skin hypopigmentation.</footnote></td><td styleCode="Rrule">24</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pruritus</td><td styleCode="Rrule">22</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Vascular disorders</content></td></tr><tr><td styleCode="Lrule Rrule">Hypertension</td><td styleCode="Rrule">10</td><td styleCode="Rrule">0</td></tr></tbody></table>

<table width="90%"><caption>Table 2: Grade 3 or 4 Treatment Emergent Laboratory Abnormalities Occurring in &#x2265; 10% of Patients Following Treatment with ZYNTEGLO<footnote>Includes lab abnormalities associated with busulfan myeloablative conditioning.</footnote> from Day 1 to Month 24 (N = 41)<footnote>The denominator is 36 for hyperglycemia, due to missing data.</footnote></caption><col width="35%" align="left" valign="middle"/><col width="65%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule" align="center" valign="top">Laboratory Abnormality<footnote>Baseline lab values were assessed prior to apheresis.</footnote></th><th styleCode="Rrule">Grade 3 or 4 (%)</th></tr></thead><tfoot><tr><td colspan="2" align="left">Abbreviations: ALT: alanine aminotransferase </td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Neutropenia</td><td styleCode="Rrule">100</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Thrombocytopenia</td><td styleCode="Rrule">100 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Leukopenia</td><td styleCode="Rrule">100 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Anemia</td><td styleCode="Rrule">95</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Lymphopenia</td><td styleCode="Rrule">61</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">ALT Increased</td><td styleCode="Rrule">24</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypophosphatemia</td><td styleCode="Rrule">20</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hyperglycemia</td><td styleCode="Rrule">14</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypokalemia</td><td styleCode="Rrule">12</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hyperbilirubinemia</td><td styleCode="Rrule">10</td></tr><tr><td styleCode="Lrule Rrule">Hyponatremia</td><td styleCode="Rrule">10</td></tr></tbody></table>