Lyfgenia

WARNING: HEMATOLOGIC MALIGNANCY Hematologic malignancy has occurred in patients treated with LYFGENIA. Monitor patients closely for evidence of malignancy through complete blood counts at least every 6 months and through integration site analysis at Months 6, 12, and as warranted [see Warnings and Precautions (5.1) ]. WARNING: HEMATOLOGIC MALIGNANCY See full prescribing information for complete boxed warning. Hematologic malignancy has occurred in patients treated with LYFGENIA. Monitor patients closely for evidence of malignancy through complete blood counts at least every 6 months and through integration site analysis at Months 6, 12, and as warranted. ( 5.1 )

5 WARNINGS AND PRECAUTIONS Delayed Platelet Engraftment : Monitor patients frequently for thrombocytopenia and bleeding until platelet engraftment and platelet recovery are achieved. ( 5.2 ) Neutrophil Engraftment Failure: Monitor absolute neutrophil counts (ANC) after LYFGENIA infusion. If neutrophil engraftment does not occur, administer rescue cells. ( 5.3 ) Insertional Oncogenesis : There is a potential risk of insertional oncogenesis after treatment with LYFGENIA. ( 5.4 ) Hypersensitivity Reactions: Monitor for hypersensitivity reactions during infusion. ( 5.5 ) 5.1 Hematologic Malignancy Hematologic malignancy has occurred in patients treated with LYFGENIA (Study 1, Group A). At the time of initial product approval, two patients treated with an earlier version of LYFGENIA using a different manufacturing process and transplant procedure (Study 1, Group A) developed acute myeloid leukemia (AML). One patient with α-thalassemia trait (Study 1, Group C) has been diagnosed with myelodysplastic syndrome (MDS) [see Adverse Reactions (6.1) ] . The additional hematopoietic stress associated with mobilization, conditioning, and infusion of LYFGENIA, including the need to regenerate the hematopoietic system, may increase the risk of a hematologic malignancy. Patients with sickle cell disease have an increased risk of hematologic malignancy as compared to the general population. 3, 4 Patients treated with LYFGENIA may develop hematologic malignancies and should have lifelong monitoring. Monitor for hematologic malignancies with a complete blood count (with differential) at least every 6 months for at least 15 years after treatment with LYFGENIA, 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. Post-Marketing Long Term Follow-Up Study Patients who intend to receive treatment with LYFGENIA are encouraged to enroll in the study, as available, to assess the long-term safety of LYFGENIA and the risk of malignancies occurring after treatment with LYFGENIA by calling Genetix Biotherapeutics at 1-833-999-6378. The study includes monitoring (at pre-specified intervals) for clonal expansion. 5.2 Delayed Platelet Engraftment Delayed platelet engraftment has been observed with LYFGENIA. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia. Two patients (4%) required more than 100 days post treatment with LYFGENIA to achieve platelet engraftment [see Adverse Reactions (6.1) ] . 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. 5.3 Neutrophil Engraftment Failure There is a potential risk of neutrophil engraftment failure after treatment with LYFGENIA. Neutrophil engraftment failure is defined as failure to achieve three consecutive absolute neutrophil counts (ANC) ≥ 0.5 × 10 9 cells/L obtained on different days by Day 43 after infusion of LYFGENIA. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a patient treated with LYFGENIA, provide rescue treatment with the back-up collection of CD34+ cells [see Adverse Reactions (6.1) ] . 5.4 Insertional Oncogenesis There is a potential risk of lentiviral vector-mediated insertional oncogenesis after treatment with LYFGENIA. 5.5 Hypersensitivity Reactions Allergic reactions may occur with the infusion of LYFGENIA. The dimethyl sulfoxide (DMSO) or dextran 40 in LYFGENIA may cause hypersensitivity reactions, including anaphylaxis. 5.6 Anti-retroviral Use Patients should not take prophylactic HIV anti-retroviral medications for at least one month prior to mobilization and until all cycles of apheresis are completed. There are some long-acting anti-retroviral medications that may require a longer duration of discontinuation for elimination of the medication [see Dosing and Administration (2.2) and Drug Interactions (7.2) ] . If a patient is taking anti-retrovirals for HIV prophylaxis, confirm a negative test for HIV before beginning mobilization and apheresis of CD34+ cells. 5.7 Hydroxyurea Use Patients should not take hydroxyurea for at least 2 months prior to mobilization and until all cycles of apheresis are completed. If hydroxyurea is administered between mobilization and conditioning, discontinue 2 days prior to initiation of conditioning [see Dosing and Administration (2.2) and Drug Interactions (7.3) ] . 5.8 Iron Chelation Do not administer myelosuppressive iron chelators for 6 months post-treatment with LYFGENIA [see Dosing and Administration (2.2) and Drug Interactions (7.4) ] . 5.9 Interference with PCR-based Testing Patients who have received LYFGENIA are likely to test positive by polymerase chain reaction (PCR) assays for HIV due to integrated BB305 LVV proviral DNA, resulting in a possible false-positive PCR assay test result for HIV. Therefore, patients who have received LYFGENIA 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: Hematologic Malignancy [see Warnings and Precautions (5.1) ] Delayed Platelet Engraftment [see Warnings and Precautions (5.2) ] Neutrophil Engraftment Failure [see Warnings and Precautions (5.3) ] Insertional Oncogenesis [see Warnings and Precautions (5.4) ] Hypersensitivity Reactions [see Warnings and Precautions (5.5) ] Most common adverse reactions ≥ Grade 3 (incidence ≥ 20%) were stomatitis, thrombocytopenia, neutropenia, febrile neutropenia, anemia, and leukopenia. ( 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. Safety was based on patients with sickle cell disease in one open-label, single-arm clinical trial and one long-term follow-up study. Of the 54 patients who initiated stem cell collection, the median (min, max) age across the studies was 25 (12, 43) years, 63% were males, 89% were Black or African American, 2% were Asian, 2% White/Caucasian and 4% were not reported. The median (min, max) duration of follow-up was 42 (12, 87) months. Mobilization and apheresis triggered SAEs of sickle cell crisis in 6 (14%, 6/44) patients who initiated mobilization in the intent-to-treat population. All patients who initiated conditioning (100%, 45/45) experienced at least one adverse event attributed to conditioning. The majority of conditioning-attributed events were non-serious and were consistent with the known effects of alkylating agents. Thirty-three (73%, 33/45) patients who received LYFGENIA experienced at least one serious adverse event (SAE). Most SAEs were related to conditioning or underlying disease. Table 1 presents the adverse drug reactions following treatment with LYFGENIA (Day 1) to Month 24. Table 1: Adverse Reactions ≥ Grade 3 (> 5%) Following Treatment with LYFGENIA from Day 1 to Month 24 (N = 45) Includes adverse events associated with busulfan myeloablative conditioning and underlying sickle cell disease. Adverse Reaction Grade 3 or Higher n (%) Blood and lymphatic system disorders -- Thrombocytopenia 31 (69) Neutropenia 27 (60) Febrile neutropenia 20 (44) Anemia Includes a patient with α-thalassemia trait who was diagnosed with myelodysplastic syndrome after Month 24. 15 (33) Leukopenia 15 (33) Sickle cell anemia with crisis Includes events prior to Month 6 and non-adjudicated occurrences. 7 (16) Gastrointestinal disorders -- Stomatitis 32 (71) Nausea 4 (9) General disorders and administration site conditions -- Pyrexia 3 (7) Infections and infestations -- Bacteremia 3 (7) Investigations -- Aspartate aminotransferase increased 8 (18) Alanine aminotransferase increased 6 (13) Gamma-glutamyl transferase increased 6 (13) Blood bilirubin increased 3 (7) Metabolism and nutrition disorders -- Decreased appetite 5 (11) Respiratory, thoracic, and mediastinal disorders -- Pharyngeal inflammation 5 (11) Three patients died during LYFGENIA clinical trials; one from sudden cardiac death due to underlying disease and two from acute myeloid leukemia who were treated with an earlier version of LYFGENIA using a different manufacturing process and transplant procedure (Study 1, Group A). Anemia Two patients developed anemia following LYFGENIA treatment; one patient continues to require monthly packed red blood cell (pRBC) transfusions. The other patient has been diagnosed with MDS. Both subjects had α-thalassemia trait (-α3.7 /-α3.7) [see Limitations of Use (1) ]. Infusion-related reactions to LYFGENIA Pre-medication for infusion reactions was managed at physician discretion. Infusion-related reactions to LYFGENIA were observed in 2 patients on the day of LYFGENIA infusion. Both infusion-related reactions resolved and were Grade 1. Events included hot flush and decreased diastolic blood pressure. Platelet engraftment delay Platelet engraftment, defined as having 3 consecutive platelet values ≥ 50 × 10 9 /L obtained on different days after the initial post-transplant nadir without receiving any platelet transfusions for 7 days immediately preceding and during the evaluation period, was achieved in all patients (median [min, max] Day 37 [19, 235]) after LYFGENIA infusion. Two patients treated with LYFGENIA achieved platelet engraftment after Day 100; one of these patients was administered eltrombopag until Day 234 [see Warnings and Precautions (5.2) ]. Neutrophil engraftment All patients achieved neutrophil engraftment. Neutrophil engraftment, defined as having 3 consecutive ANC laboratory values ≥ 0.5 × 10 9 cells/L obtained on 3 different days by Day 43, was reported on median (min, max) Day 20 (12, 35) after LYFGENIA infusion.

<table width="85%"><caption>Table 1: Adverse Reactions &#x2265; Grade 3 (&gt; 5%) Following Treatment with LYFGENIA from Day 1 to Month 24 (N = 45)<footnote>Includes adverse events associated with busulfan myeloablative conditioning and underlying sickle cell disease.</footnote></caption><col width="70%" align="left" valign="top"/><col width="30%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule">Adverse Reaction</th><th styleCode="Rrule">Grade 3 or Higher n (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Blood and lymphatic system disorders</content></td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Thrombocytopenia</td><td styleCode="Rrule">31 (69)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Neutropenia </td><td styleCode="Rrule">27 (60)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Febrile neutropenia</td><td styleCode="Rrule">20 (44)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Anemia<footnote>Includes a patient with &#x3B1;-thalassemia trait who was diagnosed with myelodysplastic syndrome after Month 24.</footnote></td><td styleCode="Rrule">15 (33)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Leukopenia</td><td styleCode="Rrule">15 (33)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Sickle cell anemia with crisis<footnote>Includes events prior to Month 6 and non-adjudicated occurrences.</footnote></td><td styleCode="Rrule">7 (16)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal disorders</content></td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Stomatitis</td><td styleCode="Rrule">32 (71)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">4 (9)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">General disorders and administration site conditions</content></td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pyrexia</td><td styleCode="Rrule">3 (7)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Infections and infestations</content></td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Bacteremia</td><td styleCode="Rrule">3 (7)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Investigations</content></td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Aspartate aminotransferase increased</td><td styleCode="Rrule">8 (18)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Alanine aminotransferase increased</td><td styleCode="Rrule">6 (13)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Gamma-glutamyl transferase increased</td><td styleCode="Rrule">6 (13)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Blood bilirubin increased</td><td styleCode="Rrule">3 (7)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Metabolism and nutrition disorders</content></td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased appetite</td><td styleCode="Rrule">5 (11)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Respiratory, thoracic, and mediastinal disorders</content></td><td styleCode="Rrule">--</td></tr><tr><td styleCode="Lrule Rrule">Pharyngeal inflammation</td><td styleCode="Rrule">5 (11)</td></tr></tbody></table>