Lovotibeglogene Autotemcel

1 INDICATIONS AND USAGE LYFGENIA is indicated for the treatment of patients 12 years of age or older with sickle cell disease and a history of vaso-occlusive events. LYFGENIA is an autologous hematopoietic stem cell-based gene therapy indicated for the treatment of patients 12 years of age or older with sickle cell disease and a history of vaso-occlusive events. ( 1 ) Limitations of Use Following treatment with LYFGENIA, patients with α-thalassemia trait (-α3.7/-α3.7) may experience anemia with erythroid dysplasia that may require chronic red blood cell transfusions. LYFGENIA has not been studied in patients with more than two α-globin gene deletions. ( 1 ) Limitations of Use Following treatment with LYFGENIA, patients with α-thalassemia trait (-α3.7/-α3.7) may experience anemia with erythroid dysplasia that may require chronic red blood cell transfusions [see Adverse Reactions (6.1) ] . LYFGENIA has not been studied in patients with more than two α-globin gene deletions.

12.1 Mechanism of Action LYFGENIA adds functional copies of a modified β A -globin gene (threonine [T] replaced with glutamine [Q] at position 87, T87Q or β A-T87Q -globin) into patients' hematopoietic stem cells (HSCs) through transduction of autologous CD34+ cells with BB305 LVV. After LYFGENIA infusion, the transduced CD34+ HSCs engraft in the bone marrow and differentiate to produce red blood cells containing biologically active β A-T87Q -globin that will combine with α-globin to produce functional Hb containing β A-T87Q -globin (HbA T87Q ). β A-T87Q -globin can be distinguished from wildtype β A -globin and from β S -globin through reverse-phase high-performance liquid chromatography (RPHPLC) or ultra-high performance liquid chromatography (UPLC). HbA T87Q has similar oxygen-binding affinity and oxygen hemoglobin dissociation curve to wild type HbA, reduces intracellular and total hemoglobin S (HbS) levels, and is designed to sterically inhibit polymerization of HbS thereby limiting the sickling of red blood cells.

2 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 LYFGENIA manufacturing. ( 2.2 ) Dosing of LYFGENIA 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 3 × 10 6 CD34+ cells/kg. ( 2.1 ) Myeloablative conditioning must be administered before infusion of LYFGENIA. ( 2.2 ) Following myeloablative conditioning, allow a minimum of 48 hours of washout before LYFGENIA infusion. ( 2.2 ) Verify that the patient's identity matches the unique patient identification information on the LYFGENIA infusion bag(s) prior to infusion. ( 2.2 ) Do not sample, alter, irradiate, or refreeze LYFGENIA. ( 2.2 ) Do not use an in-line blood filter or an infusion pump. ( 2.3 ) Administer LYFGENIA within 4 hours after thawing. ( 2.3 ) Administer each infusion bag of LYFGENIA via intravenous infusion over a period of less than 30 minutes. ( 2.3 ) 2.1 Dose LYFGENIA is provided as a single dose for infusion containing a suspension of CD34+ cells in one to four infusion bags. The minimum recommended dose of LYFGENIA is 3 × 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 LYFGENIA Infusion Confirm that autologous hematopoietic stem cell (HSC) transplantation is appropriate for the patient before mobilization and apheresis and before myeloablative conditioning are initiated. Perform screening for infectious diseases, specifically human immunodeficiency virus 1 & 2 (HIV-1/HIV-2), in accordance with clinical guidelines before collection of cells for manufacturing. There are no data on use of LYFGENIA in HIV-positive patients. Prepare for Mobilization and Apheresis Prepare patients for mobilization with at least 2 cycles of scheduled transfusions (one each month) with erythrocytapheresis being preferred. For at least 60 days prior to mobilization and through myeloablative conditioning, patients should undergo a transfusion regimen to reach a target Hb of 8-10 g/dL, not to exceed 12 g/dL, and HbS of less than 30% to reduce the risk of SCD-related complications. Perform erythrocytapheresis within a recommended 4 days preceding mobilization to reach the target of less than 30% HbS. Manage other concomitant medications (as applicable) as described below: Hydroxyurea: Discontinue at least 2 months prior to mobilization. Patients should not resume hydroxyurea until all cycles of apheresis are completed. Disease-modifying agents (e.g., L-glutamine, voxelotor and crizanlizumab): Discontinue at least 2 months prior to mobilization as the interaction between disease modifying agents and mobilization agents is unknown. Erythropoietin: Discontinue at least 2 months prior to mobilization. Iron chelation: Discontinue at least 7 days prior to mobilization. Granulocyte-colony stimulating factor (G-CSF): Do not administer G-CSF prior to or with mobilization agents. Anti-retrovirals: Discontinue prophylactic HIV anti-retroviral medications at least one month prior to mobilization and do not resume 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. Mobilization and Apheresis Perform HSC mobilization followed by apheresis to obtain CD34+ cells for product manufacturing. Administer plerixafor to mobilize stem cells prior to the apheresis procedure at a dose of 0.24 mg/kg/day. 1 Begin apheresis approximately 4 to 6 hours after plerixafor administration. If more than one apheresis day is required, confirm platelet counts to be ≥ 75 × 10 9 /L within 24 hours of subsequent apheresis sessions, prior to administration of plerixafor on that day. If platelet cou

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 t

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-retr

4 CONTRAINDICATIONS None. None. ( 4 )