Exagamglogene Autotemcel

1. INDICATIONS AND USAGE CASGEVY is indicated for the treatment of patients aged 2 years and older with: sickle cell disease (SCD) with recurrent vaso-occlusive crises transfusion-dependent β - thalassemia (TDT) CASGEVY is an autologous genome edited hematopoietic stem cell-based gene therapy indicated for the treatment of patients aged 2 years and older with: sickle cell disease (SCD) with recurrent vaso-occlusive crises (VOCs). ( 1 ) transfusion-dependent β-thalassemia (TDT). ( 1 )

12.1 Mechanism of Action After CASGEVY infusion, the edited CD34 + cells engraft in the bone marrow and differentiate to erythroid lineage cells with reduced BCL11A expression. Reduced BCL11A expression results in an increase in γ-globin expression and HbF protein production in erythroid cells. In patients with severe sickle cell disease, HbF expression reduces intracellular hemoglobin S (HbS) concentration, preventing the red blood cells from sickling and addressing the underlying cause of disease, thereby eliminating VOCs. In patients with transfusion-dependent β-thalassemia, γ-globin production improves the α-globin to non-α-globin imbalance thereby reducing ineffective erythropoiesis and hemolysis and increasing total hemoglobin levels, addressing the underlying cause of disease, and eliminating the dependence on regular red blood cell (RBC) transfusions.

2 DOSAGE AND ADMINISTRATION 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 CASGEVY manufacturing. ( 2.2 ) Dosing of CASGEVY is based on body weight. The minimum recommended dose is 3 × 10 6 CD34 + cells/kg. ( 2.1 , 2.3 ) Full myeloablative conditioning must be administered between 48 hours and 7 days before infusion of CASGEVY. ( 2.2 ) Prophylaxis for seizures should be considered prior to initiating myeloablative conditioning. ( 2.2 ) Prophylaxis for hepatic veno-occlusive disease (VOD) should be considered prior to initiating myeloablative conditioning. ( 2.2 ) Verify that the patient's identity matches the unique patient identification information on the product labels and Lot Information Sheet prior to thaw and infusion. ( 2.2 ) Do not sample, alter, or irradiate CASGEVY. ( 2.2 ) Do not use an in-line blood filter when infusing CASGEVY. ( 2.3 ) Administer each vial of CASGEVY via intravenous infusion within 20 minutes of thaw. ( 2.3 ) 2.1 Dose For autologous use only. For one-time, single dose intravenous use only. The minimum recommended dose of CASGEVY is 3 × 10 6 CD34 + cells/kg. CASGEVY is provided as a single dose for infusion containing a suspension of CD34 + cells in one or more vials. See the Lot Information Sheet provided with the product shipment for additional information pertaining to the number of vials required to achieve the patient-specific dose. Administer all vials. 2.2 Preparation Before CASGEVY Infusion Confirm that autologous hematopoietic stem cell (HSC) transplantation is appropriate for the patient before mobilization, apheresis and myeloablative conditioning are initiated. It is recommended that patients with SCD weigh at least 12 kg prior to start of mobilization since patients below this weight may experience difficulty in achieving the minimum target cell dose. Screen patients for HIV-1, HIV-2, HBV, HCV, and any other infectious agents in accordance with local guidelines before collection of cells for manufacturing. CASGEVY should not be used in patients with active HIV-1, HIV-2, HBV or HCV. Discontinue disease modifying therapies (e.g., hydroxyurea, crizanlizumab) 8 weeks before the planned start of mobilization and conditioning [see Drug Interactions (7.2 , 7.3) ] . Preparation for Mobilization and Apheresis Sickle Cell Disease : Prior to planned start of mobilization, it is recommended to transfuse red blood cells (RBCs) (simple or exchange) as needed, for a minimum of 8 weeks and continue until initiation of myeloablation or reinitiate transfusion for a minimum of 8 weeks prior to start of myeloablation with a goal to maintain hemoglobin S (HbS) levels < 30% of total hemoglobin (Hb) while keeping total Hb concentration ≤ 11 g/dL. Transfusion-dependent β thalassemia : Prior to planned start of mobilization, it is recommended to transfuse RBCs as needed, with a goal to maintain hemoglobin (Hb) ≥ 11 g/dL and continue until start of myeloablation or reinitiate transfusion for at least 60 days prior to start of myeloablation. Mobilization and Apheresis HSC mobilization followed by apheresis to isolate the CD34 + cells is required to manufacture CASGEVY. Refer to the prescribing information for the mobilization agent(s) used, prior to treatment. See Clinical Studies (14) for description of the mobilization agents used in the clinical trials. Alternative mobilization regimens may be considered if clinically indicated. Sickle Cell Disease : Administer plerixafor 0.24 mg/kg/day via subcutaneous injection 2 to 3 hours prior to planned apheresis for a maximum of 3 days. Do not use Granulocyte Colony-Stimulating Factor (G-CSF) for mobilization in patients with SCD. Transfusion-dependent β thalassemia : Administer G-CSF for 5 to 6 days, starting 4 days prior to plerixafor administration. In non-splenectomized patients, administer 5 μg/kg G-CSF every 12 hours intravenously or su

6 ADVERSE REACTIONS The most common Grade 3 or 4 non-laboratory adverse reactions (incidence ≥ 25%) were mucositis and febrile neutropenia in patients with SCD and TDT, and decreased appetite in patients with SCD. ( 6 ) The most common Grade 3 or 4 laboratory abnormalities (≥ 50%) were neutropenia, thrombocytopenia, leukopenia, anemia, and lymphopenia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Vertex Pharmaceuticals Incorporated at 1-877-634-8789 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 most common Grade 3 or 4 non-laboratory adverse reactions (occurring in ≥ 25%) were mucositis and febrile neutropenia in patients with SCD and patients with TDT, and decreased appetite in patients with SCD. All (100%) of the patients with TDT and SCD experienced Grade 3 or 4 neutropenia and thrombocytopenia. Other common Grade 3 or 4 laboratory abnormalities (≥ 50%) include leukopenia, anemia and lymphopenia. Sickle Cell Disease The safety of CASGEVY in patients with SCD was evaluated in two open-label, single-arm trials (Trial 1 and Trial 4) and a long-term follow-up trial that included patients with SCD and TDT (Trial 3). Trial 1 included 44 patients 12 years and older and Trial 4 included 11 patients 5 years to less than 12 years of age. Patients were treated with CASGEVY after undergoing myeloablative conditioning with busulfan. Trial 1 (patients 12 years and older) The median (min, max) duration of follow-up for 44 patients with SCD after being administered CASGEVY was 19.3 (0.8, 48.1) months. Serious adverse reactions after myeloablative conditioning and CASGEVY infusion were observed in 45% of patients with SCD. The most common serious adverse reactions (≥ 2 patients) were cholelithiasis, pneumonia, abdominal pain, constipation, pyrexia, abdominal pain upper, non-cardiac chest pain, oropharyngeal pain, pain, and sepsis. One (2%) patient died due to a COVID-19 infection and subsequent respiratory failure. The event was not related to CASGEVY. Trial 4 (patients 5 years to less than 12 years of age) The median (min, max) duration of follow-up after being administered CASGEVY was 16.9 (7.6, 24.3) months [see Use in Specific Populations (8.4) , Clinical Pharmacology (12.3) , and Clinical Studies (14) ] . Serious adverse reactions after myeloablative conditioning and CASGEVY infusion were observed in 46% of patients with SCD. The most common serious adverse reactions (all in 1 patient each) were enterococcal sepsis, platelet count decreased, and viral abdominal infection. Table 2 presents the Grade 3 or 4 non-laboratory adverse reactions observed after myeloablative conditioning and CASGEVY infusion in at least 10% of patients in Trial 1 with corresponding incidences for Trial 4. Table 3 presents the Grade 3 or 4 laboratory abnormalities that occurred in at least 10% of patients with SCD. Table 2: Grade 3 or 4 non-laboratory adverse reactions in ≥ 10% of patients with SCD who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 1 with corresponding incidences in Trial 4: Day 1 to Month 24 after CASGEVY infusion Table includes adverse events associated with busulfan myeloablative conditioning and treatment with CASGEVY. System organ class, preferred term Trial 1 (N=44) n (%) Trial 4 (N=11) n (%) Blood and lymphatic system disorders Febrile neutropenia 21 (48) 8 (73) Gastrointestinal disorders Mucositis Mucositis includes mucosal inflammation, pharyngeal inflammation, and stomatitis. , Encompasses preferred terms that belong to other system organ class. 38 (86) 8 (73) Abdominal pain Abdominal pain includes abdominal pain and abdominal pain upper. 5 (11) 0 Hepatobiliary disorders Cholelithiasis 5 (11) 0 Metabol

5 WARNINGS AND PRECAUTIONS Neutrophil Engraftment Failure: Monitor absolute neutrophil counts (ANC) after CASGEVY infusion. Administer rescue cells in the event of neutrophil engraftment failure. ( 5.1 ) Delayed Platelet Engraftment: Monitor platelet counts until platelet engraftment and recovery are achieved. Patients should be monitored for bleeding. ( 5.2 ) Hypersensitivity Reactions: Monitor for hypersensitivity reactions during and after infusion. ( 5.3 ) Off-Target Genome Editing Risk: The risk of unintended, off-target editing in CD34 + cells due to genetic variants cannot be ruled out. ( 5.4 ) 5.1 Neutrophil Engraftment Failure There is potential risk of neutrophil engraftment failure after treatment with CASGEVY. In the clinical trials, all treated patients achieved neutrophil engraftment and no patients received rescue CD34 + cells. Monitor absolute neutrophil counts (ANC) and manage infections according to standard guidelines and medical judgement. In the event of neutrophil engraftment failure, patients should be infused with rescue CD34 + cells [see Adverse Reactions (6.1) ] . Granulocyte Colony-Stimulating Factor (G-CSF) is not recommended for 21 days after CASGEVY infusion. 5.2 Delayed Platelet Engraftment Delayed platelet engraftment has been observed with CASGEVY treatment. There is an increased risk of bleeding until platelet engraftment is achieved [see Adverse Reactions (6.1) ] . Monitor patients for bleeding according to standard guidelines and medical judgement. 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 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, can occur due to dimethyl sulfoxide (DMSO) or dextran 40 in the cryopreservation solution. Monitor patients for hypersensitivity reactions during and after infusion. 5.4 Off-Target Genome Editing Risk The risk of unintended, off-target editing in an individual's CD34 + cells cannot be ruled out due to genetic variants. The clinical significance of potential off-target editing is unknown.

4 CONTRAINDICATIONS None. None. ( 4 )