CASGEVY

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 )

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 subcutaneously. In splenectomized patients, administer 5 μg/kg G-CSF daily. The dose may be increased to every 12 hours in splenectomized patients if there is no increase in white blood cell (WBC) or peripheral blood CD34 + counts. In all patients, administer plerixafor at 0.24 mg/kg per day for a maximum of 3 days, 4 to 6 hours prior to each planned apheresis. Perform up to three consecutive days of cell collection for product manufacturing per cycle, if clinically tolerated. A total collection target of at least 20 × 10 6 CD34 + cells/kg is recommended, but as many collected cells as possible should be sent for product manufacture even if the total collection target is not achieved. Perform additional cycles of mobilization and apheresis if the minimum dose of CASGEVY (3 × 10 6 CD34 + cells/kg) is not met. Separate each mobilization and apheresis cycle by a minimum of 14 days. Collect and cryopreserve an additional ≥ 2 × 10 6 CD34 + cells/kg of unmodified back-up rescue cells prior to myeloablative conditioning and infusion with CASGEVY. Back-up cells may be needed for engraftment failure or product compromise after myeloablation [see Warnings and Precautions (5.1) ] . Myeloablative Conditioning Administer full myeloablative conditioning with busulfan or another myeloablative conditioning regimen prior to treatment with CASGEVY. Refer to the prescribing information for the myeloablative conditioning agent prior to treatment. See Clinical Studies (14) for description of the myeloablative agent used in the clinical trials. Do the following before initiation of myeloablative conditioning: In patients with SCD, transfuse at least 8 weeks prior to the initiation of myeloablative conditioning, with a goal of maintaining hemoglobin S (HbS) levels of < 30% of total Hb while keeping total Hb concentration ≤ 11 g/dL. Discontinue disease modifying therapies for sickle cell disease (e.g., hydroxyurea, crizanlizumab) at initiation of red blood cell exchange or simple transfusions (simple or exchange). In patients with TDT, transfuse to maintain hemoglobin (Hb) ≥ 11 g/dL for 60 days prior to myeloablative conditioning. Stop iron chelation therapy for at least 7 days prior to myeloablative conditioning. Confirm availability of complete set of vial(s) comprising the total dose of CASGEVY has been received and stored at the treatment center. See the Lot Information Sheet(s) provided with the product shipment for confirmation of the total dose of CASGEVY. Confirm availability of the back-up collection of unmodified rescue cells at the treatment center. Busulfan Myeloablative Conditioning If busulfan is used for myeloablative conditioning, administer intravenously (IV) for 4 consecutive days via a central venous catheter. Measure busulfan plasma levels by serial blood sampling and adjust dose to maintain exposure in the 4-day cumulative target range. For patients 12 years and older, administer busulfan at a planned starting dose of 3.2 mg/kg/day once-daily (qd) or 0.8 mg/kg every 6 hours (q6h). For the once-daily dosing, adjust busulfan dose for a four day target cumulative busulfan exposure of 82 mg*h/L (range: 74 to 90 mg*h/L), corresponding to an AUC 0-24h of 5000 μM*min (range: 4500 to 5500 μM*min). For the every 6-hours dosing, adjust for a four day target cumulative busulfan exposure of 74 mg*h/L (range: 59 to 89 mg*h/L), corresponding to an AUC 0-6h of 1125 μM*min (range: 900 to 1350 μM*min). For patients 2 to less than 12 years of age, every 6-hour dosing is recommended. Administer busulfan for 4 consecutive days, with the first dose according to patient weight (see Table 1 ). Table 1: Busulfan weight-based starting dose for patients aged 2 years to < 12 years Patient Weight (kg) Initial Busulfan Dose 12 to < 16 kg 1.2 mg/kg/dose 16 to < 23 kg 1.1 mg/kg/dose 23 to < 34 kg 0.95 mg/kg/dose ≥ 34 kg 0.8 mg/kg/dose In patients 2 to less than 12 years of age, adjust busulfan dose with a 4-day target cumulative busulfan exposure of 82 mg*h/L (range: 74 to 90 mg*h/L), corresponding to a per-dose AUC 0-6h of 1250 μM*min (range: 1125 to 1375 μM*min). Consider anti-seizure prophylaxis (use agents other than phenytoin) and hepatic veno occlusive disease (VOD)/hepatic sinusoidal obstruction syndrome prophylaxis prior to initiating busulfan conditioning. As CASGEVY is an autologous therapy, immunosuppressive agents are not required after initial myeloablative conditioning. Administer CASGEVY between 48 hours and 7 days after the last dose of the myeloablative conditioning regimen. Receipt and Storage of CASGEVY CASGEVY is shipped to the treatment center frozen in a vapor phase of one or more liquid nitrogen shipper(s). A Lot Information Sheet is included in each liquid nitrogen shipper. Confirm patient identifiers on the product label(s) and Lot Information Sheet(s). If there are any concerns about the product or packaging upon receipt, contact Vertex at +1-877-634-8789. Transfer CASGEVY from the vapor phase of nitrogen shipper to the treatment center vapor phase of liquid nitrogen storage at ≤ -135 °C (≤ -211 °F). Preparing for CASGEVY Administration CASGEVY contains human cells. Follow universal precautions (wearing gloves, protective clothing, and eye protection) and local biosafety guidelines applicable for handling and disposal of such products to avoid potential transmission of infectious diseases. All material that has been in contact with CASGEVY (solid and liquid waste) should be handled and disposed of as potentially infectious waste in accordance with local biosafety guidelines. Coordinate the timing of CASGEVY thaw and infusion. Confirm the infusion time in advance and adjust the start time for thaw so that CASGEVY is available for infusion when the patient and healthcare providers are ready. Thaw and infuse one vial at a time. Premedication: Administer an antipyretic (e.g., acetaminophen) and an antihistamine (e.g., diphenhydramine hydrochloride) prior to administering CASGEVY. Before thaw, confirm CASGEVY is printed on the vial label and the patient's identity matches the unique patient information located on the CASGEVY vial(s). Do not infuse CASGEVY if the information on the patient-specific label on any of the vials does not match the intended patient, and contact Vertex at +1-877-634-8789. A dose of CASGEVY may be contained in one or more cryopreserved patient-specific vial(s). Ensure that the correct number of vials are present. Use the accompanying Lot Information Sheet to confirm the total number of vials to be administered and confirm that each vial is within the expiration date prior to preparation of CASGEVY for infusion. Inspect the vial(s) for any breaks or cracks prior to thawing. If a vial is compromised, do not infuse the contents. Call Vertex at +1-877-634-8789. When the dose consists of multiple vials, thaw and administer one vial at a time. While thawing and administering a vial, remaining vials must remain in cryostorage at ≤ -135 °C (≤ -211 °F). Assemble supplies needed to thaw and withdraw the product from the vial(s). With the exception of the water bath, these supplies are single use. Assemble sufficient supplies for each vial to be administered: Water bath Alcohol swabs Vial adapter (to allow for needleless extraction) 18-micron stainless steel filter 30 mL luer-lock syringe 0.9% sodium chloride (saline, 5 to 10 mL needed for each vial) 10 mL luer-lock syringe for saline rinse Thawing the CASGEVY vials Thaw each CASGEVY vial at 37 °C (98 °F) using a water bath. Thaw each vial holding the vial neck, gently agitating clockwise and counterclockwise. Thawing of each vial can take between 10 to 15 minutes. Thawing is complete when ice crystals are no longer visible in the vial. Ensure water bath temperature does not exceed 40 °C (104 °F) during thawing. Do not leave CASGEVY unattended during thaw. Remove vial from water bath immediately once thawed. The thawed product should appear as a cellular suspension, which may contain proteinaceous particles or cellular aggregates. Inspect the vial(s) for any breaks or cracks after thawing. Do not wash, spin down and/or resuspend CASGEVY in new media prior to infusion. Do not sample, alter, irradiate, or refreeze CASGEVY. Infuse within 20 minutes of thaw. 2.3 Administration CASGEVY is for autologous use only. Before infusion, confirm that the patient's identity matches the unique patient identifiers on the CASGEVY vial(s). Do not infuse CASGEVY if the information on the patient-specific label does not match the intended patient. A patient's dose may consist of multiple vials. All vials must be administered. Use the Lot Information Sheet to confirm the total number of vials to be administered. The entire volume of each vial provided should be infused. If more than one vial is provided, administer each vial completely before proceeding to thaw and infuse the next vial. 1. Attaching the vial adapter and filter a. Remove the flip-away tab of the vial cap; clean the septum with an alcohol swab. b. Remove the cap on the vial adapter spike. c. With the thumb and forefinger of both hands, push the adapter into the vial septum, applying equal pressure until there is a single pop. d. Pull up on the adapter until you feel it lock. e. Attach the filter to the vial adapter. 2. Withdrawing CASGEVY from the vial a. Attach an empty 30 mL syringe to the filter. b. Withdraw the entire vial product volume. c. Remove the product-filled syringe from the filter and set aside. d. Draw 5 - 10 mL of saline into the empty 10 mL syringe. e. Attach the saline-filled syringe to the filter. f. Inject the saline into the CASGEVY vial and remove the empty syringe from the filter. Discard the empty syringe. g. Attach the product-filled syringe to the filter. h. Withdraw the contents of the vial into the syringe, then remove the syringe from the filter. i. Peel the product/patient identifier label from the Syringe Label Sheet and affix to the product-filled syringe. 3. Administer CASGEVY through central venous catheter a. Perform a two-person confirmation and verification of patient's identification at the bedside prior to the infusion of each vial(s). b. Administer CASGEVY as an intravenous bolus (IV push) within 20 minutes of product thaw. Do not use an in-line blood filter or infusion pump when infusing CASGEVY. The total volume of CASGEVY administered within one hour must not exceed 2.6 mL/kg. c. After administration of each vial of CASGEVY, flush the primary line with 0.9% sodium chloride solution, using enough volume to flush the tubing and the length of the IV catheter. Repeat steps 1-3 for each remaining vial. If more than one vial is needed to achieve the patient-specific dose, administer each vial completely before proceeding to thaw and infuse the next vial. Follow standard procedures for patient management after autologous HSC transplantation after CASGEVY infusion. Image Image Image Image

4 CONTRAINDICATIONS None. None. ( 4 )

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.

7 DRUG INTERACTIONS No formal drug interaction studies have been performed. CASGEVY is not expected to interact with the hepatic cytochrome P-450 family of enzymes or drug transporters. Granulocyte Colony-Stimulating Factor: Granulocyte Colony-Stimulating Factor (G-CSF) must not be used for CD34 + HSC mobilization of patients with SCD. ( 7.1 ) Hydroxyurea: Discontinue hydroxyurea at least 8 weeks prior to start of mobilization and conditioning. ( 7.2 ) Crizanlizumab: Discontinue the use of crizanlizumab at least 8 weeks prior to start of mobilization and conditioning. ( 7.3 ) Iron Chelators: Discontinue iron chelators at least 7 days prior to initiation of myeloablative conditioning. Avoid the use of non-myelosuppressive iron chelators for at least 3 months and use of myelosuppressive iron chelators for at least 6 months after CASGEVY infusion. ( 7.4 ) 7.1 Use of Granulocyte Colony-Stimulating Factor (G-CSF) Granulocyte Colony - Stimulating Factor (G-CSF) must not be used for CD34 + HSC mobilization of patients with SCD [ see Warnings and Precautions (5.1) ] . 7.2 Use of Hydroxyurea Discontinue the use of hydroxyurea at least 8 weeks prior to start of each mobilization cycle and conditioning. There is no experience of the use of hydroxyurea after CASGEVY infusion. 7.3 Use of Crizanlizumab Discontinue the use of crizanlizumab at least 8 weeks prior to start of mobilization and conditioning, as its interaction potential with mobilization and myeloablative conditioning agents is not known. 7.4 Use of Iron Chelators Discontinue the use of iron chelators at least 7 days prior to initiation of myeloablative conditioning, due to potential interaction with the conditioning agent. Some iron chelators are myelosuppressive. If iron chelation is required, avoid the use of non-myelosuppressive iron chelators for at least 3 months and use of myelosuppressive iron chelators for at least 6 months after CASGEVY infusion. Phlebotomy can be used instead of iron chelation, when appropriate. 7.5 Live Vaccines The safety of immunization with live viral vaccines during or following CASGEVY treatment has not been studied.

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 Metabolism and nutrition disorders Decreased appetite 18 (41) 3 (27) Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain includes back pain, musculoskeletal chest pain, neck pain, non-cardiac chest pain, and pain in extremity. , 6 (14) 0 Skin and subcutaneous tissue disorders Pruritus 5 (11) 0 In Trial 1, other clinically important adverse reactions that occurred in less than 10% of patients or were Grade 1 or Grade 2 include the following: Hepatobiliary disorders : Veno-occlusive liver disease (1 [2%] patient). Infusion-related reactions : 6 (14%) patients, including preferred terms of abdominal pain in 3 (7%) patients; and infusion-related reaction, nausea, non-cardiac chest pain, pruritus, sinus tachycardia, and vomiting in 1 (2%) patient each. Table 3: Grade 3 or 4 laboratory abnormalities 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 laboratory abnormalities associated with busulfan myeloablative conditioning and treatment with CASGEVY. Laboratory abnormality Trial 1 N=44 The denominator for CD4 lymphocytes decreased is 43 and the denominator for all other laboratory data is 44, based on evaluable data at the time of the interim analysis. (%) Trial 4 N=11 (%) Neutropenia 100 100 Thrombocytopenia 100 100 Leukopenia 98 100 Anemia 84 100 Lymphopenia 50 64 CD4 lymphocytes decreased 23 0 Activated partial thromboplastin time prolonged 16 9 Hyperbilirubinemia 14 18 Platelet engraftment in patients with SCD (Trial 1 and Trial 4) Platelet engraftment in patients with SCD is defined as 3 consecutive measurements of platelet counts ≥ 50 × 10 9 /L, obtained on 3 different days after CASGEVY infusion, without administration of platelet transfusions for 7 days. One patient in Trial 4 received a thrombopoietin (TPO) mimetic which was initiated on Day 52 and continued through Day 151. The median time to platelet engraftment for patients with SCD by age sub-group is provided in Table 4. Table 4: Median (min, max) time to platelet engraftment in patients with SCD Age Number of patients Median (min, max) Time (days) to Platelet Engraftment 5 to < 12 years 11 47 (24, 78) 12 to < 17 years 9 40 (23, 64) 17 years and older 34 32.5 (23, 126) In both Trials 1 and 4, there was no association observed between bleeding events and time to platelet engraftment. Neutrophil engraftment in patients with SCD ( Trial 1 and Trial 4) Neutrophil engraftment is defined as 3 consecutive measurements of absolute neutrophil count (ANC) ≥ 500 cells/μL on 3 different days after CASGEVY infusion, without use of the unmodified rescue CD34 + cells. All patients achieved neutrophil engraftment in Trials 1 and 4. The median time to neutrophil engraftment for patients with SCD by age sub-group is provided in Table 5. Table 5: Median (min, max) time to neutrophil engraftment in patients with SCD Age Number of patients Median (min, max) Time (days) to Neutrophil Engraftment 5 to < 12 years 11 28 (20, 37) 12 to < 17 years 9 29 (26, 40) 17 years and older 35 26 (15, 38) In Trial 1, 19 out of 44 (43%) and in Trial 4, 8 out of 11 patients (73%) received G-CSF beginning on or after Day 21, post-infusion. Transfusion-dependent β-thalassemia The safety of CASGEVY in patients with TDT was evaluated in two open-label, single-arm trials (Trial 2 and Trial 5) and a long-term follow-up trial that included patients with SCD and TDT (Trial 3). Trial 2 included 52 patients 12 years and older and Trial 5 included 15 patients 5 years to less than 12 years of age. Patients were treated with CASGEVY after undergoing myeloablative conditioning with busulfan. Trial 2 (patients 12 years and older) The median (min, max) duration of follow-up for 52 patients with TDT after being administered CASGEVY was 20.4 (2.1, 48.1) months. Serious adverse reactions after myeloablative conditioning and CASGEVY infusion were observed in 33% of patients with TDT. The most common serious adverse reactions (≥ 2 patients) were veno-occlusive liver disease, pneumonia, hypoxia, thrombocytopenia, viral infection, and upper respiratory tract infection. Trial 5 (patients 5 years to less than 12 years of age) The median (min, max) duration of follow-up after CASGEVY infusion was 16.0 (2.2, 24.3) months. Serious adverse reactions after myeloablative conditioning and CASGEVY infusion were observed in 33% of patients with TDT. The most common serious adverse reaction was veno-occlusive liver disease, which occurred in two patients. One patient who received busulfan conditioning and CASGEVY developed veno-occlusive disease (VOD) and hemophagocytic lymphohistiocytosis (HLH) and died due to pneumonia and subsequent multi-organ failure [see Use in Specific Populations (8.4) , Clinical Pharmacology (12.3) and Clinical Studies (14) ] . Table 6 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 2 with the corresponding incidences in Trial 5. Table 7 presents the Grade 3 or 4 laboratory abnormalities that occurred in at least 10% of patients with TDT. Table 6: Grade 3 or 4 non-laboratory adverse reactions in ≥ 10% of patients with TDT who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 2 with corresponding incidences in Trial 5: 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 2 (N=52) n (%) Trial 5 (N=15) n (%) Blood and lymphatic system disorders Febrile neutropenia 28 (54) 13 (87) Gastrointestinal disorders Mucositis Mucositis includes anal inflammation, mucosal inflammation, pharyngeal inflammation, and stomatitis. , Encompasses preferred terms that belong to other system organ class. 37 (71) 12 (80) Hepatobiliary disorders Veno-occlusive liver disease 5 (10) 2 (13) Metabolism and nutrition disorders Decreased appetite 12 (23) 2 (13) Respiratory, thoracic and mediastinal disorders Epistaxis 7 (13) 1 (7) In Trial 2 or Trial 5, other clinically important adverse reactions that occurred in less than 10% of patients or were Grade 1 or Grade 2 include the following: Immune system disorders : Hemophagocytic lymphohistiocytosis (Trial 2: 1 [2%] patient; Trial 5: 1 [7%] patient). Nervous system disorders: Cerebellar hemorrhage (intracranial hemorrhage) (Trial 2: 1 [2%] patient). Infusion-related reactions: In Trial 2, 12 (23%) patients, including preferred terms of abdominal pain and nausea in 4 (8%) patients each; pruritus and vomiting in 2 (4%) patients each; and abdominal pain lower, chills, sinus tachycardia, and tachycardia in 1 (2%) patient each. In Trial 5, 2 (13%) patients, with preferred term of abdominal pain. Table 7: Grade 3 or 4 laboratory abnormalities in ≥ 10% of patients with TDT who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 2 with corresponding incidences in Trial 5: Day 1 to Month 24 after CASGEVY infusion Table includes laboratory abnormalities associated with busulfan myeloablative conditioning and treatment with CASGEVY. Laboratory abnormality Trial 2 N=52 The denominator for CD4 lymphocytes decreased is 48 and the denominator for all other laboratory data is 52, based on evaluable data at the time of the interim analysis. (%) Trial 5 N=15 The denominator for CD4 lymphocytes decreased is 13 and the denominator for all other laboratory data is 15, based on evaluable data at the time of the interim analysis. (%) Neutropenia 100 100 Thrombocytopenia 100 100 Leukopenia 98 100 Anemia 92 93 Lymphopenia 79 67 CD4 lymphocytes decreased 23 8 Hyperbilirubinemia 23 27 Alanine aminotransferase increased 19 33 Hypokalemia 19 13 Gamma-glutamyltransferase increased 17 7 Activated partial thromboplastin time prolonged 13 27 Hypocalcemia 12 7 Platelet engraftment in patients with TDT (Trial 2 and Trial 5) Platelet engraftment in patients with TDT is defined as 3 consecutive measurements of platelet counts ≥ 20 × 10 9 /L, obtained on 3 different days after CASGEVY infusion, without administration of platelet transfusions for 7 days. The median time to platelet engraftment for patients with TDT by age sub-group is provided in Table 8. Table 8: Median (min, max) time to platelet engraftment in patients with TDT Age Number of patients Median (min, max) Time (days) to Platelet Engraftment 5 to < 12 years 14 51 (22, 82) 12 to < 17 years 13 46 (20, 199) 17 years and older 39 40 (24, 200) In both Trials 2 and 5, there was no association observed between bleeding events and time to platelet engraftment. In Trial 2, patients without a spleen had an earlier median time to platelet engraftment than patients with an intact spleen. Median (min, max) time to platelet engraftment was 34.5 (20, 78) days in patients without a spleen and 47.5 (27, 200) days in patients with an intact spleen. 13 of the 14 patients achieving platelet engraftment in Trial 5 had an intact spleen. While the use of TPO mimetics was not specified in the Trial 2 protocol, five patients (10%) received a TPO mimetic at the time of platelet engraftment. All 5 patients continued TPO mimetic use for thrombocytopenia beyond engraftment. The total duration of TPO mimetic use was 98-457 days. Neutrophil engraftment in patients with TDT (Trial 2 and Trial 5) Neutrophil engraftment is defined as 3 consecutive measurements of absolute neutrophil count (ANC) ≥ 500 cells/µL on 3 different days after CASGEVY infusion, without use of the unmodified rescue CD34 + cells. All patients achieved neutrophil engraftment in Trials 2 and 5. The median time to neutrophil engraftment for patients with TDT by age sub-group is provided in Table 9. Table 9: Median (min, max) time to neutrophil engraftment in patients with TDT Age Number of patients Median (min, max) Time (days) to Neutrophil Engraftment 5 to < 12 years 15 30 (19, 38) 12 to < 17 years 13 31 (19, 56) 17 years and older 39 29 (12, 40) In Trial 2, one patient had neutrophil engraftment on Day 56. In Trial 2, 33 out of 52 (63%) patients and in Trial 5, 12 out of 15 patients (80%) received G-CSF beginning on or after Day 21 post-infusion.

8.1 Pregnancy Risk Summary There are no clinical data from the use of exagamglogene autotemcel during pregnancy. No animal reproductive and developmental toxicity studies have been conducted with exagamglogene autotemcel to assess whether it can cause fetal harm when administered to a pregnant patient. CASGEVY must not be administered during pregnancy because of the risks associated with myeloablative conditioning. Pregnancy after CASGEVY infusion should be discussed with the treating physician(s). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.