CASGEVY

1. INDICATIONS AND USAGE CASGEVY is indicated for the treatment of patients aged 12 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 12 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 ) 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 hematopoietic stem cell (HSC) transplantation is appropriate for the patient before mobilization, apheresis and myeloablative conditioning are initiated. 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, voxelotor) 8 weeks before the planned start of mobilization and conditioning [see Drug Interactions (7.2 , 7.3) ] . Sickle Cell Disease Prior to apheresis it is recommended that patients be transfused 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 apheresis procedure it is recommended that patients be transfused with a goal to maintain hemoglobin (Hb) ≥ 11 g/dL. Mobilization and Apheresis Patients are required to undergo CD34 + HSC mobilization followed by apheresis to isolate the CD34 + cells needed for CASGEVY manufacturing. Plerixafor and Granulocyte-Colony Stimulating Factor (G-CSF) were used for mobilization in patients with TDT. Single agent plerixafor was used for mobilization in patients with SCD. G-CSF should not be administered for mobilization in patients with SCD. Refer to the prescribing information for the mobilization agent(s) prior to treatment. See Clinical Studies (14) for description of the mobilization regimen used in the clinical trials. Maximize CD34 + cell collection to obtain as many CD34 + cells as possible for product manufacturing during each mobilization and apheresis cycle. 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 for product manufacture. Collected cells should be sent for product manufacturing even if the total collection target is not achieved. If the minimum dose of CASGEVY (3 × 10 6 CD34 + cells/kg) is not met after initial product manufacturing, the patient will need to undergo additional cycles of mobilization and apheresis. Each mobilization and apheresis cycle must be separated by a minimum of 14 days. An additional ≥ 2 × 10 6 CD34 + cells/kg of unmodified back-up rescue cells must be collected from the patient and be cryopreserved prior to myeloablative conditioning and infusion with CASGEVY. The unmodified back-up cells may be needed for rescue treatment under any one of the following conditions: (1) compromise of CASGEVY after initiation of myeloablative conditioning and before CASGEVY infusion; (2) neutrophil engraftment failure; or (3) loss of engraftment after infusion with CASGEVY [see Warnings and Precautions (5.1) ] . Myeloablative Conditioning In patients with SCD it is recommended that patients be transfused 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. At initiation of red blood cell exchange or simple transfusions, discontinue disease modifying therapies for sickle cell disease (e.g., hydroxyurea, crizanlizumab, voxelotor). In patients with TDT it is recommended that patients be transfused to maintain hemoglobin (Hb) ≥ 11 g/dL for 60 days prior to myeloablative conditioning. Stop iron chelation therapy at least 7 days prior to myeloablative conditioning. Do not begin myeloablative conditioning until the complete set of vial(s) comprising the total dose of CASGEVY has been received and stored at the treatment center and the availability of the back-up collection of unmodified rescue cells is confirmed. See the Lot Information Sheet provided with the product shipment for confirmation of the total dose of CASGEVY. Administer full myeloablative conditioning prior to treatment with CASGEVY 1 . Refer to the prescribing information for the myeloablative conditioning agent prior to treatment. See Clinical Studies (14) for the conditioning regimen used in the clinical trials. Consider administration of anti-seizure prophylaxis. Use agents other than phenytoin prior to initiating busulfan conditioning. Consider prophylaxis for hepatic veno-occlusive disease (VOD)/hepatic sinusoidal obstruction syndrome prior to initiating busulfan conditioning. CASGEVY must be administered between 48 hours and 7 days after the last dose of the myeloablative conditioning. Receipt and Storage of CASGEVY CASGEVY is shipped to the treatment center frozen in a vapor phase of liquid nitrogen shipper. Confirm patient identifiers on the product label(s) and Lot Information Sheet. 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 Lot Information 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. Image Image Image Image After CASGEVY Administration Follow standard procedures for patient management after HSC transplantation after CASGEVY infusion. Irradiate any blood products required within the first 3 months after CASGEVY infusion. Patients treated with CASGEVY should not donate blood, organs, tissues, or cells at any time in the future. Restarting iron chelation after CASGEVY infusion may be necessary and should be based on clinical practice. 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 in lieu of iron chelation, when appropriate [see Drug Interactions (7.4) ] .

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) ] . 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) ] . In the clinical trials, there was no association observed between incidence of bleeding events and time to platelet engraftment. 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 ) Voxelotor and Crizanlizumab: Discontinue the use of voxelotor and 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. 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 Voxelotor and Crizanlizumab Discontinue the use of voxelotor and crizanlizumab at least 8 weeks prior to start of mobilization and conditioning, as their 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 an open-label, single-arm trial (Trial 1) and a long-term follow-up trial (Trial 3), in which 44 adolescent and adult patients with SCD were treated with CASGEVY after undergoing myeloablative conditioning with busulfan. The adverse event profile was generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant. 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. Table 1 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. Table 2 presents the Grade 3 or 4 laboratory abnormalities that occurred in at least 10% of patients with SCD. Table 1: 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: Day 1 to Month 24 after CASGEVY infusion Table includes adverse events associated with busulfan myeloablative conditioning and treatment with CASGEVY. Adverse event profile generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant. System organ class, preferred term Patients with SCD (Trial 1) (N=44) n (%) Blood and lymphatic system disorders Febrile neutropenia 21 (48) Gastrointestinal disorders Mucositis Mucositis includes mucosal inflammation, pharyngeal inflammation, and stomatitis. , Encompasses preferred terms that belong to other system organ class. 38 (86) Abdominal pain Abdominal pain includes abdominal pain and abdominal pain upper. 5 (11) Hepatobiliary disorders Cholelithiasis 5 (11) Metabolism and nutrition disorders Decreased appetite 18 (41) 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) Skin and subcutaneous tissue disorders Pruritus 5 (11) 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 2: Grade 3 or 4 laboratory abnormalities in ≥ 10% of patients with SCD who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 1: Day 1 to Month 24 after CASGEVY infusion Table includes laboratory abnormalities associated with busulfan myeloablative conditioning and treatment with CASGEVY. Laboratory abnormalities were generally consistent with those expected from busulfan myeloablative conditioning and HSC transplant. Laboratory abnormality Patients with SCD (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. (%) Neutropenia 100 Thrombocytopenia 100 Leukopenia 98 Anemia 84 Lymphopenia 50 CD4 lymphocytes decreased 23 Activated partial thromboplastin time prolonged 16 Hyperbilirubinemia 14 Platelet engraftment 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. In Trial 1, the median (min, max) time to platelet engraftment was 35 (23, 126) days (n=43). There was no association observed between bleeding events and time to platelet engraftment. Neutrophil engraftment Neutrophil engraftment is defined as 3 consecutive measurements of ANC ≥ 500 cells/µL on 3 different days after CASGEVY infusion, without use of the unmodified rescue CD34 + cells. In Trial 1, the median (min, max) time to neutrophil engraftment was 27 (15, 40) days (n=44). There was no association observed between infections and time to neutrophil engraftment. There was no use of rescue CD34 + cells in any patient. Transfusion-dependent β-thalassemia The safety of CASGEVY in patients with TDT was evaluated in an open-label, single-arm trial (Trial 2) and a long-term follow-up trial (Trial 3), in which 52 adolescent and adult patients with TDT were treated with CASGEVY after undergoing myeloablative conditioning with busulfan. The adverse event profile was generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant. 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. Table 3 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. Table 4 presents the Grade 3 or 4 laboratory abnormalities that occurred in at least 10% of patients with TDT. Table 3: 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: Day 1 to Month 24 after CASGEVY infusion Table includes adverse events associated with busulfan myeloablative conditioning and treatment with CASGEVY. Adverse event profile generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant. System organ class, preferred term Patients with TDT (Trial 2) (N=52) n (%) Blood and lymphatic system disorders Febrile neutropenia 28 (54) 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) Hepatobiliary disorders Veno-occlusive liver disease 5 (10) Metabolism and nutrition disorders Decreased appetite 12 (23) Respiratory, thoracic and mediastinal disorders Epistaxis 7 (13) 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 (1 [2%] patient). Nervous system disorders: Cerebellar hemorrhage (intracranial hemorrhage) (1 [2%] patient). Infusion-related reactions: 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. Table 4: Grade 3 or 4 laboratory abnormalities in ≥ 10% of patients with TDT who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 2: Day 1 to Month 24 after CASGEVY infusion Table includes laboratory abnormalities associated with busulfan myeloablative conditioning and treatment with CASGEVY. Laboratory abnormalities were generally consistent with those expected from busulfan myeloablative conditioning and HSC transplant. Laboratory abnormality Patients with TDT (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. (%) Neutropenia 100 Thrombocytopenia 100 Leukopenia 98 Anemia 92 Lymphopenia 79 CD4 lymphocytes decreased 23 Hyperbilirubinemia 23 Alanine aminotransferase increased 19 Hypokalemia 19 Gamma-glutamyltransferase increased 17 Activated partial thromboplastin time prolonged 13 Hypocalcemia 12 Platelet engraftment 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. In Trial 2, the median (min, max) time to platelet engraftment was 44 (20, 200) days (n=52). There is an increased risk of bleeding until platelet engraftment is achieved. In the clinical trials, there was no association observed between incidence of bleeding events and time to platelet engraftment. 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. While the use of thrombopoietin (TPO) mimetics was not specified in the trial 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 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. In Trial 2, the median (min, max) time to neutrophil engraftment was 29 (12, 56) days (n=52). There was no association observed between infections and time to neutrophil engraftment. One patient had neutrophil engraftment on Day 56. There was no use of rescue CD34 + cells in any patient.

8.1 Pregnancy Risk Summary There are no clinical data from the use of exagamglogene autotemcel in pregnant women. 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 woman. 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. 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.