Marnetegragene Autotemcel

1 INDICATIONS AND USAGE KRESLADI is indicated for the treatment of pediatric patients with severe leukocyte adhesion deficiency-I (LAD-I) due to biallelic variants in ITGB2 without an available human leukocyte antigen (HLA)-matched sibling donor for allogeneic hematopoietic stem cell transplant. This indication is approved under accelerated approval based on increase in neutrophil CD18 and CD11a surface expression [see Clinical Studies (14) ]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). KRESLADI is an autologous hematopoietic stem cell-based gene therapy indicated for the treatment of pediatric patients with severe leukocyte adhesion deficiency-I (LAD-I) due to biallelic variants in ITGB2 without an available human leukocyte antigen (HLA)-matched sibling donor for allogeneic hematopoietic stem cell transplant. ( 1 ) This indication is approved under accelerated approval based on increase in neutrophil CD18 and CD11a surface expression [see Clinical Studies (14) ] . Continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

12.1 Mechanism of Action KRESLADI adds functional copies of the ITGB2 gene into patients' hematopoietic stem cells (HSCs) through transduction of autologous CD34+ cells with LV-RP-201. After KRESLADI infusion, transduced CD34+ HSCs engraft in the bone marrow and differentiate into various cell types, including leukocytes capable of expressing functional CD18 protein. Functional CD18 protein enables formation of the CD18/CD11a heterodimer (Leukocyte Function-Associated Antigen-1, LFA-1) which facilitates leukocyte adhesion to endothelial surfaces and extravasation to infectious and inflammatory sites.

2 DOSAGE AND ADMINISTRATION For autologous use only. For intravenous use only. Patients must undergo hematopoietic stem cell (HSC) mobilization followed by apheresis to obtain CD34+ cells for KRESLADI manufacturing. ( 2.2 ) Dosing of KRESLADI 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 2.8 × 10 6 CD34+ cells/kg. ( 2.1 ) Full myeloablative conditioning must be administered before infusion of KRESLADI. ( 2.2 ) Verify the patient's identity matches the unique patient identification information on the KRESLADI infusion bag(s) prior to infusion. ( 2.2 ) Do not sample, alter, or irradiate KRESLADI. ( 2.2 ) Do not use an in-line blood filter or infusion pump. ( 2.3 ) 2.1 Dose For autologous use only. For one-time single-dose intravenous use only. The recommended minimum dose of KRESLADI is a single intravenous infusion of 2.8 × 10 6 CD34+ cells/kg. The dose is calculated based on the patient's weight prior to first apheresis. See the Lot Information Sheet provided with the product shipment for additional information pertaining to dose. Up to two drug product lots may be administered to meet the minimum dose. 2.2 Preparation Before KRESLADI Infusion Before mobilization, apheresis, and conditioning are initiated, confirm that autologous hematopoietic stem cell (HSC) transplantation is appropriate for the patient. Consider administering ustekinumab prior to mobilization and apheresis and/or prior to KRESLADI infusion. Mobilization and Apheresis Administer granulocyte-colony-stimulating factor (G-CSF) and plerixafor for HSC mobilization followed by apheresis to obtain CD34+ cells for product manufacturing. Weigh the patient prior to the first apheresis collection. Collect a recommended target number of CD34+ cells of 20 × 10 6 CD34+ cells/kg. Repeat additional cycles of mobilization and apheresis after at least 14 days to obtain more cells for KRESLADI manufacture if the minimum dose of 2.8 × 10 6 CD34+ cells/kg is not met. Back-Up CD34+ Cell Collection Obtain and cryopreserve an additional collection of CD34+ cells of ≥ 2 × 10 6 CD34+ cells/kg at the treatment center prior to initiating myeloablative conditioning and infusion with KRESLADI. Administer the back-up collection for rescue treatment if there is: 1) compromise of KRESLADI after initiation of conditioning and before KRESLADI infusion, 2) primary engraftment failure, or 3) loss of engraftment after infusion with KRESLADI. Myeloablative Conditioning Do not begin conditioning until KRESLADI has been received and stored at the treatment center and the availability of the back-up collection of CD34+ cells is confirmed. Administer myeloablative conditioning before infusion of KRESLADI based on institutional guidelines. Consult the prescribing information for the conditioning agents prior to treatment. Infuse KRESLADI 24-48 hours after completion of myeloablative conditioning. Receipt and Storage of KRESLADI Ensure the availability of vapor phase of liquid nitrogen storage at less than or equal to -150°C (-238°F) at the treatment center. KRESLADI is shipped to the treatment center in the vapor phase of liquid nitrogen shipper. Confirm the patient's identity with the patient identifiers on the shipper and labels. If there are any concerns about the product or packaging upon receipt, contact Rocket Pharmaceuticals at 1-800-982-2410. Keep the infusion bag(s) in the metal cassette(s) and transfer KRESLADI from the vapor phase of liquid nitrogen shipper to the onsite vapor phase of liquid nitrogen storage (at ≤ -150°C (≤ -238°F) until ready for thaw and administration). Preparation of KRESLADI for infusion Confirm the infusion time in advance and adjust the start time of KRESLADI thaw such that it will be available for infusion when the patient and the healthcare provider are ready. Complete infusion of each bag of KRESLADI within 30 minutes of the start of thaw. 1. Confirm patient identity: Prior to KRESLADI

6 ADVERSE REACTIONS The most common non-laboratory adverse reactions (≥ 30%): mucositis, upper respiratory tract infection, viral infection, febrile neutropenia, skin lesion, nausea/vomiting, rash/dermatitis, pyrexia, device related infection, and skin infection. ( 6.1 ) The most common laboratory adverse reactions (≥ 30%): hemoglobin decreased, platelet count decreased, neutrophil count decreased, leukocyte count decreased, aspartate aminotransferase increased, and alanine aminotransferase increased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Rocket Pharmaceuticals at 1-800-982-2410 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience As 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 safety data described in this section reflect exposure to KRESLADI in one clinical study (Study RP-L201-0318). A total of 9 pediatric patients with severe LAD-I received a single dose of intravenous KRESLADI with a median dose of 4.3 × 10 6 CD34+ cells/kg (range: 2.8 to 10 CD34+ cells/kg) [see Clinical Studies (14) ]. The median duration of follow up after KRESLADI administration was 4.2 years (range: 3.6 to 5.7 years). Serious adverse reactions were reported in 4 patients (44%) including serious infections (n=4), pulmonary arterial hypertension (n=1), sensorineural deafness (n=1), and veno-occlusive disease (n=1). Table 1 presents the most common adverse reactions reported in Study RP-L201-0318. Table 1: Non-Laboratory Adverse Reactions Reported in ≥ 20% of Patients in Study RP-L201-0318 (N=9) Adverse Reaction All Grades (%) Grade ≥3 (%) Gastrointestinal disorders Note: Adverse reactions are defined as adverse events that occurred from myeloablative conditioning administration through year 2 following KRESLADI administration. Nausea/Vomiting Includes multiple related terms 4 (44%) 0 Constipation 2 (22%) 0 General disorders and administration site conditions Mucositis 8 (89%) 5 (56%) Febrile neutropenia 6 (67%) 6 (67%) Pyrexia 3 (33%) 0 Infections and infestations Upper respiratory tract infection 8 (89%) 5 (56%) Viral infection 7 (78%) 1 (11%) Skin infection 3 (33%) 0 Device-related infection Device-related infection includes vascular device infection, device related bacteremia, and bacteremia that occurred with a central line in place 3 (33%) 2 (22%) Lower respiratory tract infection 2 (22%) 1 (11%) Gastroenteritis 2 (22%) 1 (11%) Skin candidiasis 2 (22%) 0 Urinary tract infection 2 (22%) 0 Skin and subcutaneous tissue disorders Skin lesion Skin lesion includes pyoderma gangrenosum, skin lesion, aseptic pustule, lip erythema, hand erythema, skin erythema at port site, and skin hyperpigmentation 6 (67%) 1 (11%) Rash Rash includes rash, eczema, atopic dermatitis and diaper dermatitis 4 (44%) 0 Alopecia 2 (22%) 0 Table 2 presents laboratory abnormalities that worsened from baseline in ≥20% of patients in Study RP-L201-0318. Table 2: Laboratory Abnormalities that Worsened from Baseline Reported in ≥ 20% of Patients in Study RP-L201-0318 (N=9) Baseline laboratory values were assessed prior to myeloablative conditioning Laboratory Abnormality All events occurred within 30 days post-infusion except for liver enzymes increased, which occurred in 3 patients within 30 days and in one patient after 90 days post-infusion All Grades (%) Grade ≥ 3 (%) Hemoglobin decreased 9 (100%) 9 (100%) Platelet count decreased 9 (100%) 9 (100%) Neutrophil count decreased 9 (100%) 9 (100%) Leukocyte count decreased 5 (56%) 5 (56%) Aspartate aminotransferase increased 4 (44%) 0 Alanine aminotransferase increased 3 (33%) 0

5 WARNINGS AND PRECAUTIONS Serious Infections: Monitor patients for signs and symptoms of infection before and after KRESLADI infusion and treat appropriately. Administer prophylactic antimicrobials according to institutional guidelines. ( 5.1 ) Veno-Occlusive Disease: Monitor patients for signs and symptoms of veno-occlusive disease including assessment of liver function tests during the first month following KRESLADI infusion. ( 5.2 ) Neutrophil Engraftment Failure: Monitor absolute neutrophil counts (ANC) after KRESLADI infusion. If neutrophil engraftment does not occur administer rescue cells. ( 5.3 ) Delayed Platelet Engraftment: Monitor patients for thrombocytopenia and bleeding until platelet engraftment and count recovery. ( 5.4 ) LVV-mediated Insertional Oncogenesis: Monitor patients at least annually for hematologic malignancies for at least 15 years after KRESLADI infusion. ( 5.5 ) Hypersensitivity Reactions: Monitor for hypersensitivity reactions during the infusion. ( 5.6 ) 5.1 Serious Infections Serious infections have occurred with KRESLADI administration [see Adverse Reactions (6.1) ]. Increased susceptibility to infections may occur due to administration of myeloablative conditioning prior to KRESLADI infusion. Monitor patients for signs and symptoms of infection before and after KRESLADI infusion and treat appropriately. Administer prophylactic antimicrobials according to institutional guidelines. Avoid administration of KRESLADI in patients with active bloodstream infections or other serious, untreated infections. Any blood products required after KRESLADI infusion should be irradiated. 5.2 Veno-Occlusive Disease Veno-occlusive disease has occurred with KRESLADI treatment [see Adverse Reactions (6.1) ]. Increased susceptibility to veno-occlusive disease may occur due to administration of myeloablative conditioning prior to KRESLADI infusion. Monitor patients for signs and symptoms of veno-occlusive disease including assessment of liver function tests during the first month following KRESLADI infusion. 5.3 Neutrophil Engraftment Failure Neutrophil engraftment failure may occur after treatment with KRESLADI. Neutrophil engraftment failure is defined as failure to achieve three consecutive absolute neutrophil counts (ANC) ≥ 500 cells/microliter obtained on different days by Day 43 after infusion of KRESLADI. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a patient treated with KRESLADI, provide rescue treatment with the back-up collection of CD34+ cells [see Preparation Before KRESLADI Infusion (2.2) ] . 5.4 Delayed Platelet Engraftment Delayed platelet engraftment may occur after treatment with KRESLADI. Monitor platelet counts and bleeding until platelet engraftment and platelet recovery are achieved. 5.5 LVV-Mediated Insertional Oncogenesis Lentiviral vector (LVV)-mediated insertional oncogenesis may occur after treatment with KRESLADI. Hematologic malignancy is a lifelong risk and patients treated with KRESLADI may develop hematologic malignancy at any time following treatment. Monitor for hematologic malignancies clinically, and with a complete blood count (with differential) at least annually and integration site analysis as warranted for at least 15 years after treatment with KRESLADI and as clinically indicated. If malignancy is detected in any patient who received KRESLADI, contact Rocket Pharmaceuticals, Inc. at 1-800-982-2410 for reporting and to obtain instructions on collection of samples for testing. 5.6 Hypersensitivity Reactions Hypersensitivity reactions including anaphylaxis may occur with the infusion of KRESLADI. The dimethyl sulfoxide (DMSO) in KRESLADI may cause hypersensitivity reactions which may occur in patients with and without prior exposure to DMSO. Monitor patients for signs and symptoms of hypersensitivity reactions during and after KRESLADI infusion. If a hypersensitivity reaction occurs, pause infusion if ongoing and ma

4 CONTRAINDICATIONS None. None. ( 4 )