OMIDUBICEL-ONLV: 13 Adverse Event Reports & Safety Profile

OMISIRGE (omidubicel-onlv) is a cryopreserved nicotinamide modified unrelated allogeneic hematopoietic progenitor cell therapy derived from cord blood consisting of 2 cell fractions; a Cultured Fraction (CF) and a Non-cultured Fraction (NF) which are both derived from the same patient-specific cord blood unit (CBU). 1) The CF is a yellowish suspension consisting of allogeneic, hematopoietic CD34+ progenitor cells. In addition to the CD34+ hematopoietic progenitor cells (HPCs), the CF consists of other cell populations, including more differentiated myelomonocytic cells, dendritic cells and granulocytes. The CF formulation contains a maximum of 35 mg gentamicin. Following manipulation, the cells are washed, formulated into a suspension, and cryopreserved in a patient specific bag in 10% dimethyl sulfoxide (DMSO). The product is thawed and diluted prior to infusion [see Dosage and Administration (2.2) , How Supplied/Storage and Handling (16) ] . The CF contains approximately 2.42 mg of DMSO. The diluted CF contains ≤ 2% DMSO. 2) The NF is a reddish suspension consisting of allogeneic, hematopoietic mature myeloid and lymphoid cells that are washed, formulated into a suspension, and cryopreserved in a patient specific bag in 10% DMSO. In addition to the mature myeloid and lymphoid cells, the NF consists of other cell populations, including more lineage committed hematopoietic cells. The product is thawed and diluted prior to infusion [see Dosage and Administration (2.2) , How Supplied/Storage and Handling (16) ] . The NF contains approximately 1.1 mg of DMSO. The diluted NF contains ≤2% DMSO.

Two Infusion

Solution bags are also provided for diluting each fraction after thawing, one specifically for the CF and one specifically for the NF.

The Infusion

Solutions contain 8% w/v HSA and 6.8% w/v Dextran 40 in 0.9% sodium chloride [see Dosage and Administration (2.2) ] . The NF and IS are Released for Shipment (RFS) following full release testing, including sterility test. The CF is RFS at the end of manufacturing, prior to final product testing completion. OMISIRGE is Released for Infusion (RFI) after acceptable results from the CF's Rapid Contamination Test for microbial contamination and quantitative PCR-based mycoplasma test are obtained. The RFI includes all CF DP release testing as detailed in the CF CoA, except the pending Colony Forming Unit (CFU) and final Sterility tests results. RFI certificate is accompanied with the respective IS, NF, and CF CoA's. Receipt of the RFI Certificate for the patient-specific batch of OMISIRGE must be confirmed prior to preparation.

Rfi

Certificate receipt is via the Gamida Cell Assist Hospital Portal, ~approximately 72 h of the end of manufacturing.

AND USAGE OMISIRGE is a nicotinamide modified allogeneic hematopoietic progenitor cell therapy derived from cord blood indicated for the treatment of: adults and pediatric patients 12 years and older with hematologic malignancies who are planned for umbilical cord blood transplantation following myeloablative conditioning to reduce the time to neutrophil recovery and the incidence of infection ( 1.1 ) adults and pediatric patients 6 years and older with severe aplastic anemia (SAA) following reduced intensity conditioning. ( 1.2 )

1.1 Hematologic Malignancies OMISIRGE is indicated for the treatment of adults and pediatric patients 12 years and older with hematologic malignancies who are planned for umbilical cord blood transplantation following myeloablative conditioning to reduce the time to neutrophil recovery and the incidence of infections.

1.2 Severe Aplastic Anemia OMISIRGE is indicated for the treatment of adults and pediatric patients 6 years of age and older with severe aplastic anemia (SAA) following reduced intensity conditioning.

AND ADMINISTRATION For intravenous use only. Do not irradiate. Do not use a leukodepleting filter. ( 2 ) Verify patient's identity upon receipt, prior to thaw and prior to infusion. Do not open the metal cassettes until time of thaw. ( 2 ) Thawing should only take place immediately prior to use. ( 2 ) Premedicate the patient approximately 30 to 60 minutes prior to infusion. ( 2 ) The recommended dose of OMISIRGE is a one-time infusion delivered in two separate bags. ( 2 ) The CF (Cultured Fraction) bag must be administered FIRST, and infusion should not exceed 2 hours from the end of dilution. Infusion of the NF (Non-cultured) bag should not exceed 1 hour from the end of dilution. ( 2 ) Administration of OMISIRGE should be under the supervision of a physician experienced in treatment of hematologic malignancies or SAA, as appropriate, in centers with expertise in hematopoietic stem cell transplants. ( 2 ) See full prescribing information for details for preparation and administration of OMISIRGE.

2.1 Dose For intravenous use only. The recommended dose of OMISIRGE is a one-time infusion delivered in two separate bags which consists of a Cultured Fraction (CF): a minimum of 8.0 × 10 8 total viable cells of which a minimum of 8.7% is CD34+ cells and a minimum of 9.2 × 10 7 CD34+ cells, and a Non-cultured Fraction (NF): a minimum of 4.0 × 10 8 total viable cells with a minimum of 2.4 × 10 7 CD3+ cells The CF and NF are supplied cryopreserved. OMISIRGE requires thaw and dilution with two infusion solution (IS) bags (one IS bag for the CF, and one IS bag for the NF) prior to administration. Infusion of the NF bag should begin within 1 hour after completion of the CF infusion. For timing of dosing of each fraction, refer to section 2.2 under "Planning prior to OMISIRGE preparation".

2.2 Preparation and Administration Administration of OMISIRGE should be under the supervision of a physician experienced in treatment of hematologic malignancies or SAA, as appropriate, in centers with expertise in hematopoietic stem cell transplants.

Preparation Pretreatment

Confirm the Release For Infusion Certificate (RFI Certificate) is available for OMISIRGE before starting the conditioning regimen. Before infusion of OMISIRGE, administer as appropriate: For patients with hematologic malignancies, administer a myeloablative conditioning regimen according to institutional guidelines. For patients with SAA, administer a reduced intensity conditioning regimen according to institutional guidelines. Administer prophylactic and supportive therapies [including Granulocyte-Colony Stimulating Factor (G-CSF)] for prevention or treatment of transplant complications (GvHD, infections) according to institutional guidelines. Confirm emergency medications are available prior to infusion and during the recovery period as per institutional guidelines. Premedication for Patients with Hematologic Malignancies Premedicate the patient approximately 30 to 60 minutes prior to OMISIRGE infusion. Premedicate with diphenhydramine 50 mg IV (or 0.5 mg/kg up to a maximum of 50 mg) or dexchlorpheniramine 10 mg IV, hydrocortisone 50 mg IV (or 0.5 mg/kg up to a maximum of 50 mg) and acetaminophen 650 mg PO (or 10 mg/kg up to a maximum of 650 mg). Avoid prophylactic use of methylprednisolone in conjunction with OMISIRGE. Ensure the patient is adequately hydrated. Premedication for Patients with SAA For patients receiving Anti-thymocyte globulin (ATG) – administer oral prednisone at 1 mg/kg/day (or IV methylprednisolone if clinically indicated) 1 day prior to the first dose of ATG and continue according to institutional guidelines. Administer diphenhydramine 25-50 mg PO or IV and acetaminophen 650 mg PO or weight-based dosing for pediatric patients as per institutional guidelines, approximately 30 minutes prior to OMISIRGE infusion. Ensure the patient is adequately hydrated. Receipt of OMISIRGE Do not irradiate. OMISIRGE is shipped directly to the transplant center in 2 shipping containers: [see How supplied/ Storage and Handling (16) ] A liquid nitrogen dry vapor shipper containing the CF, the NF and a Chimerism Testing Sample(s) at ≤ - 150℃. A refrigerated shipping container containing the Infusion Solution for CF and the Infusion Solution for NF at 2-8℃. Confirm that the batch number and patient-specific identifiers on both shipping container labels match the intended patient and the information on the documents from the Gamida Cell Assist Hospital Portal. Confirm receipt of the Release for Shipping Certificate. Confirm patient-specific identifiers on the RFI Certificate and Certificates of Analysis (CoAs) match the patient's identity. Ensure that OMISIRGE was received in appropriate conditions and confirm that the temperature of the liquid nitrogen dry vapor shipper upon receipt was ≤ -150℃ and the temperature of the refrigerated shipping container was 2-8℃. If either of the shippers have expired upon arrival, or if you cannot confirm the patient identity with the patient-specific identifiers on any of the labels, contact Gamida Cell at (844) 477-7478. You should receive a total of 4 bags [i.e., CF Drug Product (DP) bag, NF DP bag, IS bag for CF DP and IS bag for NF DP] and vial or segment(s) containing Chimerism Testing Sample(s) in the OMISIRGE shipment. The liquid nitrogen dry vapor shipper contains two metal cassettes, one labeled for the CF containing the CF cryopreserved bag and one labeled for the NF containing the NF cryopreserved bag. The shipper also contains a Chimerism Testing Sample(s). Do NOT open the metal cassettes until time of thaw since the product's overwrap bag may inflate preventing cassette closure. Verify that the products are within their expiry date by checking the label located on the front of the metal cassettes and through the cassette windows. Do NOT open the cassettes to locate the expiration date. Verify that the patient-specific identifiers on the labels on the outside of the CF and NF metal cassettes and on the CF and NF cryopreserved bags visible through the cassette window (see Figure 1 ) match the intended patient. Transfer the metal cassettes containing the CF and NF cryopreserved bags and the Chimerism Testing Sample(s) to onsite vapor phase of liquid nitrogen storage at ≤ -150℃.

Figure

1: CF or NF Cryopreserved Bag inside closed Metal Cassette. Patient-specific identifiers are visible on the cryopreserved bag through the cassette window. Do NOT open the cassettes. The refrigerated shipping container contains 2 IS bags, the IS for CF and the IS for NF, each with tubing and an attached spike adaptor. Each IS bag is packed inside a sterile bag. Ensure that both bags are intact and verify that the Infusion Solutions are within their expiry date by checking the expiration date on the labels located on the IS bags. Verify that the patient-specific identifiers on the IS bag labels match the intended patient (see Figure 2 ). Transfer both IS bags to refrigerated storage at 2-8°C.

Figure

2: Infusion Solution for CF Bag with Patient-Specific Label. The IS bag has tubing with an attached spike adaptor and is packed inside a sterile bag.

Figure

1 Figure 2 Planning prior to OMISIRGE preparation OMISIRGE must not be prepared until after receipt of the RFI Certificate for this patient-specific batch of OMISIRGE. CoAs for the CF, NF and IS batches are attached to the RFI Certificate. The RFI certificate will be issued via Gamida Cell Assist Hospital Portal up to 72 hours after completion of manufacturing. Confirm receipt of the RFI Certificate. Confirm patient-specific identifiers on the RFI Certificate and CoAs match the patient's identity. The CF bag must be administered FIRST. Confirm the infusion time in advance and adjust the start time of CF cryopreserved bag thaw so that it will be available for infusion when the patient is ready. Once the CF cryopreserved bag is removed from the metal cassette, thawing and dilution must be carried to completion and the cells administered within 2 hours post-dilution. Do not thaw the NF cryopreserved bag until you have determined that the CF has been safely administered. Once the NF cryopreserved bag is removed from the metal cassette, thawing and dilution must be carried to completion and the cells administered within 1 hour post-dilution. The infusion of the NF bag should begin within 1 hour after completion of the CF infusion. Preparation of OMISIRGE for Infusion Follow universal precautions and local biosafety guidelines for handling and disposal of human cells to avoid potential transmission of infectious diseases. Use aseptic technique for all processing steps, including spiking of all transfusion infusion bag ports. No samples should be drawn from OMISIRGE.

The Cultured Fraction

Preparation of the Infusion Solution for CF 1. Remove the IS for CF bag from the 2-8°C storage location. Remove only the IS for CF bag at this time. 2. Confirm patient-specific identifiers on the label of the IS for CF match the intended patient. 3. Wipe the IS for CF sterile bag with 70% alcohol. Place it in the Biological Safety Cabinet (BSC) (if available), for at least 20 minutes with a maximum of 24 hours at room temperature. 4. Prior to dilution, remove the IS for CF bag from its sterile bag. Check that the pinch clamp is closed. Thawing and diluting the CF 5. Remove the CF metal cassette from the liquid nitrogen storage. 6. Prior to opening the CF metal cassette, verify that the patient-specific identifiers on the label on the outside of the cassette and on the CF cryopreserved bag (visible through the cassette window) match the intended patient (see Figure 1 ). 7. Once patient identity has been verified, open the CF metal cassette to remove the CF cryopreserved bag from the cassette. Leave the CF cryopreserved bag in the overwrap bag during thawing and dilution. 8. Visually inspect the CF cryopreserved bag for damage. If the bag is damaged, contact Gamida Cell at (844) 477-7478. The cryopreserved CF should be white in color. 9. Once the CF cryopreserved bag is removed from the metal cassette, the thaw and dilution must be carried to completion and the cells administered within 2 hours post-dilution. 10. Incubate the CF cryopreserved bag for 5 minutes at room temperature. 11. Place the CF cryopreserved bag in an approximately 37°C water bath until the product reaches a liquid consistency. This generally takes about 3-8 minutes. Do not massage, knead or apply pressure on the product bag. Keep the bag fully submerged until thawed – do not remove before thawing completion. 12. Remove the thawed bag from the water bath as soon as the cells have completely thawed. Do not remove the overwrap bag. 13. Wipe the overwrap with 70% alcohol. Put the bag into the BSC (if available). 14. Open the overwrap as follows: – Wipe a pair of clean scissors with 70% alcohol. – Cut the sealed area at the top of the overwrap. Be careful not to damage the CF bag or the CF bag's ports/ tubing. 15. Insert the spike adapter attached to the IS for CF bag into one of the ports of the CF bag, while it remains in the overwrap bag. 16. Open the pinch clamp on the IS tubing and double the volume of the CF by adding IS for CF (approximately 20 mL) to the CF bag. Gently swirl the bag until mixed well. 17. Add the remaining IS for CF (approximately 60 mL) to the CF bag. Close the valve and swirl gently. 18. Remove the overwrap of the CF bag and check the integrity of the CF bag. 19. Check the appearance of the contents of the CF bag. The thawed and diluted CF should appear as a yellowish suspension, essentially free of visible white clumps and foreign particulates. 20. Inspect the contents of the thawed and diluted CF bag for any visible cell clumps. If visible cell clumps remain, gently invert and/or massage the bag with fingertips. Small clumps of cellular material should disperse with gentle manual mixing. Do not infuse the CF if clumps are not dispersed, the bag is damaged or leaking, or otherwise appears to be compromised. If this occurs, call Gamida Cell at (844) 477-7478. 21. Heat seal and detach the emptied Infusion Solution for CF bag. 22. Connect the Transfusion Infusion Set to the free port on the CF bag. Alternatively, the infusion set may be connected in accordance with internal procedures. 23. Place the CF bag containing the thawed and diluted CF in a new sterile bag. Note: Do not wash, spin down, and/or resuspend CF in new media prior to infusion. 24. Transport the product to the patient at room temperature. Unless prepared at the patient's bedside, transport the product to the bedside in a closed box/bag to protect the product during transport. The CF bag should be completely infused within 2 hours post-dilution. 25. See the ‘ Administration ’ section on how to infuse the CF.

The

Non-cultured Fraction Preparation of the Infusion Solution for NF 1. Remove the IS for NF bag from the 2-8°C storage location. 2. Repeat steps 2-4 from the CF process, for the IS for NF. Thawing and diluting the NF 3. Repeat steps 5-8 from the CF process, for the NF. The cryopreserved NF should be red in color. 4. Once the NF cryopreserved bag is removed from the metal cassette, the thaw and dilution must be carried to completion and the cells administered within 1 hour post-dilution. 5. Repeat steps 10-14 from the CF process, for the NF. 6. Insert the spike adapter attached to the IS for NF bag into one of the ports of the NF bag, while it remains in the overwrap bag. 7. Open the pinch clamp on the IS tubing and double the volume of the NF by adding Infusion Solution for NF (approximately 10 mL) to the NF bag. Gently swirl the bag until mixed well. 8. Add the remaining IS for NF (approximately 30 mL) to the NF bag. Close the valve and swirl gently. 9. Repeat steps 18-21 from the CF process, for the NF. The thawed and diluted NF should appear as a reddish suspension essentially free of visible clumps and foreign particulates. 10. Repeat steps 22-25 from the CF process, for the NF. The NF should be completely infused within 1 hour post-dilution. Administration Do NOT use a leukodepleting filter Central venous access is recommended for the infusion of OMISIRGE. Confirm that the patient's identity matches the patient-specific identifiers on the CF and NF bags. Administer OMISIRGE by gravity infusion. Prior to spiking both the CF and NF bags, prime the infusion set tubing with normal saline. Infuse the entire contents of the CF and NF bags. The rate of infusion should not exceed a maximum of 10 mL per kg per hour. Administration: The thawed and diluted CF bag must be infused FIRST . The infusion time should not exceed 2 hours from the end of dilution to the end of CF infusion. Should an infusion reaction occur, appropriately manage the reaction before thawing the NF. The thawed and diluted NF should be infused within 1 hour of safely administering the CF infusion. The infusion time should not exceed 1 hour from the end of dilution to the end of infusion. In the event of any deviation from the dosing schedule, contact Gamida Cell at (844) 477-7478. After the entire contents of the CF and NF bags are each infused, wash the tubing with normal saline at the same infusion rate to ensure as many cells as possible are delivered to the patient. Follow universal precautions and local biosafety guidelines for handling and disposal of human cells to avoid potential transmission of infectious diseases.

Monitoring

Monitor the patient for hypersensitivity or other infusion-related reactions during the infusion and post-infusion, per institutional guidelines. Reduce the infusion rate if the fluid load is not tolerated. Pause the infusion in the event of a hypersensitivity reaction or if the patient develops a moderate to severe infusion reaction. Administer appropriate medical therapy as needed. [See Warnings and Precautions (5.2) ] Conduct frequent clinical and laboratory assessments and vital signs and monitor for graft failure, GvHD, infections and other post-transplant complications according to institutional guidelines.

OMISIRGE is contraindicated in patients with known hypersensitivity to dimethyl sulfoxide (DMSO), Dextran 40, gentamicin, human serum albumin, or bovine products. Known sensitivity to dimethyl sulfoxide (DMSO), Dextran 40, gentamicin, human serum albumin or bovine material. ( 4 )

REACTIONS Hematological malignancies: The most common adverse reactions (incidence > 20%) are infections, GvHD, and infusion and hypersensitivity reactions. ( 6.1 ) SAA: The most common adverse reactions (incidence > 20%) are infections, hyperglycemia, skin rash, febrile neutropenia, immune thrombocytopenia, acute kidney injury, acute GvHD, hypertension, hypoxia, and infusion related reactions. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gamida Cell at (844) 477-7478 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.

Hematologic Malignancies

The safety of OMISIRGE is based on data from Study P0501 for 52 patients transplanted with OMISIRGE and 56 patients transplanted with umbilical cord blood (UCB) [see Clinical Studies (14) ] . The median duration of follow up for the overall safety population was 14 months (range, 1-19 months). All patients received myeloablative preparative regimens and GvHD prophylaxis with tacrolimus or cyclosporin plus mycophenolate mofetil. Fatal adverse reactions occurred in 17% of patients treated with OMISIRGE, including infection (6%), acute GvHD (6%), veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) (2%), thrombotic thrombocytopenic purpura (TTP)/thrombotic microangiopathy (TMA) (2%), and pulmonary hemorrhage (2%). Fatal adverse reactions occurred in 29% of subjects treated with UCB, including infection/sepsis (11%), respiratory disorders (11%), GvHD (5%), and VOD/SOS (2%). The most common non-laboratory adverse reactions occurring in ≥ 10% of patients in Study P0501 are listed in Table 2 below. The most common Grade 3-5 adverse reactions for patients treated with OMISIRGE, were pain (33%), mucosal inflammation (31%), hypertension (25%), and gastrointestinal toxicity (19%).

Table

2: Adverse Reactions in ≥ 10% of Patients with Hematologic Malignancies Following Transplantation with OMISIRGE (N-52) or UCB (N=56) in Study P0501 Adverse Reaction OMISIRGE Any Grade n (%)

Omisirge

Grade 3 or Higher n (%)

Ucb

Any Grade n (%)

Ucb

Grade 3 or Higher n (%) Abbreviation: CTCAE: common terminology criteria for adverse events; n: number; UCB: umbilical cord blood. General disorders and administration site conditions - - - - Pain 41(79) 17 (33) 43 (77) 10 (18)

Fever

42 (81) 1 (2) 54 (96) 6 (11) Mucosal inflammation 39 (75) 16 (31) 47 (84) 19 (34)

Fatigue

Fatigue includes asthenia and fatigue 31(60) 2 (4) 42 (75) 12 (21)

Edema

24 (46) 1 (2) 37 (66) 4 (7)

Chills

19 (37) 0 32 (57) 0 Gastrointestinal disorders - - - - Gastrointestinal toxicity 40 (77) 10 (19) 48 (86) 19 (34)

Vomiting

33 (63) 3 (6) 40 (71) 2 (4)

Dysphagia

17 (33) 6 (12) 21 (38) 7 (13)

Constipation

12 (23) 0 21 (38) 0 Dyspepsia 12 (23) 0 12 (21) 0 Abdominal distention 10 (19) 0 16 (29) 1 (2) Infections and infestations Infections and infestations were graded according to the BMT-CTN grading system - - - - Viral infections 39 (75) 4 (8) 45 (80) 15 (27) Bacterial infections 34 (65) 4 (8) 45 (80) 13 (23) Fungal infections 11 (21) 3 (6) 15 (27) 10 (18)

Immune System

Disorder - - - - Acute Graft versus host disease Acute Graft-versus-host disease was graded according to the Consensus Conference on Acute GvHD grading 32 (62) 8 (15) 24 (43) 12 (21)

Chronic

Graft versus host disease Chronic Graft-versus-host disease was graded according to the 2014 NIH consensus criteria 18 (35) 12 (23) 14 (25) 11 (20) Vascular disorders - - - - Hypertension 29 (56) 13 (25) 37 (66) 21 (38)

Hemorrhage

Hemorrhage include cystitis hemorrhagic, epistaxis, gastrointestinal hemorrhage, hemorrhage, pulmonary alveolar hemorrhage, subarachnoid hemorrhage, and upper gastrointestinal hemorrhage 25 (48) 6 (12) 34 (61) 10 (18)

Hypotension

16 (31) 2 (4) 19 (34) 5 (9) Psychiatric disorders - - - - Insomnia 24 (46) 1 (2) 26 (46) 2 (4)

Anxiety

15 (29) 1 (2) 21(38) 3 (5)

Depression

13 (25) 0 16 (29) 2 (4)

Cardiac

Disorders - - - - Arrythmia 24 (46) 0 30 (54) 1 (2) Investigations - - - - Weight decrease/Decrease appetite 23 (44) 4 (8) 22 (39) 1 (2) Musculoskeletal and connective tissue disorders - - - - Muscular weakness 16 (31) 1 (2) 22 (39) 2 (4) Nervous system disorder - - - - Dysgeusia 15 (29) 0 9 (16) 0 Dizziness 10 (19) 0 13 (23) 0 Tremor 8 (15) 0 12 (21) 1 (2)

Somnolence

7 (13) 1 (2) 12 (21) 0 Respiratory, thoracic, and mediastinal disorders - - - - Cough 14 (27) 0 30 (54) 0 Dyspnea 13 (25) 4 (8) 26 (46) 9 (16)

Dehydration

11 (21) 3 (6) 10 (18) 2 (4)

Respiratory Failure

Respiratory failure includes acute respiratory distress syndrome, acute respiratory failure, hypoxia, and respiratory failure 8 (15) 6 (12) 26 (46) 17 (30) Neoplasms benign, malignant and unspecified (incl cysts and polyps) - - - - Disease recurrence 11 (21) 8 (15) 7 (13) 5 (14) Renal and urinary disorders - - - - Renal impairment Renal impairment includes acute kidney injury, blood creatinine increased and renal failure 9 (17) 6 (12) 3 (5) 3 (5) Eye disorders - - - - Dry eyes 6 (12) 0 10 (18) 0 Injury, poisoning and procedural complications - - - - Primary graft failure 1 (2) 1 (2) 6 (11) 6 (11) Secondary graft failure 1 (2) 1 (2) 0 0 Table 3 summarizes selected chemistry abnormalities by treatment arm for patients treated in Study P0501.

Table

3: Chemistry Laboratory Abnormalities in ≥10% of Patients in Study P0501 OMISIRGE N = 52 UCB N = 56 Laboratory Abnormality Grade 1-4 % Grade 3-4 % Grade 1-4 % Grade 3-4 % Abbreviation: N: number; UCB: umbilical cord blood. Decreased magnesium 94 4 91 2 Increased aspartate aminotransferase 56 13 61 7 Increased alanine aminotransferase 56 13 57 9 Increased creatinine 50 4 57 2 Increased bilirubin 42 12 61 21 Increased alkaline phosphatase 42 0 54 2 Increased magnesium 15 2 29 9 Severe Aplastic Anemia The safety data described in this section reflects exposure of OMISIRGE in one clinical study (Study 17-H-0091) for the treatment of severe aplastic anemia (SAA). A total of 17 patients received a single dose of OMISIRGE with a median dose of 8.5 ×10 6 cells/kg CD34+ cells (range, 2.3- 21.4 cells/kg CD34+ cells). Three out of 17 patients received OMISIRGE with haploidentical CD34+ cells [see Clinical Studies (14) ] . All patients received a reduced intensity preparative conditioning regimen of cyclophosphamide, fludarabine, TBI and horse-ATG, and GvHD prophylaxis according to institutional guidelines. The median duration of follow-up was 25 months (range, 2-60 months). Serious adverse reactions were reported in 15 patients including infections (n=15), diarrhea (n=3), nausea/vomiting (n=4), pyrexia (n=2), hypoxia (n=2), thrombotic microangiopathy (n=1), cardiac arrest (n=1), pericarditis (n=1), colitis (n=1), febrile neutropenia (n=1), cholecystitis (n=1), portal vein thrombosis (n=1), graft versus host disease (n=1), weight decreased (n=1), dehydration (n=1), Guillain-Barre Syndrome (n=1), uterine hemorrhage (n=1), pleural effusion (n=1), pulmonary hemorrhage (n=1), and respiratory failure (n=1). One patient (6%) treated with OMISIRGE had a fatal adverse event. The patient engrafted but died on Day 62 from disseminated adenovirus infection. The most common adverse reactions occurring in ≥15% of patients in Study 17-H-0091 are listed in Table 4 below.

Ctcae

Grade 3-5 non-laboratory adverse reactions in the SAA Study with greater or equal to 15% incidence are summarized in Table 4. The most common Grade 3-5 adverse reactions for patients treated with OMISIRGE were febrile neutropenia (41%), bacterial infections (41%), hyperglycemia (41%), Epstein-Barr virus infection (29%), immune thrombocytopenia (24%) and pneumonia (24%).

Table

4: Adverse Reactions in ≥15% of Patients with SAA Following Transplantation with OMISIRGE (N=17) in Study 17-H-0091 Adverse Reaction OMISIRGE Any Grade n (%)

Omisirge

Grade 3 or Higher n (%) Abbreviation: n: number. Infections and infestations - - Human herpesvirus 6 infection 16 (94) 0 BK virus infection 13 (76) 0 Bacterial infections Includes skin infection, clostridium difficile infection, device related infections and urinary tract infections. 10 (59) 7 (41) Epstein-Barr virus infection 9 (53) 5 (29) Cytomegalovirus infection Is a composite that includes multiple related terms. 8 (47) 3 (18)

Pneumonia

6 (35) 4 (24) Adenovirus infection 4 (24) 1 (6) Rhinovirus infection 4 (24) 1 (6)

Sepsis

3 (18) 3 (18) Upper respiratory tract infection 3 (18) 1 (6) Metabolism and nutrition disorders - - Hyperglycemia 11 (65) 7 (41)

Hypertriglyceridemia

3 (18) 2 (12) Skin and subcutaneous tissue disorders - - Skin rash 8 (47) 0 Blood and lymphatic system disorders - - Febrile neutropenia 7 (41) 7 (41) Immune thrombocytopenia 4 (24) 4 (24) Injury, poisoning and procedural complications - - Infusion related reaction Includes hypertension, headache and hypoxia. 4 (24) 2 (12) Immune system disorders - - Acute graft-versus-host disease 4 (24) 1 (6) Respiratory, thoracic and mediastinal disorders - - Hypoxia 4 (24) 3 (18) Respiratory failure Includes dyspnea, respiratory distress and respiratory failure. 3 (18) 3 (18) Vascular disorders - - Hypertension 4 (24) 3 (18) Renal and urinary disorders - - Acute kidney injury 4 (24) 2 (12) Gastrointestinal disorders - - Diarrhea 3 (18) 3 (18)

Nausea

3 (18) 2 (12)

Vomiting

3 (18) 2 (12) Other clinically significant adverse reactions occurring in <15% of patients include the following: Post-transplant lymphoproliferative disorder in two patients (12%), primary graft failure (defined as failure to achieve an absolute neutrophil count ≥500 cells / µl for 3 consecutive measurements on different days) in 1 patient (6%), and engraftment syndrome in 1 patient (6%).

Table

5 summarizes laboratory abnormalities that worsened from baseline in ≥ 15% of patients in Study 17-H-0091.

Table

5: Laboratory Abnormalities that Worsened from Baseline in ≥15% of Patients in Study 17-H-0091 (N=17)

Laboratory Abnormality Grade

1-4 N (%)

Grade

3-4 N (%) Abbreviation: N: number. Decreased potassium 5 (29) 0 Increased potassium 4 (24) 1 (6) Decreased phosphorous 4 (24) 0 Increased alanine aminotransferase 3 (18) 2 (12)

AND PRECAUTIONS Malignancies of donor origin: Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs after treatment with OMISIRGE, contact Gamida Cell at (844) 477-7478. ( 5.5 ) Transmission of serious infections: Monitor patients closely for serious infections. ( 5.7 ) Transmission of rare genetic diseases: Monitor patients for rare genetic diseases. ( 5.8 )

5.1 Graft-versus-Host Disease Acute and chronic graft versus host disease (GvHD) have occurred following treatment with OMISIRGE <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Acute GvHD manifests as maculopapular rash, gastrointestinal symptoms, and elevated bilirubin. Chronic GvHD manifests as skin rash, oral symptoms, ocular dryness, transaminase elevations, gastrointestinal symptoms, or serositis. Patients treated with OMISIRGE should receive immunosuppressive drugs to decrease the risk of GvHD, and be monitored for signs and symptoms of GvHD, and treated if GvHD develops.

5.2 Hypersensitivity and Infusion-Related Reactions Hypersensitivity and infusion-related reactions have occurred with OMISIRGE administration <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>. Serious hypersensitivity reactions, including anaphylaxis, may be due to DMSO, residual gentamicin, Dextran 40, human serum albumin (HSA) and bovine material in OMISIRGE. OMISIRGE may contain residual antibiotics if the cord blood donor was exposed to antibiotics in utero. Patients with a history of allergic reactions to antibiotics should be monitored for allergic reactions following OMISIRGE administration. Signs and symptoms of hypersensitivity reactions may include bronchospasm, wheezing, angioedema, pruritus, hives, fever, and hypotension during or after OMISIRGE infusion. Infusion-related reactions may begin within minutes of the start of infusion of OMISIRGE, although symptoms may continue to intensify and not peak for several hours after the completion of the infusion. Premedicate patients with antipyretics, histamine antagonists, and corticosteroids and monitor closely for signs and symptoms of hypersensitivity and infusion-related reactions. When a reaction occurs, pause the infusion and institute supportive care as needed.

5.3 Autoimmune Cytopenias Autoimmune cytopenias (AICs) have occurred with OMISIRGE administration in patients with SAA. AIC is characterized by thrombocytopenia, anemia, and neutropenia, alone or in combination, occurring weeks to months post-transplant, often after initial hematopoietic recovery. Risk factors for post-transplant AIC include younger age, ATG-containing conditioning, underlying SAA, and delayed T cell chimerism. Monitor blood counts prior to and after OMISIRGE infusion. Manage cytopenias according to local institutional guidelines.

5.4 Graft Failure Graft failure has occurred with OMISIRGE administration <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Primary graft failure, which may be fatal, is defined as failure to achieve an absolute neutrophil count greater than 500 per microliter blood by Day 42 after transplantation. Immunologic rejection is the primary cause of graft failure. Patients should be monitored for laboratory evidence of hematopoietic recovery.

5.5 Malignancies of Donor Origin Malignancy of donor origin including post-transplant lymphoproliferative disorder (PTLD) has occurred with OMISIRGE administration. PTLD manifests as a lymphoma-like disease favoring non-nodal sites. PTLD is usually fatal if not treated. The etiology is thought to be donor lymphoid cells transformed by Epstein-Barr virus (EBV). Serial monitoring of blood for EBV DNA may be warranted in patients with persistent cytopenias. A donor-cell derived myelodysplastic syndrome (MDS) has occurred with OMISIRGE administration. The natural history is presumed to be the same as that for de novo MDS. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Gamida Cell at (844) 477-7478.

5.6 Engraftment Syndrome Engraftment syndrome may occur because OMISIRGE is derived from umbilical cord blood. Monitor patients for unexplained fever, rash, hypoxemia, weight gain, and pulmonary infiltrates in the peri-engraftment period. Treat with corticosteroids as soon as engraftment syndrome is recognized to ameliorate symptoms. If untreated, engraftment syndrome may progress to multiorgan failure and death.

5.7 Transmission of Serious Infections Transmission of infectious disease may occur because OMISIRGE is derived from umbilical cord blood. Disease may be caused by known or unknown infectious agents. Donors are screened for increased risk of infection with human immunodeficiency virus (HIV), human T-cell lymphotropic virus (HTLV), hepatitis B virus (HBV), hepatitis C virus (HCV), T. pallidum, West Nile Virus (WNV), transmissible spongiform encephalopathy (TSE) agents, vaccinia, and Zika virus (for umbilical cord blood collected since March 2016). Donors are also screened for clinical evidence of sepsis, and communicable disease risks associated with xenotransplantation. Maternal blood samples are tested for HIV types 1 and 2, HTLV types I and II, HBV, HCV, T. pallidum, and WNV. OMISIRGE is tested for sterility. There may be an effect on the reliability of the sterility test results if the cord blood donor was exposed to antibiotics in utero. OMISIRGE is tested for sterility, endotoxin, and mycoplasma. These measures do not totally eliminate the risk of transmitting these or other transmissible infectious diseases and disease agents. Testing of maternal and infant donor blood is also performed for evidence of donor infection due to cytomegalovirus (CMV). Test results may be found on the container label and/or in accompanying records. Product manufacturing includes bovine-derived reagents. While all animal-derived reagents are tested for animal viruses, bacteria, fungi, and mycoplasma before use, these measures do not eliminate the risk of transmitting these or other transmissible infectious diseases and disease agents. Final sterility test results may not be available at the time of use, but Quality Assurance (QA) will communicate any positive results from sterility testing to the physician. Report the occurrence of transmitted infection to Gamida Cell at (844) 477-7478.

5.8 Transmission of Rare Genetic Diseases OMISIRGE may transmit rare genetic diseases involving the hematopoietic system because it is derived from umbilical cord blood. Cord blood donors have been screened to exclude donors with sickle cell anemia, and anemias due to abnormalities in hemoglobins C, D, and E. Because of the age of the donor at the time cord blood collection takes place, the ability to exclude rare genetic diseases is severely limited. Report the occurrence of transmitted rare genetic disease to Gamida Cell at (844) 477-7478.