Omidubicel

1 INDICATIONS 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 infections. ( 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.

12.1 Mechanism of Action OMISIRGE is a nicotinamide (NAM) modified allogeneic hematopoietic progenitor cell therapy derived from cord blood used as an allogeneic stem cell donor source. OMISIRGE is manufactured utilizing a proprietary NAM based technology producing enriched HPCs. NAM technology overcomes the induction of accelerated proliferation, differentiation, cellular stress and signaling pathways that are typically activated when HPCs are removed from their natural environment. Ex-vivo culturing of cord blood derived HPCs in the presence of NAM leads to preservation of their stemness, homing to the bone marrow (BM) and retained engraftment capacity as demonstrated by rapid neutrophil engraftment and multi lineage immune reconstitution as observed in the clinical trials with OMISIRGE.

2 DOSAGE 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. ( 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 Hand

6 ADVERSE 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: 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 (4

5 WARNINGS 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 [see Adverse Reactions (6.1) ] . 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 [see Adverse Reactions (6.1) ]. 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 [see Adverse Reactions (6.1) ] . 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 occu

4 CONTRAINDICATIONS 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 )