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.

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 × 108 total viable cells of which a minimum of 8.7% is CD34+ cells and a minimum of 9.2 × 107 CD34+ cells, and
• a Non-cultured Fraction (NF): a minimum of 4.0 × 108 total viable cells with a minimum of 2.4 × 107 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.

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 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.

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.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and efficacy of OMISIRGE have been established in pediatric patients with hematologic malignancy 12 years of age and older and in pediatric patients with severe aplastic anemia (SAA) 6 years of age and older.

The use of OMISIRGE in pediatric patients with hematologic malignancy was supported by evidence from one clinical study (Study P0501) which included 2 pediatric patients age 12 to 16 years. The use of OMISIRGE in pediatric patients with SAA was supported by evidence from one clinical study (Study 17-H-0091) which included 7 pediatric patients age 6 to 16 years of age.

8.5 Geriatric Use

Clinical studies of OMISIRGE did not include patients aged 65 and over; therefore, it cannot be determined whether patients 65 years and over respond differently from younger patients.

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.

12.2. Pharmacodynamics

Transplantation with OMISIRGE resulted in rapid and broad immune reconstitution of dendritic cells, monocytes, Natural Killer (NK), CD4+ T cells and CD8+ T cells as early as one-week post-transplantation, and B cells 28 days post transplantation and all lineages throughout the one-year follow-up period. Robust positive linear correlations between the CD34(+) cell content in the OMISIRGE CF, and the reconstitution of T-cells and NK cells were identified. Additionally, dose-response analyses demonstrated a strong correlation between the total CD34+ cell counts and dose / kg for OMISIRGE with the kinetics of neutrophil recovery. The model demonstrated that days to neutrophil recovery decreased with an increase in OMISIRGE CD34(+) cell dose.

12.3 Pharmacokinetics

OMISIRGE is a cryopreserved nicotinamide modified allogeneic hematopoietic progenitor cell therapy derived from cord blood. The nature of OMISIRGE is such that conventional pharmacokinetic studies on absorption, distribution, metabolism, and excretion are not applicable.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No in vivo carcinogenicity, mutagenicity and fertility studies were conducted to evaluate the effects of OMISIRGE.

14.1 Hematologic Malignancies

OMISIRGE was evaluated in Study P0501 (NCT02730299), an open-label, multicenter, randomized study of OMISIRGE transplantation or UCB transplantation following myeloablative conditioning in patients with hematologic malignancies.

In total, 125 patients with the availability of at least one ≥ 4/6 human leukocyte antigen (HLA)-matched (HLA-A, B and DR loci) cord blood unit were randomized to the study, 62 patients were randomized to receive OMISIRGE and 63 patients were randomized to the UCB group. The minimum specifications of OMISIRGE were a Total Nucleated Viable Cell (TNVC) count of 8.0 × 108 cells and CD34+ cell count of 5.6 × 107. Fifty-two patients were transplanted with OMISIRGE at a median CD34+ cell dose of 9.0 × 106 cells/kg (range 2.1 – 47.6 × 106 cells/kg). Fifty-six patients were transplanted in the UCB arm with one or two cord units (66% received two cord units); among patients in whom the post-thaw cell dose was reported (n = 42), the median CD34+ cell dose was 0.2 × 106 cells/kg (range 0.0 – 0.8 × 106 cells/kg). Multiple conditioning regimens were used, including Total Body Irradiation (TBI)-based or chemotherapy-based options.

Demographic and baseline patient characteristics were similarly distributed among the treatment arms. The overall study population included 72 males (58%) and 53 females (42%) with median age 41 years (range: 13–65). Fifty-eight percent of patients were White, 16% were Black, 14% were Asian and 13% were of other races or unknown. Thirteen percent of patients identified as Hispanic or Latino. Forty-eight percent of patients had Acute Myelogenous Leukemia (AML), 33% had Acute Lymphoblastic Leukemia (ALL), 7% had Myelodysplastic Syndrome (MDS), 5% had Chronic myeloid leukemia (CML), 4% had lymphoma and 3% had other rare leukemias. Baseline disease status (remission vs. overt disease) varied depending on the hematologic malignancy. Disease risk index was high/very high for 34% and moderate for 42%. HCT specific comorbidity index was ≥ 3 in 51% and 1-2 in 28% of patients.

Of the patients randomized to OMISIRGE, 8% of patients (5/62) were not able to receive OMISIRGE due to manufacturing failure.

The efficacy of OMISIRGE was established based on time to neutrophil recovery following transplantation and the incidence of BMT CTN Grade 2/3 bacterial or Grade 3 fungal infections through Day 100 following transplantation. The efficacy outcomes are summarized below.

Eighty-seven percent of patients in the OMISIRGE arm and 83% in the UCB arm achieved neutrophil recovery. The median time to neutrophil recovery was 12 days in the OMISIRGE arm and 22 days in the UCB arm. BMT CTN Grade 2/3 bacterial or Grade 3 fungal infections through Day 100 following transplantation occurred in 39% of patients in the OMISIRGE arm and 60% of patients in the UCB arm.

14.2 Severe Aplastic Anemia

The efficacy of OMISIRGE in patients with severe aplastic anemia (SAA) was evaluated in study 17- H-0091 (NCT 03173937), an open-label, single center study. The study enrolled patients with SAA who had intolerance or failure to respond to immunosuppressive therapy and availability of at least one ≥ 4/8 human leukocyte antigen (HLA)-matched (HLA-A, B, C and DR loci) cord blood unit. Patients were excluded if there was availability of an HLA identical (12/12) matched related or unrelated donor.

In total, 17 patients were treated with OMISIRGE, among them 14 patients were treated with OMISIRGE alone and three patients were treated with both OMISIRGE and haploidentical CD34+ cells. The minimum specifications of OMISIRGE were a Total Nucleated Viable Cell (TNVC) count of 8.0 × 108 cells and CD34+ cell count of 9.2 × 107. The fourteen patients who were transplanted with OMISIRGE alone were included in the efficacy evaluation. The median CD34+ cell dose of OMISIRGE was 9.5 ×106 cells/kg (range, 2.3 - 21.4 cells/kg). All patients received reduced intensity conditioning which included cyclophosphamide, fludarabine, TBI and horse-ATG. GvHD prophylaxis was administered according to institutional guidelines.

The demographic characteristic of the population included the following: median age was 17 years (range: 6 – 45), 10 patients (59%) were male, 6 patients (35%) were Black, 3 patients (18%) were White, 5 patients (29%) were Asian and 3 patients (18%) were of "other races" or "unknown". Twenty-nine percent of patients identified as Hispanic or Latino. Median absolute neutrophil count at baseline was 0.3 ×109/L (range, 0.0 – 1.0) and median platelet count at baseline was 35 × 109/L (range, 10-89). Hematopoietic stem cell transplantation (HCT) specific comorbidity index was ≥ 3 in 76% and 0-2 in 24% of patients. Twelve percent of patients received 4/8 HLA match, 59% 5/8 HLA match, 18% 6/8 HLA match, 6% 7/8 HLA match and 6% 8/8 HLA match.

The primary efficacy outcome measure was the incidence of early and sustained neutrophil recovery, defined as ANC ≥500 cells/µl for 3 consecutive measurements on different days by Day 26, maintained at Days 42 and 100 posttransplant. Other secondary efficacy outcomes were neutrophil recovery (days to first of three consecutive ANC≥500 cells/µL), red blood cell (RBC) transfusion independence (days to 30-day transfusion independence), platelet recovery ≥20,000/µL (days to first of 3 consecutive platelet count of 20,000/µL with no preceding transfusion in 7 days) and platelet transfusion independence (days to 30-day platelet transfusion independence).

The efficacy results are summarized in Table 7 below.

The Cryopreserved Cell Fractions

OMISIRGE is comprised of two cryopreserved cell fractions, a Cultured Fraction (CF) and a Non-cultured Fraction (NF) each in a separate cryopreserved bag labeled for the specific patient. Each cryopreserved bag is protected by a corresponding transparent overwrap bag and each cryopreserved bag enclosed in its overwrap bag is individually packed in a metal cassette. The cassettes are NOT to be opened upon receipt. Both cryopreserved OMISIRGE cell fractions are shipped together in the vapor phase of liquid nitrogen in a liquid nitrogen dry vapor shipper with the Prescribing Information (PI) and a Chimerism Testing Sample(s).

At the time of cryopreservation, the CF contains a minimum of 8.0 × 108 total viable cells with a minimum of 8.7% CD34+ cells and a minimum of 9.2 × 107 CD34+ cells suspended in 20 mL of a cryopreservation solution containing 10% DMSO.

See the CoA for the CF for actual cell counts. CoAs are attached to the RFI Certificate available via the Gamida Cell Assist Hospital Portal.

Upon cryopreservation, the CF appears white and is frozen at the bottom of the cryopreserved bag. The cassette may not be opened until the time of thaw for the specific fraction.

At the time of cryopreservation, the NF contains a minimum of 4.0 × 108 total viable cells with a minimum of 2.4 × 107 CD3+ cells suspended in 10 mL cryopreservation solution containing 10% DMSO.

See the CoA for the NF for actual cell counts.

Upon cryopreservation, the NF appears red and is frozen at the bottom of the cryopreserved bag. The cassette may not be opened until the time of thaw for the specific fraction.

• Do NOT open the metal cassettes until the time of thaw.
• Match the identity of the patient with the patient-specific identifiers on the cassettes and cryopreserved bag labels (visible through the cassette window) upon receipt.
• Store OMISIRGE frozen in the vapor phase of liquid nitrogen (≤ -150°C) in a temperature-controlled system.
• Thaw immediately prior to use [see Dosage and Administration (2.2)]
• Use closed containers when transporting the bags within the facility.

The Refrigerated Infusion Solutions

The Infusion Solutions (IS) used to dilute OMISIRGE CF and NF are provided in two IS bags labeled for the specific patient and for diluting the specific fraction. The IS for diluting the CF contains approximately 80 mL and the IS for diluting the NF contains approximately 40 mL of IS consisting of 6.8% Dextran 40 and 8% HSA. The Infusion Solutions are shipped in a refrigerated shipping container with the PI.

• Match the identity of the patient with the patient-specific identifiers on the IS bag labels upon receipt.
• Store the IS bags in a 2-8℃ refrigerated storage until the time of thaw of the OMISIRGE CF and NF.

Graft-versus-Host-Disease:

Report immediately any signs and symptoms suggestive of graft vs host disease, including rash, diarrhea or yellowing of the eyes [see Warnings and Precautions (5.1), Adverse Reactions (6.1)].

Hypersensitivity and Infusion-Related Reactions:

Report immediately any signs and symptoms of hypersensitivity reactions including wheezing, swelling, itching, or hives [See Warnings and Precautions (5.2)].

Report immediately any signs and symptoms of infusion reactions including fever, chills, fatigue, tachycardia, hypoxia, severe nausea, severe vomiting, diarrhea, muscle pain, joint pain, low blood pressure, high blood pressure, or dizziness/lightheadedness [see Warnings and Precautions (5.2), Adverse Reactions (6.1)].

Autoimmune Cytopenias

Report immediately any signs and symptoms of Autoimmune Cytopenias including pallor and fatigue, tachycardia (from anemia) and mild to moderate splenomegaly, petechiae, easy bruising or prolonged bleeding from cuts, and recurrent bacterial infections, persistent oral ulcers and gingivitis and frequent fevers [See Warnings and Precautions (5.3)].

Graft Failure:

Advise patients that primary graft failure, which may be fatal, can occur [See Warnings and Precautions (5.4), Adverse Reactions (6.1)].

Malignancies of Donor Origin:

Advise patients of the need to contact Gamida Cell at (844)-477-7478 if they are diagnosed with a secondary malignancy after treatment with OMISIRGE [See Warnings and Precautions (5.5), Adverse Reactions (6.1)].

Engraftment Syndrome:

Report immediately any signs and symptoms suggestive of engraftment syndrome including fever, rash, or unexplained weight gain [See Warnings and Precautions (5.6)].

Transmission of Serious Infections:

Advise patients of the risk of transmission of infectious disease [See Warnings and Precautions (5.7)].

Transmission of Rare Genetic Diseases:

Advise patients of the risk of transmission of rare genetic diseases [See Warnings and Precautions (5.8)].