Donislecel

1 INDICATIONS AND USAGE LANTIDRA is an allogeneic pancreatic islet cellular therapy indicated for the treatment of adults with Type 1 diabetes who are unable to approach target HbA1c because of current repeated episodes of severe hypoglycemia despite intensive diabetes management and education. Use LANTIDRA in conjunction with concomitant immunosuppression. LANTIDRA is an allogeneic pancreatic islet cellular therapy indicated for the treatment of adults with Type 1 diabetes who are unable to approach target HbA1c because of current repeated episodes of severe hypoglycemia despite intensive diabetes management and education. Use in conjunction with concomitant immunosuppression. ( 1 ) Limitations of Use When considering the risks associated with the infusion procedure and long-term immunosuppression, there is no evidence to show a benefit of administration of LANTIDRA in patients whose diabetes is well-controlled with insulin therapy or patients with hypoglycemic unawareness who are able to prevent current repeated severe hypoglycemic events (neuroglycopenia requiring active intervention from a third party) using intensive diabetes management (including insulin, devices, and education). Repeated intraportal islet infusions are not recommended in patients who have experienced prior portal thrombosis, unless the thrombosis was limited to second- or third-order portal vein branches. There is no evidence to support the safe and effective use of LANTIDRA in patients with liver disease, renal failure, or who have received a renal transplant.

12.1 Mechanism of Action Pancreatic islets regulate blood glucose levels through secretion of multiple hormones in response to increases and decreases in blood glucose. Endocrine cells within pancreatic islets release insulin, glucagon, somatostatin, pancreatic peptide, and ghrelin. Insulin stimulates glucose uptake by peripheral tissues; glucagon mobilizes glucose from the liver into circulation; somatostatin inhibits both α- and β-cell secretions; pancreatic peptide inhibits pancreatic exocrine secretion; and ghrelin inhibits insulin secretion. The primary mechanism of action of LANTIDRA is believed to be secretion of insulin by infused (transplanted) β- cells.

2 DOSAGE AND ADMINISTRATION For infusion into the hepatic portal vein only. For infusion into the hepatic portal vein only. Do not irradiate. Do not use leukodepleting filters . Do not use if product time exceeds 48-hours post product release or if temperature is not maintained between 15 and 25° C To be prepared and administered only by medical professionals experienced in islet cell transplantation ( 2.2 ) ( 2.3 ) The recommended minimum dose is 5,000 equivalent islet number (EIN) per kg patient body weight for initial infusion (transplant) and 4,500 EIN/kg for subsequent infusions (same recipient). ( 2.1 ) Administer cells through the hepatic portal vein using a 5 or 6 French angiographic catheter indicated for infusion of LANTIDRA ( 2.3 ). The estimated tissue volume should not exceed 10 cc per transplant infusion. ( 2.1 ) 2.1 Recommended Dose The recommended minimum dose is 5,000 EIN/kg for initial infusion and 4,500 EIN/kg for subsequent infusion in the same recipient. The maximum dose per infusion is dictated by the estimated tissue volume, which should not exceed 10 cc per infusion, and the total EIN present in the infusion bag (up to a maximum of 1 × 10 6 EIN per bag). A second infusion may be performed if the patient does not achieve independence from exogenous insulin within one year of infusion or within one year after losing independence from exogenous insulin after a previous infusion. A third infusion may be performed using the same criteria as for the second infusion. There are no data regarding the effectiveness or safety for patients receiving more than three infusions. Pre-procedural medications Provide pre-procedural induction immunosuppression 30 – 360 minutes prior to LANTIDRA infusion. Include the following, at the discretion of the treating physician who is experienced with management of immunosuppression regimens for islet cell transplantation: Non-depleting monoclonal anti-interleukin-2 (anti-IL-2) receptor antibody 120 minutes prior to islet infusion Note: In patients who are sensitized (hypersensitivity with a past history of anaphylactic reaction) to non-depleting monoclonal anti-interleukin-2 (anti-IL-2) receptor antibody therapies, a polyclonal, T-cell-depleting antibody should be used instead. Calcineurin inhibitor Mammalian target of rapamycin (mTOR) inhibitor Tumor necrosis factor (TNF) blocker. Periprocedural antibiotic prophylaxis is recommended. 2.2 Preparation Keep LANTIDRA in the insulated container at 15°C to 25°C no longer than 48 hours from time of product release (See carton label and certificate of analysis). Dispose of any product not used within 48 hours. Do not irradiate. Select and prepare units under the direction of a medical professional who is experienced in islet infusion (transplantation). Use LANTIDRA as supplied and without further dilution. 2.3 Administration Failure to follow these directions may result in damage and decreased viability of the islets. Do not administer with leukodepleting filters. To optimize viability, administer LANTIDRA as soon as possible after product release. LANTIDRA should be administered only by interventional radiologists and surgeons with experience in islet cell transplantation under aseptic conditions in an interventional radiology or operating suite. Perform all steps aseptically. Use a 5 or 6 French angiographic catheter indicated for the delivery of drugs or other therapeutic fluids for infusion of LANTIDRA. Catheter length: 65 cm or less. Internal diameter: 0.97mm (0.038 inches) or greater. Use only sheaths and introducers in combination with a catheter with the specified dimensions listed above to deliver LANTIDRA. Pre-Infusion Patient Preparation 1. Confirm the identity of the patient for the specified unit of LANTIDRA. 2. Confirm that the patient has received appropriate premedication [See Pre-procedural medication (2.1) ] . 3. Confirm that appropriate medications and blood products are available to manage any potential emergencies,

6 ADVERSE REACTIONS Ninety percent (90%) of subjects had at least one serious adverse reaction. The major causes were attributed to: Infusion procedure liver laceration/hematoma, hemorrhage, and intra-abdominal bleeding (13%) elevation of portal pressure (7%) Immunosuppression Infection (87%) Malignancy (37%) Ninety percent (90%) of subjects had at least one serious adverse reaction. ( 6.1 ) The major causes are attributed to: Infusion procedure liver laceration/hematoma, hemorrhage, and intra-abdominal bleeding (13%) elevation of portal pressure (7%) Immunosuppression Infection (87%) Malignancy (37%) To report SUSPECTED ADVERSE REACTIONS, contact CellTrans at 1-800-500-1617 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 safety of LANTIDRA in subjects with type 1 diabetes and hypoglycemic unawareness was demonstrated in two clinical trials (Study 1, Study 2) involving a total of 30 subjects who received between one and three doses of LANTIDRA. Duration between first and second transplant was one month to 2.8 years and between second and third dose from 3 months to 7.8 years (See Figure 1 ). Because of the variable duration of follow-up, number of infusions, and interval between infusions, adverse reactions were reported for the total duration for which each subject was followed. [Clinical Studies (14)] Subjects were followed for 0.3 to 14.5 years (mean 3 ± 3.7 years) after the first infusion. Serious reactions were reported in 27 (90%) of subjects. There were two (7%) deaths; one death from multi-organ failure with sepsis (1.6 years after the first infusion), and one from progressive confusion, global atrophy and micro-ischemic disease (9.7 years after the first infusion). Both subjects were using immunosuppression at the time of the event. Additionally, 8 (27%) subjects experienced at least one life-threatening adverse reaction and 26 (87%) subjects experienced at least one severe reaction before their last follow-up. Immunosuppression-Related Adverse Reactions Risks of common community-acquired infections and opportunistic infections increases with immunosuppression. In total, 211 infections were reported for 26 subjects; one was life-threatening, 22 reactions severe, and 115 events moderate in severity. Additionally, one subject died of multi-organ failure from sepsis in the second year after infusion. Discontinuation of immunosuppression resulted in loss of islet cell function and if achieved insulin independence. This was described for 8 (27%) subjects. Malignancy risk is known to increase with immunosuppression. In total, 16 adverse reactions of malignancy were reported in 11 subjects; three malignancies were life-threatening. The malignancies included 12 skin cancers, and one post-transplant lymphoproliferative disease, one breast cancer, and one thyroid cancer. Anemia was reported in 24 (80%) of subjects. Of the 90 adverse reactions reported, one reaction was life-threatening (Hgb <6.5gm/dL), 9 reactions were severe (<8-6.5 gm/dL), and 27 reactions were moderate in severity (<10-8 gm/dL). Anemia was attributed to bleeding because of procedural complications as well as immunosuppression. Transfusion was required for severe and life-threatening reactions. Overall, five transfusions were administered to five subjects. Three transfusions were for procedural related complications and two were non-procedure related. Alterations in red blood cell turnover and transfusion can alter the accuracy of HbA1c measurements. Therefore, in addition to monitoring for the development of anemia as a result of immunosuppression or a result of a procedural complications, healthcare providers should consider the occurrence of anemia in the inter

5 WARNINGS AND PRECAUTIONS Risks from Concomitant Immunosuppression: Increased risk of severe infections including opportunistic infections, malignancy, and severe anemia. Monitor closely. Administer PCP and CMV prophylaxis. ( 5.1 ) Procedural Complications: Liver laceration and hemorrhage have occurred. Monitor for bleeding, portal hypertension, and portal vein thrombosis during and immediately following infusion. ( 5.2 ) Increased Risk of Graft Rejection : Patients with a positive T- and B-cell crossmatch between recipient serum and donor lymphocytes may be at increased risk for graft rejection. ( 5.3 ) Transmission of Donor-Derived Infections : Monitor for signs of infection following infusion and treat accordingly. ( 5.4 ) Panel Reactive Antibodies (PRA) : Product administration may elevate PRA and negatively impact candidacy for renal transplant. ( 5.5 ) 5.1 Risks from Concomitant Immunosuppression Concomitant use of immunosuppression is required to maintain islet cell viability. The use of immunosuppression in patients receiving LANTIDRA increases the risk of serious and potentially fatal adverse reactions. [Adverse Reactions (6.1)] Patients receiving immunosuppressants are at increased risk of: Bacterial, viral, fungal, and parasitic infections, including opportunistic infections. Lymphomas and other malignancies, particularly of the skin. Severe anemia, sometimes requiring transfusion. Before Treatment Vaccination: To mitigate the risk of infection, patients should receive recommended immunizations prior to treatment. After Treatment Administer PCP and CMV prophylaxis following administration of LANTIDRA. Avoid live vaccination while receiving immunosuppression. Monitor for fever and other signs of infection; initiate appropriate treatment early. Clinically monitor for malignancy, including skin cancer. Monitor hemoglobin/hematocrit and give blood products as indicated. Considerations for discontinuation of immunosuppression If a patient develops a life-threatening infection or cancer and treatment requires discontinuation of immunosuppression. If a patient has been dependent on exogenous insulin for two years after their last infusion, then immunosuppression should be discontinued. However, the treatment team may consider continuation of immunosuppression if they determine that the patient has achieved target HbA1c without recurrent severe hypoglycemia in the presence of clinically relevant C-peptide, that provides a potential ongoing benefit that outweighs the risks of severe and potentially life-threatening effects of immunosuppression. If a patient becomes pregnant. 5.2 Procedural Complications Liver laceration, hemorrhage and intra-abdominal bleeding have occurred with portal administration of LANTIDRA. Manage hemostasis in the catheter track using standard practices following infusion of LANTIDRA to reduce the risk of bleeding. Monitor for bleeding clinically and with laboratory assessments. Blood transfusions have been required. Elevation in portal blood pressure has occurred during and following intraportal islet infusion [Adverse Reactions (6.1)] . Monitor portal pressure; pause infusion if portal pressure rises above 22 mmHg and do not resume until it falls below 18 mmHg. Terminate infusion if portal pressure remains above 22 mmHg for longer than 10 minutes. [Dosage and Administration (2.3)] Portal vein branch thrombosis may occur following infusion of LANTIDRA. Repeated intraportal islet infusions are not recommended in patients who have experienced prior portal thrombosis unless the thrombosis was limited to second- or third-order portal vein branches. [Limitations of Use (2.1)] 5.3 Increased Risk of Islet Graft Rejection Patients with a positive T- and B-cell crossmatch between recipient serum and donor lymphocytes may immediately reject the islet cells. The T- and B-cell crossmatch assay is binary. T- and B-cell both need to be negative. 5.4 Transmission of Donor-Derived Infections There is a risk of comm

4 CONTRAINDICATIONS Do not administer LANTIDRA to patients who have concomitant diseases or conditions, including pregnancy, that contraindicate the procedure for LANTIDRA infusion or immunosuppression. LANTIDRA is contraindicated in patients for whom immunosuppression is contraindicated. ( 4 )