RETHYMIC

1 INDICATIONS AND USAGE RETHYMIC ® is indicated for immune reconstitution in pediatric patients with congenital athymia. RETHYMIC is indicated for immune reconstitution in pediatric patients with congenital athymia. ( 1 ) Limitations of Use : RETHYMIC is not indicated for the treatment of patients with severe combined immunodeficiency (SCID). Limitations of Use RETHYMIC is not indicated for the treatment of patients with severe combined immunodeficiency (SCID).

2 DOSAGE AND ADMINISTRATION RETHYMIC is administered by a surgical procedure. The recommended dose range is 5,000 to 22,000 mm 2 of RETHYMIC/m 2 recipient body surface area (BSA). (2) Immunosuppressive therapy is recommended for patients receiving RETHYMIC based on disease phenotype and PHA levels. ( 14 ) 2.1 Dosage RETHYMIC is administered by a surgical procedure. The dosage is determined by the total surface area of the RETHYMIC slices and recipient body surface area (BSA). A RETHYMIC slice is defined as the contents on a single filter membrane; the RETHYMIC slices are variable in size and shape. The recommended dose range is 5,000 to 22,000 mm 2 of RETHYMIC surface area/m 2 recipient BSA. The manufacturer calculates the dose in advance for the specific patient; the amount of product provided is adjusted at the manufacturing facility to ensure the maximum dose for the patient cannot be exceeded. Up to 42 cultured RETHYMIC slices will be provided for each patient. At the time of surgery, the manufacturing personnel communicate to the surgical team the portion of the product that represents the minimum dose. Patients with evidence of maternal engraftment or an elevated response to phytohemagglutinin (PHA) should receive RETHYMIC with immunosuppressive medications (Table 2). 2.2 Administration Instructions Surgical implantation of RETHYMIC should be done by a qualified surgical team in a single surgical session at a qualified hospital. RETHYMIC should be implanted in the quadriceps muscle in accordance with the instructions provided below. Implantation of RETHYMIC into the quadriceps requires a healthy bed of muscle tissue. Preparation for the Implantation Procedure: Operating room culture dishes (sterile 100 mm tissue culture dishes) and saline for injection are supplied by the operating room; a sufficient supply of operating room culture dishes and saline must be provided by the hospital for use in the implantation procedure. The product is delivered to the operating room by manufacturing personnel. The recommended dose is determined based on the patient's BSA. The manufacturer calculates the dose in advance for the specific patient. Manufacturing personnel and the operating room staff confirm that the lot delivered is for the intended recipient. Manufacturing personnel communicate to the surgical team the minimum number of RETHYMIC slices to be implanted to achieve the minimum dose. The product expiration date and time for the entire lot is labeled on each polystyrene dish (drug product dish). Always handle RETHYMIC slices aseptically. Do not use if there is evidence of contamination. Outside the sterile field, manufacturing personnel unpack RETHYMIC from the shipping box. One drug product dish at a time is removed from the drug product box and shipping box. Manufacturing personnel inspect the drug product box and each drug product dish for signs of contamination, damage, spills, or leakage. If damage to the drug product dishes, leaks, spillage or evidence of contamination is noted, manufacturing personnel will notify the surgical team that the lot cannot be implanted. When the surgical team is ready, manufacturing personnel and surgical staff begin the transfer of drug product to the sterile operative field. Manufacturing personnel carry one drug product dish, which contains up to 4 RETHYMIC slices on up to 2 surgical sponges, with each RETHYMIC slice on a filter membrane, to the surgical staff near the sterile field. Manufacturing personnel open the drug product dish to expose the RETHYMIC slices. The surgical staff team member uses a pair of forceps to remove individual RETHYMIC slices with their filter membranes from the drug product dish (Figure 1). The surgical team member places each RETHYMIC slice with its filter membrane into a sterile 100 mm tissue culture dish ("operating room culture dish") containing approximately 2 mL preservative-free saline that resides in the sterile field on the instrument table. This is re…

5 WARNINGS AND PRECAUTIONS Immune reconstitution sufficient to protect from infection is unlikely to develop prior to 6 to 12 months after treatment with RETHYMIC. Given the immunocompromised condition of athymic patients, infection control measures should be followed until the development of thymic function can be established. ( 5.1 ) Monitor and treat patients at risk for the development of graft versus host disease (GVHD). ( 5.2 ) Monitor for the development of autoimmune disorders, including complete blood counts with differential, liver enzymes, serum creatinine, urinalysis, and thyroid function. ( 5.3 ) Pre-existing renal impairment is a risk factor for death. ( 5.4 ) Pre-existing cytomegalovirus infection may result in death prior to the development of thymic function. ( 5.5 ) Monitor for the development of lymphoproliferative disorder (blood cancer). ( 5.6 ) Transmission of infectious diseases may occur because RETHYMIC is derived from human tissue. ( 5.7 ) Immunizations should not be administered in patients who have received RETHYMIC until immune-function criteria have been met. ( 5.8 ) Patients should be tested for anti-HLA antibodies prior to treatment. ( 5.9 ) 5.1 Infection Control and Immunoprophylaxis Immune reconstitution sufficient to protect from infection is unlikely to develop prior to 6-12 months after treatment with RETHYMIC. Given the immunocompromised condition of athymic patients, follow infection control measures until the development of thymic function is established as measured through flow cytometry. This should include counseling patients and their caregivers on good handwashing practices and minimizing exposure to visitors. Monitor patients closely for signs of infection, including fever. If a fever develops, assess the patient by blood and other cultures and treat with antimicrobials as clinically indicated. Patients should be maintained on immunoglobulin replacement therapy until all of the following criteria are met: No longer on immunosuppression (at least 10% of CD3 + T cells are naïve in phenotype). At least 9 months post-treatment. Phytohemagglutinin (PHA) response within normal limits. Normal serum IgA is also desirable but not required. Two months after stopping immunoglobulin replacement therapy, the IgG trough level should be checked. If the IgG trough level is in the normal range for age, the patient can remain off of immunoglobulin replacement. If the IgG trough level is lower than the normal range for age, immunoglobulin replacement therapy should be restarted and continued for a year before being retested using the above guidelines. Prior to and after treatment with RETHYMIC, patients should be maintained on Pneumocystis jiroveci pneumonia prophylaxis until all of the following criteria are met: No longer on immunosuppression (at least 10% of CD3+ T cells are naïve in phenotype). At least 9 months post-treatment. PHA response within normal limits. CD4+ T cell count > 200 cells/mm 3 . 5.2 Graft versus Host Disease In clinical studies with RETHYMIC, GVHD occurred in 11 (10%) RETHYMIC-treated patients of whom 6 (55%) died. RETHYMIC may cause or exacerbate pre-existing GVHD. Seven patients (7%) experienced autologous GVHD, 3 patients (3%) experienced GVHD due to maternal cells and 1 patient (1%) experienced GVHD due to cells from a prior hematopoietic cell transplant (HCT). Risk factors for GVHD include atypical complete DiGeorge anomaly phenotype, prior HCT and maternal engraftment. GVHD may manifest as fever, rash, lymphadenopathy, elevated bilirubin and liver enzymes, enteritis, and/or diarrhea. Patients with elevated baseline T cell proliferative response to PHA > 5,000 cpm or > 20-fold over background should receive immunosuppressive therapies to decrease the risk of GVHD (Table 2 and Table 3). Development of GVHD symptoms should be closely monitored and promptly treated. 5.3 Autoimmune Disorders Thirty-seven patients (35%) in the RETHYMIC clinical program experienced autoimmune-r…

4 CONTRAINDICATIONS None. None.

7 DRUG INTERACTIONS No drug interaction studies have been conducted with RETHYMIC. If possible, prolonged use of immunosuppressive therapies, including high-dose corticosteroids, should be avoided.

8.1 Pregnancy Risk Summary There are no clinical data with RETHYMIC in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with RETHYMIC. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

6 ADVERSE REACTIONS The most common adverse reactions (incidence in at least 10% of patients) reported following administration of RETHYMIC were hypertension (high blood pressure), cytokine release syndrome, rash, hypomagnesemia (low magnesium), renal impairment / failure (decrease of kidney function), thrombocytopenia (low platelets), and graft versus host disease. The most common (>10%) adverse events related to RETHYMIC included: hypertension (high blood pressure, 19%), cytokine release syndrome (18%), rash (15%), hypomagnesemia (low magnesium, 16%), renal impairment / failure (decrease of kidney function, 12%), thrombocytopenia (low platelets, 12%), and graft versus host disease, (10%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sumitomo Pharma America at 833-369-9868 or FDA at 1-800-FDA-1088 or https://www.fda.gov/safety/medwatch-fda-safety-information-and-adverse-event-reporting-program. 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 data described in this section are derived from 10 prospective, single-center, open-label studies, and include 105 patients who were treated with RETHYMIC in these studies and who had at least one year of follow-up. Table 1 lists the adverse reactions occurring in 105 patients who were treated with RETHYMIC in these studies. Table 1: Adverse Reactions Occurring in at least 5% of Patients Treated with RETHYMIC During Clinical Studies System Organ Class Preferred Term RETHYMIC (N=105) n (%) Number of Patients with Adverse Reactions Reactions which occurred in the 2 years after treatment. 80 (76) Hypertension (high blood pressure) 20 (19) Cytokine release syndrome All events (19/19) of cytokine release syndrome occurred in association with ATG-R treatment. 19 (18) Hypomagnesemia (low magnesium) 17 (16) Rash Rash includes rash, granuloma skin, rash papular, urticaria. 16 (15) Renal impairment / failure Renal impairment / failure includes renal failure and acute kidney injury, proteinuria and blood creatinine increased. (decrease of kidney function) 13 (12) Thrombocytopenia Thrombocytopenia includes thrombocytopenia and Immune thrombocytopenic purpura. (low platelets) 13 (12) Graft versus host disease GVHD includes GVHD, GVHD-gut, GVHD-skin, Omenn syndrome. 11 (10) Hemolytic anemia Hemolytic anemia includes autoimmune hemolytic anemia, Coombs-positive hemolytic anemia, hemolysis, hemolytic anemia. (low red bloods cells) 9 (9) Neutropenia (low white blood cells) 9 (9) Respiratory distress Respiratory distress includes respiratory distress, hypoxia, respiratory failure. (difficulty breathing) 8 (8) Proteinuria (protein in urine) 7 (7) Pyrexia (fever) 6 (6) Acidosis Acidosis includes acidosis, renal tubular acidosis and blood bicarbonate decreased. 6 (6) Diarrhea Diarrhea includes diarrhea and hemorrhagic diarrhea. 5 (5) Seizure Seizures include infantile spasms, seizures and febrile convulsion. 5 (5) Of the 105 patients, 29 patients died after receiving RETHYMIC, including 23 deaths in the first year (<365 days) after treatment with RETHYMIC. Causes of death in the first year included 13 deaths due to infection or complications due to infection, 5 deaths due to respiratory failure / hypoxia, 3 deaths due to hemorrhage-related events, and 2 deaths due to cardiorespiratory arrest. Of the 6 patients who died more than 1 year after treatment with RETHYMIC, the deaths were considered unrelated to study treatment: 2 died due to respiratory failure and 1 died due to each of the following: cardiopulmonary arrest, intracranial hemorrhage, infection, and unknown cause. Severe combined immunodeficiency (SCID) Patients Two patients with SCID were treated in the RETHYMIC clinical program. One patient died two years after receiving RETHYMIC, and …