RETHYMIC

RETHYMIC consists of yellow to brown slices of allogeneic processed thymus tissue for administration by surgical implantation. Three to 11 drug product containers, with a total of 10 to 42 RETHYMIC slices, are provided for each patient. Each drug product container provides up to 4 RETHYMIC slices of variable size. The total dose, based on the number of slices administered to the patient, is 5,000 to 22,000 mm 2 of RETHYMIC/m 2 recipient BSA. Thymus tissue is obtained from donors less than or equal to 9 months of age undergoing cardiac surgery. This thymus tissue is aseptically processed and cultured for 12 to 21 days to produce RETHYMIC slices. Each product lot is manufactured from a single unrelated donor and one product lot treats a single patient. The manufacturing process preserves the thymic epithelial cells and tissue structure and depletes most of the donor thymocytes from the tissue. These RETHYMIC slices are then surgically implanted into patients with congenital athymia. The product manufacture uses reagents derived from animal materials. The surgical sponge used during culturing is porcine-derived. Fetal bovine serum is a component in the culture medium used to culture the thymus slices and RETHYMIC is formulated in media that is supplemented with fetal bovine serum. Therefore, bovine- and porcine-derived proteins will be present in RETHYMIC. These animal-derived reagents are tested for animal viruses, retroviruses, bacteria, fungi, yeast, and mycoplasma before use.

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).

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 repeated to transfer all RETHYMIC slices from the first drug product dish into a sterile operating room culture dish. After the first set of RETHYMIC slices has been prepared for surgical implantation and provided to the surgeon, another drug product dish with RETHYMIC slices is passed to the surgical staff member for removal from their filter membranes as described above. Using 2 pairs of sterile forceps, the surgical staff team member should use one pair of forceps to hold the filter in place while using the other forceps to scrape and loosen the RETHYMIC slice from the filter membrane (Figure 1). Then, while using one pair of forceps to hold the filter in place, the surgical staff team member uses the other forceps to lift the RETHYMIC slice away from the filter membrane by pulling the tissue up. The surgical staff team member places each RETHYMIC slice separately into the saline-containing operating room culture dish in the sterile field on top of its original filter membrane. The RETHYMIC slice will change from a flatter slice to a condensed, lumpy shape at this stage of the procedure. The surgeon then implants the first set of RETHYMIC slices. The surgical team staff member should process the next set of up to 4 RETHYMIC slices from the next drug product dish into a second operating room culture dish in the same manner while the surgeon continues implanting the first set of up to 4 slices. When the surgeon finishes implanting the first set of RETHYMIC slices, the surgical staff team member transfers and prepares the next operating room culture dish on the surgical field. Continue this cycle until all the desired tissue is transferred during the implantation procedure. Figure 1: Preparing for the Implantation Procedure Figure 1: Within the sterile field, forceps are used to move individual RETHYMIC slices with their filter membranes from the drug product dish to the operating room culture dish (left images). A pair of forceps is used to gently scrape and lift the RETHYMIC slice off the filter membrane in the operating room culture dish in preparation for easy removal prior to implantation (right images). Figure 1 Implantation of RETHYMIC: After induction of general anesthesia, a cranial-caudal skin incision (typically ~5 cm in length; Figure 2) should be made over the anterior thigh compartment. The size of the incision and the use of one or both legs for the implantation procedure is determined by the size of the patient, his/her muscle mass, and the amount of tissue to be implanted. If all or nearly all of the tissue can be implanted in one leg, then only one leg should be used. Figure 2: Surgical Incision and Opening of Fascia Open fascia to expose the anterior compartment muscles (Figure 2). Create a pocket in between the muscle fibers using a tonsil clamp or similar instrument. Each pocket should be made along the natural furrows throughout the quadriceps muscle group. Individual RETHYMIC slices should be implanted approximately 1 cm in depth and approximately 1 cm apart into the pockets between the muscle fibers in the quadriceps muscle (Figure 3). Figure 3: Implant Individual RETHYMIC Slices A large or thick RETHYMIC slice may be cut in half, at the surgeon's discretion, to ensure the slice is surrounded by muscle tissue once implanted. Implant as many RETHYMIC slices as possible within the recommended dose range of 5,000 to 22,000 mm 2 of processed thymus tissue/m 2 recipient BSA. During the procedure, the surgeon uses their judgment to balance the benefit of implanting additional RETHYMIC slices against the risk(s) that may be associated with implantation into limited muscle mass, number of implantations sites and other patient considerations. Once each RETHYMIC slice has been implanted, it should be fully covered by muscle tissue. Then a single absorbable suture should be used to close the pocket where the RETHYMIC slice was implanted (Figure 4). Figure 4: Close the Site of Implantation Once the intended dose has been implanted, confirm hemostasis. Close the skin incision with 2 layers of absorbable sutures and apply a standard dressing, such as wound closure strips or skin glue. Leave the fascia open to allow room for muscle compartment swelling. An occlusive dressing may be used to prevent contamination. Figure 2 Figure 3 Figure 4

None. None.

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 the other patient died three years after receiving RETHYMIC. Patients with Prior hematopoietic cell transplant Six patients with a prior hematopoietic cell transplant (HCT) were treated in the RETHYMIC clinical program. Two patients died within the first 2 years after receiving RETHYMIC.

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

Storage and Handling Use RETHYMIC prior to the time and date of expiration printed on the polycarbonate container. Store RETHYMIC at room temperature in the polycarbonate container in the insulated shipping box until ready for use. Do not refrigerate, freeze, agitate, or sterilize RETHYMIC. In the operating room, manufacturing personnel inspect the drug product containers as they are removed from the shipping box. 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. Match the patient's identity with the patient identifiers on the patient label on the polycarbonate container. Do not remove the drug product containers from the polycarbonate container if the information on the patient label does not match the intended patient. Manufacturing personnel record which RETHYMIC slices are used during the surgery. If any RETHYMIC slices are not administered to the patient, manufacturing personnel return this tissue to the manufacturing facility and dispose of this tissue as biohazardous waste in accordance with local requirements. Manufacturing personnel calculate the total dose that was administered to the patient.