Allogenic Thymocyte-Depleted Thymus Tissue

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 consists of yellow to brown slices of processed thymus tissue with varying thickness and shape. Each drug product dish contains up to 4 RETHYMIC slices that adhere to circular filter membranes on top of surgical sponges in 5 mL of medium. The RETHYMIC slices are variable in size and shape; a RETHYMIC slice is defined as the contents of a single filter membrane. The dosage is based on the total surface area of the RETHYMIC slices, and the amount administered is calculated based on recipient BSA. The surgeon should implant as many RETHYMIC slices as possible within the recommended dose range of 5,000 to 22,000 mm 2 of RETHYMIC/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 RETHYMIC slices will be provided for each patient. At the time of surgery, the manufacturing personnel will inform the surgical team of the portion of the product that represents the minimum dose. RETHYMIC consists of yellow to brown slices of processed tissue with varying thickness and shape. The dosage is determined by the surface area of the RETHYMIC slices and recipient BSA. ( 3 )

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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-related adverse reactions. These events included: thrombocytopenia (including idiopathic thrombocytopenic purpura) in 13 patients (12%), neutropenia in 9 patients (9%), proteinuria in 7 patients (7%), hemolytic anemia in 7 patients (7%), alopecia in 4 patients (4%), hypothyroidism in 2 patients (2%), autoimmune hepatitis in 2 patients (2%), and autoimmune arthritis (juvenile idiopathic and psoriatic arthritis) in 2 patients (2%). One patient (1%) each experienced transverse myelitis, albinism, hyperthyroidism, and ovarian failure. The onset of autoimmune related events ranged from the three days before the surgical implantation procedure until 16 years post-treatment. Most events occurred within the first year after treatment. Monitor complete blood counts with differential weekly for the first 2 months post-treatment and then monthly through 12 months post-treatment. Liver enzymes including aspartate aminotransferase and alanine aminotransferase, serum creatinine levels, and urinalysis should be performed monthly for 3 months and then every 3 months through 12 months post-treatment. Thyroid function studies should be performed prior to treatment and then at 6 months and 12 months post-treatment. After 12 months, testing should be performed annually.

5.4 Renal Impairment Ten patients with renal impairment (elevated serum creatinine at baseline) were treated in studies with RETHYMIC. Five of these patients died within 1 year and a sixth patient died 3 years after treatment with RETHYMIC. Renal impairment at baseline is considered a risk factor for death.

5.5 Cytomegalovirus Infection In clinical studies with RETHYMIC, 4 out of 4 patients with preexisting CMV infection prior to treatment with RETHYMIC died. The benefits/risks of treatment should be considered prior to treating patients with pre-existing CMV infection.

5.6 Malignancy Because of the underlying immune deficiency, patients who receive RETHYMIC may be at risk of developing post-treatment lymphoproliferative disorder (blood cancer). The infant tissue donor is screened for Epstein-Barr virus (EBV) and cytomegalovirus (CMV), but patients should be tested for EBV and CMV using PCR prior to and 3 months following treatment with RETHYMIC, or after any exposure to or suspected infection with CMV or EBV.

5.7 Transmission of Serious Infections and Transmissible Infectious Diseases Transmission of infectious disease may occur because RETHYMIC is derived from human tissue. 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), Treponema pallidum, Trypanosoma cruzi , West Nile virus (WNV), transmissible spongiform encephalopathy (TSE) agents, vaccinia. Donors are also screened for clinical evidence of sepsis, and communicable disease risks associated with xenotransplantation. Blood samples (from the infant tissue donor or the birth mother, as applicable) are tested for HIV types 1, 2, and O, HTLV types I and II, HBV, HCV, T. pallidum , WNV, and T. cruzi . Blood from the infant tissue donor is also tested for Toxoplasma gondii , Epstein-Barr virus (EBV) and CMV. RETHYMIC is tested for sterility, endotoxin, and mycoplasma. These measures do not eliminate the risk of transmitting these or other infectious diseases and disease agents. Testing of maternal and infant donor blood is also performed for evidence of donor infection due to cytomegalovirus (CMV). Product manufacturing includes porcine- and 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. […]

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.

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.

8.2 Lactation Risk Summary There is no information regarding the presence of cellular components of RETHYMIC in human milk, the effect breastfeeding may have on RETHYMIC, the effect of being breastfed from a mother who received RETHYMIC as a child, or the effects of RETHYMIC on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for RETHYMIC and potential adverse effects on the breastfed infant from RETHYMIC.

8.3 Females and Males of Reproductive Potential No nonclinical or clinical studies were performed to evaluate the effects of RETHYMIC on fertility.

8.4 Pediatric Use The efficacy and safety of RETHYMIC have been established in pediatric patients with congenital athymia. The efficacy of RETHYMIC has been established in 95 pediatric patients (median age 9 months [range: 33 days to 3 years], including 65 patients age <1 year, 24 patients age 1 to <2 years, and 6 patients age 2 to <3 years at time of treatment) who were treated with RETHYMIC and included in the analysis of efficacy [ see Clinical Studies (14) ]. The safety of RETHYMIC has been established in 105 pediatric patients (median age 9 months [range: 33 days to 16.9 years] at time of treatment) with congenital athymia who were evaluated for safety following RETHYMIC administration. The safety population included 65 patients age <1 year, 27 patients age 1 to <2 years, 9 patients age 2 to <3 years, 1 patient age 3 to <6 years, and 3 patients age 13 to 17 years at time of treatment. Within the safety population, survival was similar across age groups. Adverse reactions were reported at similar frequencies across the age groups and were generally of similar types and severities.

8.6 Renal Impairment In the clinical studies with RETHYMIC, 10 of 105 patients had impaired renal function at baseline based on elevated screening creatinine [see Warnings and Precautions (5.4) ] . Baseline renal function should be considered when selecting immunosuppressants. Ensure appropriate involvement of a nephrologist in care of patients with renal impairment.

RETHYMIC is intended to reconstitute immunity in patients who are athymic. The proposed mechanism of action involves the migration of recipient T cell progenitors from the bone marrow to the implanted RETHYMIC slices, where they develop into naïve immunocompetent recipient T cells. Evidence of thymic function can be observed with the development of naïve T cells in the peripheral blood; this is unlikely to be observed prior to 6-12 months after treatment with RETHYMIC.