These Highlights Do Not Include All The Information Needed To Use Rethymic Safely And Effectively. See Full Prescribing Information For Rethymic.

Limitations of Use

• RETHYMIC is not indicated for the treatment of patients with severe combined immunodeficiency (SCID).

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.

PRINCIPAL DISPLAY PANEL - 22,000 mm Container Label

NDC 72359–001–02

allogeneic processed thymus tissue–agdc

RETHYMIC

Dosage for entire lot is 5000 – 22,000 mm^2

RETHYMIC /m^2 recipient body surface area.

Handle aseptically. Do not agitate or sterilize.

Formulated in media that is supplemented with fetal

bovine serum. Preservative Free. Store at room

temperature. Do not freeze or refrigerate.

Lot # GMP–423

Container 1 of 11

Expiration: 13JUN2023

Contains up to 4 slices of RETHYMIC

adhered to filter membranes on top of

surgical sponges in 5 mL of media.

For intended recipient only. Rx Only.

For administration by surgical implantation.

See package insert for full prescribing

information and instructions for administration.

Manufactured for Sumitomo Pharma America, Inc.

Marlborough, MA 01752

Telephone: 1–833–369–9868

Lic. #: 2368

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 mm² of RETHYMIC surface area/m² 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).

The maximum recommended dose is 22,000 mm² of RETHYMIC/m² recipient body surface area (BSA). Standard clinical care is recommended for patients receiving a dose > 22,000 mm² of RETHYMIC/m² recipient BSA. The product, as provided, has been adjusted at the manufacturing facility to not exceed the maximum dose based on the patient body surface area.

During clinical development one patient received a dose higher (23,755 mm²/m²) than the maximum recommended dose. This patient developed enteritis. A biopsy showed T cell, B cell, and neutrophil infiltration of the gut which resolved after treatment with immunosuppression, 5 months after treatment with RETHYMIC. The enteritis may have been related to the high dose of 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 mm² of RETHYMIC/m² 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.

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.

HLA matching is required in patients who have received a prior hematopoietic cell transplantation (HCT) or a solid organ transplant. Patients who have received a prior HCT are at increased risk of developing GVHD after RETHYMIC if the HCT donor did not fully match the recipient. To minimize this risk, HLA matching of RETHYMIC to recipient alleles that were not expressed in the HCT donor is recommended.

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.

The efficacy of RETHYMIC was evaluated in 10 prospective, single-center, open-label studies that enrolled a total of 105 patients, including 95 patients in the primary efficacy analysis. The demographics and baseline characteristics of the patients enrolled in the clinical studies were similar across studies. Across the efficacy population, 59% were male; 70% were White, 22% were Black, 4% were Asian/Pacific Islander; 2% were American Indian/Alaskan Native; and 2% were multi-race. The median (range) age at the time of treatment was 9 months (1-36). The diagnosis of congenital athymia was based on flow cytometry documenting fewer than 50 naïve T cells/mm³ (CD45RA⁺, CD62L⁺) in the peripheral blood or less than 5% of total T cells being naïve in phenotype in 91/95 patients (range 0-98 naïve T cells/mm³). In addition to congenital athymia, patients also had complete DiGeorge syndrome (cDGS; also referred to as complete DiGeorge anomaly (cDGA)) if they also met at least one of the following criteria: congenital heart defect, hypoparathyroidism (or hypocalcemia requiring calcium replacement), 22q11 hemizygosity, 10p13 hemizygosity, CHARGE (coloboma, heart defect, choanal atresia, growth and development retardation, genital hypoplasia, ear defects including deafness) syndrome, or CHD7 mutation. Across the efficacy population, 93 patients (98%) were diagnosed with cDGS, and the most common DiGeorge gene mutations or syndromic associations were Chromosome 22q11.2 deletion (36 patients; 38%) and CHARGE syndrome (23 patients; 24%). There were 35 patients with missing or no identified genetic mutations. Two (2%) patients had FOXN1 deficiency, and 1 patient (1%) had a TBX variant. There were 50 (53%) patients with typical cDGS; these patients had congenital athymia with the absence of a T cell-related rash. There were 42 (44%) patients diagnosed with atypical cDGS; these patients may have had a rash, lymphadenopathy, or oligoclonal T cells. Patients who did not have congenital athymia (e.g. SCID) and patients with prior transplants, including thymus and HCT, were excluded from the efficacy analysis population. The baseline demographics and disease characteristics were similar in the safety population.

Patients with heart surgery anticipated within 4 weeks prior to, or 3 months after, the planned RETHYMIC treatment date, patients with human immunodeficiency virus (HIV) infection, and patients who were not considered good surgical candidates were excluded from study participation.

Patients in the efficacy population received RETHYMIC in a single surgical procedure at a dose of 4,900 to 24,000 mm² of RETHYMIC / recipient BSA in m². Patients were assigned to receive immunosuppressive therapy prior to and/or after treatment according to their disease phenotype and pre-RETHYMIC PHA response. Table 2 summarizes the criteria used to administer immunosuppression. Table 3 summarizes the specific immunosuppressant dosing used in RETHYMIC clinical studies. No patients were retreated with RETHYMIC.

The Kaplan-Meier estimated survival rates were 77% (95% CI [0.670, 0.841]) at 1 year and 76% (95% CI [0.658, 0.832]) at 2 years. For patients who were alive at 1 year after treatment with RETHYMIC, the survival rate was 94% at a median follow-up of 10.7 years.

Without treatment, congenital athymia is fatal in childhood. In a natural history population observed from 1991 through 2017, 49 patients diagnosed with congenital athymia received supportive care only. The 2-year survival rate was 6%, with all patients dying by 3 years of age. This population included 33 (67%) males. The most common cause of death was infection in 26 (53%) patients. Other common causes (≥10%) included support withdrawn in 7 (14%) patients, respiratory arrest in 5 (10%) patients, and cardiac arrest in 5 (10%) patients.

The Kaplan-Meier estimated survival rates for the RETHYMIC clinical trial population and the natural history population are shown in Figure 5. Four patients with >50 naïve T cells/mm³ (CD45RA⁺, CD62L⁺) at time of RETHYMIC administration have been treated; 2 (50%) were alive with follow-up less than 2 years.

Figure 5: Kaplan-Meier Survival by Year (RETHYMIC Efficacy Analysis Population and Natural History Population)

RETHYMIC significantly reduced the number of infections over time. In the first year after treatment with RETHYMIC, the number of patients with an infection event onset 6 to ≤ 12 months after treatment decreased by 38% (from 63 to 39) relative to the number of patients with an infection event onset in the first 6 months post-treatment. A two-year analysis showed a decrease in both the number of patients with an infection event and the mean number of infection events per patient, with an onset in the first 12 months post-treatment as compared to 12 to ≤ 24 months after treatment. There was a mean difference of 2.9 events (p<0.001) per patient.

Naïve CD4⁺ and CD8⁺ T cells reconstituted over the first year, with a durable increase through Year 2. Median (minimum, maximum) naïve CD4⁺ T cells/mm³ increased from a baseline of 1 (0, 38) to values of 42 (0, 653), 212 (1, 751), and 275 (33, 858) at 6, 12, and 24 months after treatment with RETHYMIC, respectively. Median naïve CD8⁺ T cells/mm³ increased from a baseline of 0 (0, 46) to values of 9 (0, 163), 58 (0, 304), and 86 (6, 275) at 6, 12, and 24 months after treatment with RETHYMIC, respectively. This was accompanied by functional improvements based on T cell proliferative responses to PHA.

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.

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

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.

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.

The pharmacodynamic effects of RETHYMIC are not known.

The pharmacokinetic effects of RETHYMIC are not known.

RETHYMIC^® is indicated for immune reconstitution in pediatric patients with congenital athymia.

All patients should be screened for anti-HLA antibodies prior to receiving RETHYMIC. Patients testing positive for anti-HLA antibodies should receive RETHYMIC from a donor who does not express those HLA alleles.

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.

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.

• 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)

Immunizations should not be administered in patients who have received RETHYMIC until immune-function criteria have been met.

RETHYMIC is administered by a surgical procedure. The recommended dose range is 5,000 to 22,000 mm² of RETHYMIC/m² recipient body surface area (BSA). (2) Immunosuppressive therapy is recommended for patients receiving RETHYMIC based on disease phenotype and PHA levels. (14)

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 mm² of RETHYMIC/m² 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.

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.

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.

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.

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.

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.

Advise patients and/or their caregivers that:

• Immune reconstitution sufficient to protect from infection usually develops between 6-12 months after treatment with RETHYMIC, but for some patients elevated naïve T cell numbers are not observed until 2 years after treatment. Strict infection control measures should be observed until the healthcare provider confirms that immune function has been reconstituted through the evaluation of blood using flow cytometry and the criteria for the discontinuation of immunoglobulin replacement therapy and Pneumocystis jiroveci pneumonia prophylaxis have been met. Patients and caregivers should follow good handwashing practices, minimize contact with others, and immediately report signs and symptoms of infection to their healthcare provider [see Warnings and Precautions (5.1)].
• Congenital athymia alters the immune response to vaccines. Instruct patients and/or their caregivers to notify their healthcare professional to evaluate the immune status of RETHYMIC recipients prior to receiving vaccinations [see Warnings and Precautions (5.8)].
• Immunosuppression should be administered in patients with elevated T cell response, maternal engraftment, or oligoclonal T cell expansion and autoreactive T cells manifested by rash, lymphadenopathy and/or diarrhea. Inform patients and/or their caregivers on risks associated with short-term and long-term use of immunosuppression and refer them to review the risks of the specific immunosuppressants prescribed with their physician.
• Congenital athymia is associated with a wide spectrum of genetic anomalies. Instruct patients and/or their caregiver to consult with a clinical geneticist prior to receiving RETHYMIC.

Advise patients and/or their caregivers of the following risks:

• Graft versus Host Disease [see Warnings and Precautions (5.2)]
• Autoimmune Disorders (patient's immune (defense) system mistakenly attacks patient's body) [see Warnings and Precautions (5.3)]
• Renal Impairment (decrease of kidney function) [see Warnings and Precautions (5.4)]
• Cytomegalovirus Infection [see Warnings and Precautions (5.5)]
• Malignancy (Cancer) [see Warnings and Precautions (5.6)]
• Transmission of Serious Infections and Transmissible Infectious Diseases [see Warnings and Precautions (5.7)]

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/mm³.

No nonclinical or clinical studies were performed to evaluate the effects of RETHYMIC on fertility.

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.

Final sterility and mycoplasma test results are not available at the time of use, but manufacturing personnel will communicate any positive results from sterility testing to the physician. Report the occurrence of transmitted infection to Sumitomo Pharma America at 833-369-9868.

Limitations of Use

• RETHYMIC is not indicated for the treatment of patients with severe combined immunodeficiency (SCID).

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.

PRINCIPAL DISPLAY PANEL - 22,000 mm Container Label

NDC 72359–001–02

allogeneic processed thymus tissue–agdc

RETHYMIC

Dosage for entire lot is 5000 – 22,000 mm^2

RETHYMIC /m^2 recipient body surface area.

Handle aseptically. Do not agitate or sterilize.

Formulated in media that is supplemented with fetal

bovine serum. Preservative Free. Store at room

temperature. Do not freeze or refrigerate.

Lot # GMP–423

Container 1 of 11

Expiration: 13JUN2023

Contains up to 4 slices of RETHYMIC

adhered to filter membranes on top of

surgical sponges in 5 mL of media.

For intended recipient only. Rx Only.

For administration by surgical implantation.

See package insert for full prescribing

information and instructions for administration.

Manufactured for Sumitomo Pharma America, Inc.

Marlborough, MA 01752

Telephone: 1–833–369–9868

Lic. #: 2368

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 mm² of RETHYMIC surface area/m² 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).

The maximum recommended dose is 22,000 mm² of RETHYMIC/m² recipient body surface area (BSA). Standard clinical care is recommended for patients receiving a dose > 22,000 mm² of RETHYMIC/m² recipient BSA. The product, as provided, has been adjusted at the manufacturing facility to not exceed the maximum dose based on the patient body surface area.

During clinical development one patient received a dose higher (23,755 mm²/m²) than the maximum recommended dose. This patient developed enteritis. A biopsy showed T cell, B cell, and neutrophil infiltration of the gut which resolved after treatment with immunosuppression, 5 months after treatment with RETHYMIC. The enteritis may have been related to the high dose of 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 mm² of RETHYMIC/m² 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.

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.

HLA matching is required in patients who have received a prior hematopoietic cell transplantation (HCT) or a solid organ transplant. Patients who have received a prior HCT are at increased risk of developing GVHD after RETHYMIC if the HCT donor did not fully match the recipient. To minimize this risk, HLA matching of RETHYMIC to recipient alleles that were not expressed in the HCT donor is recommended.

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.

The efficacy of RETHYMIC was evaluated in 10 prospective, single-center, open-label studies that enrolled a total of 105 patients, including 95 patients in the primary efficacy analysis. The demographics and baseline characteristics of the patients enrolled in the clinical studies were similar across studies. Across the efficacy population, 59% were male; 70% were White, 22% were Black, 4% were Asian/Pacific Islander; 2% were American Indian/Alaskan Native; and 2% were multi-race. The median (range) age at the time of treatment was 9 months (1-36). The diagnosis of congenital athymia was based on flow cytometry documenting fewer than 50 naïve T cells/mm³ (CD45RA⁺, CD62L⁺) in the peripheral blood or less than 5% of total T cells being naïve in phenotype in 91/95 patients (range 0-98 naïve T cells/mm³). In addition to congenital athymia, patients also had complete DiGeorge syndrome (cDGS; also referred to as complete DiGeorge anomaly (cDGA)) if they also met at least one of the following criteria: congenital heart defect, hypoparathyroidism (or hypocalcemia requiring calcium replacement), 22q11 hemizygosity, 10p13 hemizygosity, CHARGE (coloboma, heart defect, choanal atresia, growth and development retardation, genital hypoplasia, ear defects including deafness) syndrome, or CHD7 mutation. Across the efficacy population, 93 patients (98%) were diagnosed with cDGS, and the most common DiGeorge gene mutations or syndromic associations were Chromosome 22q11.2 deletion (36 patients; 38%) and CHARGE syndrome (23 patients; 24%). There were 35 patients with missing or no identified genetic mutations. Two (2%) patients had FOXN1 deficiency, and 1 patient (1%) had a TBX variant. There were 50 (53%) patients with typical cDGS; these patients had congenital athymia with the absence of a T cell-related rash. There were 42 (44%) patients diagnosed with atypical cDGS; these patients may have had a rash, lymphadenopathy, or oligoclonal T cells. Patients who did not have congenital athymia (e.g. SCID) and patients with prior transplants, including thymus and HCT, were excluded from the efficacy analysis population. The baseline demographics and disease characteristics were similar in the safety population.

Patients with heart surgery anticipated within 4 weeks prior to, or 3 months after, the planned RETHYMIC treatment date, patients with human immunodeficiency virus (HIV) infection, and patients who were not considered good surgical candidates were excluded from study participation.

Patients in the efficacy population received RETHYMIC in a single surgical procedure at a dose of 4,900 to 24,000 mm² of RETHYMIC / recipient BSA in m². Patients were assigned to receive immunosuppressive therapy prior to and/or after treatment according to their disease phenotype and pre-RETHYMIC PHA response. Table 2 summarizes the criteria used to administer immunosuppression. Table 3 summarizes the specific immunosuppressant dosing used in RETHYMIC clinical studies. No patients were retreated with RETHYMIC.

The Kaplan-Meier estimated survival rates were 77% (95% CI [0.670, 0.841]) at 1 year and 76% (95% CI [0.658, 0.832]) at 2 years. For patients who were alive at 1 year after treatment with RETHYMIC, the survival rate was 94% at a median follow-up of 10.7 years.

Without treatment, congenital athymia is fatal in childhood. In a natural history population observed from 1991 through 2017, 49 patients diagnosed with congenital athymia received supportive care only. The 2-year survival rate was 6%, with all patients dying by 3 years of age. This population included 33 (67%) males. The most common cause of death was infection in 26 (53%) patients. Other common causes (≥10%) included support withdrawn in 7 (14%) patients, respiratory arrest in 5 (10%) patients, and cardiac arrest in 5 (10%) patients.

The Kaplan-Meier estimated survival rates for the RETHYMIC clinical trial population and the natural history population are shown in Figure 5. Four patients with >50 naïve T cells/mm³ (CD45RA⁺, CD62L⁺) at time of RETHYMIC administration have been treated; 2 (50%) were alive with follow-up less than 2 years.

Figure 5: Kaplan-Meier Survival by Year (RETHYMIC Efficacy Analysis Population and Natural History Population)

RETHYMIC significantly reduced the number of infections over time. In the first year after treatment with RETHYMIC, the number of patients with an infection event onset 6 to ≤ 12 months after treatment decreased by 38% (from 63 to 39) relative to the number of patients with an infection event onset in the first 6 months post-treatment. A two-year analysis showed a decrease in both the number of patients with an infection event and the mean number of infection events per patient, with an onset in the first 12 months post-treatment as compared to 12 to ≤ 24 months after treatment. There was a mean difference of 2.9 events (p<0.001) per patient.

Naïve CD4⁺ and CD8⁺ T cells reconstituted over the first year, with a durable increase through Year 2. Median (minimum, maximum) naïve CD4⁺ T cells/mm³ increased from a baseline of 1 (0, 38) to values of 42 (0, 653), 212 (1, 751), and 275 (33, 858) at 6, 12, and 24 months after treatment with RETHYMIC, respectively. Median naïve CD8⁺ T cells/mm³ increased from a baseline of 0 (0, 46) to values of 9 (0, 163), 58 (0, 304), and 86 (6, 275) at 6, 12, and 24 months after treatment with RETHYMIC, respectively. This was accompanied by functional improvements based on T cell proliferative responses to PHA.

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.

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

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.

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.

The pharmacodynamic effects of RETHYMIC are not known.

The pharmacokinetic effects of RETHYMIC are not known.

RETHYMIC^® is indicated for immune reconstitution in pediatric patients with congenital athymia.

All patients should be screened for anti-HLA antibodies prior to receiving RETHYMIC. Patients testing positive for anti-HLA antibodies should receive RETHYMIC from a donor who does not express those HLA alleles.

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.

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.

• 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)

Immunizations should not be administered in patients who have received RETHYMIC until immune-function criteria have been met.

RETHYMIC is administered by a surgical procedure. The recommended dose range is 5,000 to 22,000 mm² of RETHYMIC/m² recipient body surface area (BSA). (2) Immunosuppressive therapy is recommended for patients receiving RETHYMIC based on disease phenotype and PHA levels. (14)

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 mm² of RETHYMIC/m² 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.

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.

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.

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.

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.

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.

Advise patients and/or their caregivers that:

• Immune reconstitution sufficient to protect from infection usually develops between 6-12 months after treatment with RETHYMIC, but for some patients elevated naïve T cell numbers are not observed until 2 years after treatment. Strict infection control measures should be observed until the healthcare provider confirms that immune function has been reconstituted through the evaluation of blood using flow cytometry and the criteria for the discontinuation of immunoglobulin replacement therapy and Pneumocystis jiroveci pneumonia prophylaxis have been met. Patients and caregivers should follow good handwashing practices, minimize contact with others, and immediately report signs and symptoms of infection to their healthcare provider [see Warnings and Precautions (5.1)].
• Congenital athymia alters the immune response to vaccines. Instruct patients and/or their caregivers to notify their healthcare professional to evaluate the immune status of RETHYMIC recipients prior to receiving vaccinations [see Warnings and Precautions (5.8)].
• Immunosuppression should be administered in patients with elevated T cell response, maternal engraftment, or oligoclonal T cell expansion and autoreactive T cells manifested by rash, lymphadenopathy and/or diarrhea. Inform patients and/or their caregivers on risks associated with short-term and long-term use of immunosuppression and refer them to review the risks of the specific immunosuppressants prescribed with their physician.
• Congenital athymia is associated with a wide spectrum of genetic anomalies. Instruct patients and/or their caregiver to consult with a clinical geneticist prior to receiving RETHYMIC.

Advise patients and/or their caregivers of the following risks:

• Graft versus Host Disease [see Warnings and Precautions (5.2)]
• Autoimmune Disorders (patient's immune (defense) system mistakenly attacks patient's body) [see Warnings and Precautions (5.3)]
• Renal Impairment (decrease of kidney function) [see Warnings and Precautions (5.4)]
• Cytomegalovirus Infection [see Warnings and Precautions (5.5)]
• Malignancy (Cancer) [see Warnings and Precautions (5.6)]
• Transmission of Serious Infections and Transmissible Infectious Diseases [see Warnings and Precautions (5.7)]

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/mm³.

No nonclinical or clinical studies were performed to evaluate the effects of RETHYMIC on fertility.

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.

Final sterility and mycoplasma test results are not available at the time of use, but manufacturing personnel will communicate any positive results from sterility testing to the physician. Report the occurrence of transmitted infection to Sumitomo Pharma America at 833-369-9868.