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The safety and efficacy of RETHYMIC® (allogeneic processed thymus tissue–agdc) was evaluated in 105 patients across 10 clinical trials. The effectiveness of RETHYMIC was evaluated in 95 of those patients with congenital athymia in 10 clinical trials with follow-up of up to 25.5 years.

The primary end point of the analysis was the Kaplan Meier estimated survival at one year post administration of RETHYMIC. Kaplan Meier estimated survival at two years post treatment was a supportive endpoint. Secondary endpoints included naïve and total T-cell numbers and function at one year post treatment. Reductions in the number of infections over time and survival in patients alive one year post treatment were also analyzed.

Natural History Population

Without treatment, congenital athymia is fatal in childhood. A natural history population was observed from 1991 through 2017 in which 49 patients diagnosed with congenital athymia received supportive care only5. The 2-year survival rate was 6%, with all patients dying by 3 years of age.

RETHYMIC Efficacy Safety Dosage and Administration

RETHYMIC Efficacy

Patient Demographics
RETHYMIC Efficacy

The Kaplan-Meier estimated survival rates at year 1 and year 2 were 77% (95% CI, 0.670-0.841) and 76% (95% CI, 0.658-0.832), respectively5.

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

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 years5.

Kaplan-Meier Estimated Survival Rate:
Follow-up of Patients Who Were Alive 1 Year After RETHYMIC (EAS)3
Immune System Development

Naive CD4 and CD8T cells reconstituted over the first year following treatment and increased through year 2. Immune reconstitution sufficient to protect from infection is unlikely to develop prior to 6-12 months after treatment with RETHYMIC5.

Development of Naive T-cells Following Treatment
With RETHYMIC in the Primary Efficacy Analysis Population

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 2-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 to12 to ≤24 months after treatment. There was a mean difference of 2.9 events (P<0.001) per patient5.

Safety

Adverse Reactions

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. The following table lists the adverse reactions occurring in 105 patients who were treated with RETHYMIC in these studies5.

Adverse Reactions Occuring in at least 5% of Patients
Treated with RETHYMIC During Clinical Studies

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%)
  • Graft versus host disease (10%)

Please see the Important Safety Information for RETHYMIC below.

Dosage and Administration

The recommended dose range is 5,000 to 22,000 mm2 of RETHYMIC/m2 recipient body surface area (BSA). RETHYMIC is surgically implanted in one (or both, if necessary) of the patient’s quadriceps muscles during a single surgical procedure. The quadriceps muscle is used as the implantation site due to its high vascularization5.

RETHYMIC administration and development of patients T cells5.
Surgical incision is made over the anterior thigh
RETHYMIC is implanted between muscle fibers
RETHYMIC is covered with muscle tissue

After general anesthesia, a ~5 cm long vertical skin incision is made over the anterior thigh compartment

Individual slices of RETHYMIC are implanted into pockets between muscle fibers*

Each implanted RETHYMIC slice is fully covered by muscle tissue and the pockets stitched closed with a single absorbable suture

Following implantation, confirm hemostasis. Close the skin incision with absorbable sutures and apply a standard dressing. Leave the fascia open to allow room for muscle compartment swelling

Subsequently, the patient's own bone marrow stem cells migrate to the implanted RETHYMIC, where they develop into naive, immunocompetent T cells

Following administration, capillaries grow from the muscle into RETHYMIC, providing oxygen and nutrients migrating to RETHYMIC, the bone marrow stem cells develop into naive, immunocompetent T-cells3.

For patients who respond to RETHYMIC, a diverse T-cell population is established. Immune reconstitution sufficient to protect from infection is unlikely to develop prior to 6 to 12 months after treatment with RETHYMIC5. For some patients elevated naïve T-cell numbers are not observed until 2 years after treatment. Supportive care measures should be continued until immune reconstitution is established.

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Indication and Important Safety Information
IMPORTANT SAFETY INFORMATION

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. 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 specified criteria are met, and two months after stopping, IgG trough level should be checked. Prior to and after treatment with RETHYMIC, patients should be maintained on Pneumocystis jiroveci pneumonia prophylaxis until specified criteria are met.

RETHYMIC may cause or exacerbate pre-existing graft versus host disease (GVHD). Monitor and treat patients at risk for the development of GVHD. Risk factors for GVHD include atypical complete DiGeorge anomaly phenotype, prior hematopoietic cell transplantation (HCT) and maternal engraftment. GVHD may manifest as fever, rash, lymphadenopathy, elevated bilirubin and liver enzymes, enteritis, and/or diarrhea.

Autoimmune-related adverse events occurred in patients treated with RETHYMIC. These events included: thrombocytopenia, neutropenia, proteinuria, hemolytic anemia, alopecia, hypothyroidism, autoimmune hepatitis, autoimmune arthritis, transverse myelitis, albinism, hyperthyroidism, and ovarian failure. Monitor for the development of autoimmune disorders, including complete blood counts with differential, liver enzymes, serum creatinine, urinalysis, and thyroid function.

Pre-existing renal impairment is a risk factor for death.

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

Because of the underlying immune deficiency, patients who receive RETHYMIC may be at risk of developing post-treatment lymphoproliferative disorder. Patients should be monitored for the development of lymphoproliferative disorder.

Transmission of infectious disease may occur because RETHYMIC is derived from human tissue and because product manufacturing includes porcine- and bovine-derived reagents.

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

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. HLA matching is required in patients who have received a prior 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.

Of the 105 patients in clinical studies, 29 patients died, including 23 deaths in the first year (< 365 days) after implantation.

The most common (>10%) adverse events related to RETHYMIC included: hypertension, cytokine release syndrome, rash, hypomagnesemia, renal impairment/failure, thrombocytopenia, and graft versus host disease.

To report suspected adverse reactions, please contact the FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch.

INDICATION

RETHYMIC® (allogeneic processed thymus tissue–agdc) is indicated for immune reconstitution in pediatric patients with congenital athymia.

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

REFERENCES

1. Collins C, Sharpe E, Silber A, Kulke S, Hsieh EWY. Congenital athymia: genetic etiologies, clinical manifestations, diagnosis, and treatment. J Clin Immunol. 2021;41(5):881-895. doi.org/10.1007/s10875-021-01059-7

2. Data on file, Enzyvant.

3. Markert ML, Gupton SE, McCarthy EA. Experience with cultured thymus tissue in 105 children. J Allergy Clin Immunol. Published online August 3, 2021. doi:10.1016/j.jaci.2021.06.028

4. Hsieh EWY, Kim-Chang JJ, Kulke S, Silber A, O’Hara M, Collins C. Defining the clinical, emotional, social, and financial burden of congenital athymia. Adv Ther. 2021;38(8):4271-4288. doi.org/10.1007/s12325-021-01820-9

5. RETHYMIC [package insert]. Cambridge, MA: Enzyvant Therapeutics, Inc; 2021.

6. Markert ML. Defects in thymic development. In: Sullivan KE, Stiehm ER, eds. Stiehm’s Immune Deficiencies. 2nd ed. New York, NY: Elsevier; 2020:357-379.

7. Gupton SE, McCarthy EA, Markert ML. Care of children with DiGeorge before and after cultured thymus tissue implantation. J Clin Immunol. 2021;41(5):896-905. doi.org/10.1007/s10875-021-01044-0

8. Markert ML, Devlin BH, Alexieff MJ, et al. Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants. Blood. 2007;109(10):4539-4547.

9. Markert ML, McCarthy EA, Gupton SE, Lim AP. Cultured thymus tissue transplantation. In: Sullivan KE, Stiehm ER, eds. Stiehm's Immune Deficiencies. 2nd ed.: Academic Press; 2020:1229-1239.

Indication and Important Safety Information
IMPORTANT SAFETY INFORMATION

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. 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 specified criteria are met, and two months after stopping, IgG trough level should be checked. Prior to and after treatment with RETHYMIC, patients should be maintained on Pneumocystis jiroveci pneumonia prophylaxis until specified criteria are met.

RETHYMIC may cause or exacerbate pre-existing graft versus host disease (GVHD). Monitor and treat patients at risk for the development of GVHD. Risk factors for GVHD include atypical complete DiGeorge anomaly phenotype, prior hematopoietic cell transplantation (HCT) and maternal engraftment. GVHD may manifest as fever, rash, lymphadenopathy, elevated bilirubin and liver enzymes, enteritis, and/or diarrhea.

Autoimmune-related adverse events occurred in patients treated with RETHYMIC. These events included: thrombocytopenia, neutropenia, proteinuria, hemolytic anemia, alopecia, hypothyroidism, autoimmune hepatitis, autoimmune arthritis, transverse myelitis, albinism, hyperthyroidism, and ovarian failure. Monitor for the development of autoimmune disorders, including complete blood counts with differential, liver enzymes, serum creatinine, urinalysis, and thyroid function.

Pre-existing renal impairment is a risk factor for death.

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

Because of the underlying immune deficiency, patients who receive RETHYMIC may be at risk of developing post-treatment lymphoproliferative disorder. Patients should be monitored for the development of lymphoproliferative disorder.

Transmission of infectious disease may occur because RETHYMIC is derived from human tissue and because product manufacturing includes porcine- and bovine-derived reagents.

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

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. HLA matching is required in patients who have received a prior 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.

Of the 105 patients in clinical studies, 29 patients died, including 23 deaths in the first year (< 365 days) after implantation.

The most common (>10%) adverse events related to RETHYMIC included: hypertension, cytokine release syndrome, rash, hypomagnesemia, renal impairment/failure, thrombocytopenia, and graft versus host disease.

To report suspected adverse reactions, please contact the FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch.

INDICATION

RETHYMIC® (allogeneic processed thymus tissue–agdc) is indicated for immune reconstitution in pediatric patients with congenital athymia.

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

REFERENCES

1. Collins C, Sharpe E, Silber A, Kulke S, Hsieh EWY. Congenital athymia: genetic etiologies, clinical manifestations, diagnosis, and treatment. J Clin Immunol. 2021;41(5):881-895. doi.org/10.1007/s10875-021-01059-7

2. Data on file, Enzyvant.

3. Markert ML, Gupton SE, McCarthy EA. Experience with cultured thymus tissue in 105 children. J Allergy Clin Immunol. Published online August 3, 2021. doi:10.1016/j.jaci.2021.06.028

4. Hsieh EWY, Kim-Chang JJ, Kulke S, Silber A, O’Hara M, Collins C. Defining the clinical, emotional, social, and financial burden of congenital athymia. Adv Ther. 2021;38(8):4271-4288. doi.org/10.1007/s12325-021-01820-9

5. RETHYMIC [package insert]. Cambridge, MA: Enzyvant Therapeutics, Inc; 2021.

6. Markert ML. Defects in thymic development. In: Sullivan KE, Stiehm ER, eds. Stiehm’s Immune Deficiencies. 2nd ed. New York, NY: Elsevier; 2020:357-379.

7. Gupton SE, McCarthy EA, Markert ML. Care of children with DiGeorge before and after cultured thymus tissue implantation. J Clin Immunol. 2021;41(5):896-905. doi.org/10.1007/s10875-021-01044-0

8. Markert ML, Devlin BH, Alexieff MJ, et al. Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants. Blood. 2007;109(10):4539-4547.

9. Markert ML, McCarthy EA, Gupton SE, Lim AP. Cultured thymus tissue transplantation. In: Sullivan KE, Stiehm ER, eds. Stiehm's Immune Deficiencies. 2nd ed.: Academic Press; 2020:1229-1239.