Rethymic (allogeneic processed thymus tissue-agdc)

The first FDA-approved treatment for congenital athymia and the first thymus tissue product approved in the US. Before it, children received only supportive care, and investigational stem cell transplant offered limited benefit.

The thymus is a small organ in the chest where immature immune cells from the bone marrow develop into T cells, the white blood cells that fight many infections. Children born without a thymus make very few new (naive) T cells, so ordinary infections can become life-threatening. Rethymic starts as thymus tissue removed from infants 9 months or younger during heart surgery. It is processed and grown in the lab for 12 to 21 days, which keeps the tissue's structure while removing most of the donor's immature T cells. Surgeons implant the slices into the child's thigh muscle, where the child's own T cell precursors move in and mature into naive T cells. New T cells usually start showing up in the blood 6 to 12 months later, and for some children it takes up to 2 years^[1].

Rethymic has no boxed warning and no contraindications. Protection against infection is unlikely before 6 to 12 months, so strict infection precautions, immunoglobulin replacement and Pneumocystis pneumonia prevention continue until blood tests show the new immune system is working. Of 105 children treated in the studies, 29 died, 23 of them in the first year, most often from infection. Graft versus host disease (GVHD), where immune cells attack the body's own tissues, occurred in 11 children (10%), and 6 of them died. Autoimmune problems affected 35%, most often low platelets (12%), low neutrophils (9%), protein in the urine (7%) and breakdown of red blood cells (hemolytic anemia, 7%), starting anywhere from days before surgery to 16 years after. Children with kidney problems before treatment had a higher risk of death, and all 4 children who had cytomegalovirus (CMV) infection before treatment died. Other warnings cover a risk of lymphoproliferative disorder (a type of blood cancer), so children are tested for Epstein-Barr virus and CMV before and 3 months after treatment; possible transmission of infection from the human tissue or the animal-derived materials used to make it; and delaying vaccines until immune tests allow them. The most common side effects were high blood pressure (19%), cytokine release syndrome (18%, all in children given rabbit anti-thymocyte globulin, an immune-suppressing medicine), low magnesium (16%), rash (15%), kidney problems (12%), low platelets (12%) and GVHD (10%). The studies had no placebo group^[1].

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Approved for immune reconstitution in children with congenital athymia. It is not for severe combined immunodeficiency (SCID), a different condition. In the studies, athymia was confirmed by very low naive T cell counts in the blood (fewer than 50 per cubic millimeter or under 5% of T cells), and 98% of children had complete DiGeorge syndrome, most often associated with a 22q11.2 deletion (38%) or CHARGE syndrome (24%). Children needing heart surgery within 4 weeks before or 3 months after the planned implant, children with HIV and children who were not good surgical candidates were excluded. All children are screened for anti-HLA antibodies, and HLA matching is required after a prior stem cell or organ transplant. The label advises seeing a clinical geneticist before treatment.

Source: RETHYMIC Connect patient support

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Approval rested on 10 prospective, open-label studies at a single center, Duke University, which treated 105 patients from 1993 to 2020^[3][5]. The review was associated with NCT00576407, NCT00576836, NCT00579527 and NCT01220531^[2]. Among 95 children in the main efficacy analysis (median age 9 months), estimated survival was 77% at 1 year and 76% at 2 years, and children alive at 1 year had 94% survival at a median follow-up of 10.7 years. In comparison, 49 children with congenital athymia who received only supportive care between 1991 and 2017 had a 2-year survival of 6%, and all died by age 3. Naive CD4+ T cells rose from a median of 1 per cubic millimeter before treatment to 212 at 12 months and 275 at 24 months, and the number of children with a new infection fell by 38% from the first 6 months to months 6 to 12^[1].

Thymus tissue implantation grew out of more than 25 years of research at Duke University^[6]. Enzyvant Therapeutics, then a subsidiary of Sumitovant Biopharma and Sumitomo Dainippon Pharma, developed it under the code RVT-802^[6]. It received orphan drug designation on August 15, 2003, breakthrough therapy and regenerative medicine advanced therapy (RMAT) designations on April 13, 2017, and rare pediatric disease designation on April 5, 2019. The FDA issued a complete response letter on December 4, 2019 over manufacturing and facility concerns, and after Enzyvant changed its manufacturing and testing and resubmitted on April 9, 2021, the FDA approved Rethymic on October 8, 2021 with a rare pediatric disease priority review voucher^[3][2]. In April 2023, Sumitomo Pharma announced that Enzyvant would be combined with its other US subsidiaries into Sumitomo Pharma America, effective July 1, 2023^[7], and Sumitomo Pharma America is now named on the label^[1]. A patient registry (NCT05329935) follows treated children to learn more about long-term survival and side effects^[11].