# Regenerative medicine advanced therapy

Regenerative Medicine Advanced Therapy (RMAT) is a designation given by the Food and Drug Administration to drug candidates intended to treat serious or life-threatening conditions under the 21st Century Cures Act. A RMAT designation allows for accelerated approval based surrogate or intermediate endpoints.
RMAT goes beyond breakthrough therapy features by allowing for accelerated approval of drugs based on surrogate endpoints. A surrogate endpoint is a biomarker that substitutes for a direct endpoint, such as clinical benefit.

## Legal background

Section 3033 of the 21st Century Cures Act introduces section 506(g) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) that allows for the designation of certain therapies as a 'regenerative medicine advanced therapy' (RMAT) (21 U.S.C. § 356).

### Qualifying criteria

In order to qualify for RMAT status, a treatment must
* meet the definition of a regenerative medicine therapy,
* intend to treat, modify, reverse or cure a serious condition, and
* be supported by preliminary clinical evidence that indicates the RMAT candidate can address the clinical need.
A regenerative medicine therapy is defined in section 506(g)(8) of the FD&C Act to include cell therapies, therapeutic tissue engineering, human cell and tissue products. Under the FDA's interpretation, gene therapies and genetically modified cells that have a lasting effect, such as CAR-T antitumor therapies, may also qualify as regenerative medicine therapies.

## Effect

A RMAT designation includes all benefits of the Fast Track and breakthrough therapy designations. In addition, it opens up early interactions between the FDA and sponsors to facilitate accelerated approval. In this context, accelerated approval means approval based on
* previously agreed-upon surrogate or intermediate endpoints, or
* data from a limited but meaningful number of sites.
The ability to use 'Real World Evidence' (RWE), i.e. post-market evidence of safety and effectiveness, is particularly useful in the context of orphan diseases, where recruiting a sufficiently large cohort for pre-marketing clinical trials may not be feasible. RWE may include data from patient registries, clinical records and case studies.
Where a RMAT's sponsor fails to comply with the requirements for accelerated approval, the RMAT designation and the benefits conferred by it can be withdrawn (21 CFR 601.43).

## Examples

List of pharmaceuticals designated as RMATs :
| Name | Designee | Type | Biological target | Therapeutic indication |
| RPESC-RPE-4W | Luxa Biotechnology | autologous stem cell | retinal pigment epithelium | Dry age-related macular degeneration and geographic atrophy |
| ED-101 | Abeona Therapeutics | cell therapy | Collagen, type VII, alpha 1 | Recessive dystrophic epidermolysis bullosa |
| ABO-102 | Abeona Therapeutics | gene therapy | SGSH | Mucopolysaccharidosis Type III (Sanfilippo syndrome) |
| ADP-A2M4 | Adaptimmune Therapeutics | SPEAR T-cells | MAGEA4 | Synovial sarcoma |
| ALLO-715 | Allogene Therapeutics | allogeneic CAR-T | B-cell maturation antigen | Refractory/relapsed multiple myeloma |
| ALVR-105 Viralym-M | Allovir | allogeneic CAR-T | BK virus, CMV, adenoviridae, Epstein–Barr virus, human herpesvirus 6, JC virus (human polyomavirus 2) | BK virus associated hemorrhagic cystitis after hematopoietic stem cell transplantation |
| AB205 | Angiocrine Bioscience | allogeneic cord endothelial cells | | Severe regiment-related toxicities from conditioning chemotherapy prior to hematopoietic stem cell transplantation in patients with lymphomas |
| AST-OPC1 | Asterias Biotherapeutics | allogeneic oligodendrocyte progenitor cells | | Spinal cord injuries |
| AT132 | Audentes Therapeutics | gene therapy | Myotubularin 1 | X-linked myotubular myopathy |
| Valoctocogene roxaparvovec (Roctavian, Valrox) | BioMarin Pharmaceutical | gene therapy | F8 | Haemophilia A |
| Betibeglogene autotemcel (Lentiglobin) | bluebird bio | gene therapy | Hemoglobin subunit beta | Sickle cell disease |
| Lisocabtagene maraleucel (Breyanzi) | Bristol Myers Squibb | autologous CAR-T | CD19 | Diffuse large B-cell lymphoma |
| CLBS14 (Ologo) | Caladrius Biosciences | autologous cell therapy | CD34 | Refractory angina |
| CAP-1002 | Capricor Therapeutics | allogeneic cell therapy | | Duchenne muscular dystrophy |
| CT053 | CARsgen Therapeutics | autologous CAR-T | B-cell maturation antigen | Refractory or relapsed multiple myeloma |
| Descartes-08 | Cartesian Therapeutics, Inc. | autologous RNA CAR-T | B-cell maturation antigen | Generalized myasthenia gravis |
| Romyelocel-L | Cellerant Therapeutics | allogeneic cell therapy | | Serious bacterial and fungal infections during induction chemotherapy in acute myeloid leukemia |
| CTX001 | CRISPR Therapeutics Vertex Pharmaceuticals | gene therapy | Fetal hemoglobin | Sickle cell disease Transfusion-dependent beta thalassemia |
| RVT-802 | Enzyvant | allogeneic cell therapy | Thymus tissue | Congenital athymia in DiGeorge syndrome |
| ECT-001 | ExCellThera | allogeneic cell therapy | | Hematologic malignancies |
| FCX-007 (dabocemagene autoficel) | Fibrocell Castle Creek Biosciences | gene therapy | Collagen, type VII, alpha 1 | Recessive dystrophic epidermolysis bullosa |
| Ilixadencel | Immunicum AB | allogeneic cell therapy | | Renal cell carcinoma |
| Lifileucel | Iovance Biotherapeutics | autologous cell therapy | | Metastatic melanoma that progresses after an anti-PD-1 treatment |
| MGTA-456 | Magenta Therapeutics | allogeneic cell therapy | CD34 | Promoting hematopoietic stem cell transplant engraftment in Hurler syndrome, metachromatic leukodystrophy and Krabbe disease |
| MDR-101 | Medeor Therapeutics | allogeneic cell therapy | CD34, CD3 | Prevention of kidney transplant rejection |
| MB-107 | Mustang Bio St. Jude Children's Research Hospital | gene therapy | Common gamma chain | X-linked severe combined immunodeficiency |
| RP-L102 | Rocket Pharmaceuticals Inc. | gene therapy | FANCA | Fanconi anemia |
| VY-AADC | Voyager Therapeutics | gene therapy | Aromatic L-amino acid decarboxylase | Parkinson's disease |
| RP-L201 | Rocket Pharmaceuticals Inc. | gene therapy using autologous CD34+ enriched cells | Integrin beta 2 | Leukocyte adhesion deficiency Type I |
| OTL-103 | Orchard Therapeutics | gene therapy using autologous cells | WASp | Wiskott–Aldrich syndrome |

## Statistics

In 2020, the FDA received 34 requests for RMAT status, of which 12 (35.3%) were granted. RMAT designated drugs include the novel CAR-T therapy Kymriah and betibeglogene autotemcel for beta thalassemia. As of 31 March 2021, 62 requests for RMAT status have been granted.
More than half of the RMAT applications received by March 2019 involved autologous or allogeneic cell therapy products, including CAR-T therapies.