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.[1] A RMAT designation allows for accelerated approval based surrogate or intermediate endpoints.[2]

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.[3]

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

  1. meet the definition of a regenerative medicine therapy,
  2. intend to treat, modify, reverse or cure a serious condition, and
  3. be supported by preliminary clinical evidence that indicates the RMAT candidate can address the clinical need.[4]

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

  1. previously agreed-upon surrogate or intermediate endpoints, or
  2. data from a limited but meaningful number of sites.[4]

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.[5] RWE may include data from patient registries, clinical records and case studies.[6]

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to comply with the requirements for accelerated approval, the RMAT designation and the benefits conferred by it can be withdrawn (21 CFR 601.43).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
ED-101[7] Abeona Therapeutics cell therapy Collagen, type VII, alpha 1 Recessive dystrophic epidermolysis bullosa
ABO-102[8] Abeona Therapeutics gene therapy SGSH Mucopolysaccharidosis Type III (Sanfilippo syndrome)
ADP-A2M4[9] Adaptimmune Therapeutics SPEAR T-cells MAGEA4 Synovial sarcoma
ALLO-715[10] Allogene Therapeutics allogeneic CAR-T B-cell maturation antigen Refractory/relapsed multiple myeloma
ALVR-105

Viralym-M[11]

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[12] 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[13] Asterias Biotherapeutics allogeneic oligodendrocyte progenitor cells Spinal cord injuries
AT132[14] Audentes Therapeutics gene therapy Myotubularin 1 X-linked myotubular myopathy
Valoctocogene roxaparvovec

(Roctavian,

Valrox)

BioMarin Pharmaceutical gene therapy F8 Haemophilia A
Betibeglogene autotemcel

(Lentiglobin)[15]

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)[16]

Caladrius Biosciences autologous cell therapy CD34 Refractory angina
CAP-1002[17] Capricor Therapeutics allogeneic cell therapy Duchenne muscular dystrophy
CT053[18] CARsgen Therapeutics autologous CAR-T B-cell maturation antigen Refractory or relapsed multiple myeloma
Descartes-08[19] Cartesian Therapeutics, Inc. autologous RNA CAR-T B-cell maturation antigen Generalized myasthenia gravis
Romyelocel-L[20] Cellerant Therapeutics allogeneic cell therapy Serious bacterial and fungal infections during induction chemotherapy in acute myeloid leukemia
CTX001[21] CRISPR Therapeutics

Vertex Pharmaceuticals

gene therapy Fetal hemoglobin Sickle cell disease

Transfusion-dependent beta thalassemia

RVT-802[22] Enzyvant allogeneic cell therapy Thymus tissue Congenital athymia in DiGeorge syndrome
ECT-001[23] ExCellThera allogeneic cell therapy Hematologic malignancies
FCX-007 (dabocemagene autoficel)[24] Fibrocell

Castle Creek Biosciences

gene therapy Collagen, type VII, alpha 1 Recessive dystrophic epidermolysis bullosa
Ilixadencel[25] Immunicum AB allogeneic cell therapy Renal cell carcinoma
Lifileucel[26] Iovance Biotherapeutics autologous cell therapy Metastatic melanoma that progresses after an anti-PD-1 treatment
MGTA-456[27] Magenta Therapeutics allogeneic cell therapy CD34 Promoting hematopoietic stem cell transplant engraftment in Hurler syndrome, metachromatic leukodystrophy and Krabbe disease
MDR-101[28] Medeor Therapeutics allogeneic cell therapy CD34, CD3 Prevention of kidney transplant rejection
MB-107[29] Mustang Bio

St. Jude Children's Research Hospital

gene therapy Common gamma chain X-linked severe combined immunodeficiency
RP-L102[30] Rocket Pharmaceuticals Inc. gene therapy FANCA Fanconi anemia
VY-AADC[31] Voyager Therapeutics gene therapy Aromatic L-amino acid decarboxylase Parkinson's disease
RP-L201[32] Rocket Pharmaceuticals Inc. gene therapy using autologous CD34+ enriched cells Integrin beta 2 Leukocyte adhesion deficiency Type I
OTL-103[33] 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.[34] As of 31 March 2021, 62 requests for RMAT status have been granted.[35]

More than half of the RMAT applications received by March 2019 involved autologous or allogeneic cell therapy products, including CAR-T therapies.[6]

See also

References

  1. ^ "Regenerative Medicine Advanced Therapy Designation". Food and Drug Administration. Archived from the original on 2 August 2021. Retrieved 25 June 2021.
  2. ^ Vaggelas, Annegret; Seimetz, Diane (2019-05-01). "Expediting Drug Development: FDA's New Regenerative Medicine Advanced Therapy Designation". Therapeutic Innovation & Regulatory Science. 53 (3): 364–373. doi:10.1177/2168479018779373. ISSN 2168-4804. PMID 29895180. S2CID 48355647.
  3. ^ Aronson, J K (2005). "Biomarkers and surrogate endpoints". British Journal of Clinical Pharmacology. 59 (5): 491–494. doi:10.1111/j.1365-2125.2005.02435.x. PMC 1884846. PMID 15842546.
  4. ^ a b Food and Drug Administration (February 2019). "Expedited Programs for Regenerative Medicine Therapies for Serious Conditions: Guidance for Industry". Food and Drug Administration. Archived from the original on 13 March 2021. Retrieved 25 June 2021.
  5. ^ Barlas, Stephen (March 2018). "The 21st Century Cures Act: FDA Implementation One Year Later". Pharmacy and Therapeutics. 43 (3): 149–179. ISSN 1052-1372. PMC 5821241. PMID 29491696.
  6. ^ a b "Regulatory intelligence: Update on regenerative medicine advanced therapies designations". Endpoints News. Archived from the original on 2021-06-25. Retrieved 2021-06-25.
  7. ^ Abeona Therapeutics Inc. (2018-01-29). "Abeona Receives FDA Regenerative Medicine Advanced Therapy Designation for EB-101 Gene Therapy in Epidermolysis Bullosa". GlobeNewswire News Room (Press release). Archived from the original on 2021-07-09. Retrieved 2021-07-01.
  8. ^ "Abeona Announces FDA Grants RMAT Designation to ABO-102 Gene Therapy in MPS IIIA". Abeona Therapeutics Inc. Archived from the original on 2021-07-09. Retrieved 2021-07-01.
  9. ^ "Regenerative Medicine Advanced Therapy Designation Granted to ADP-A2M4 for Synovial Sarcoma". Journal of Oncology Navigation & Survivorship. 2019-12-11.
  10. ^ "FDA Grants RMAT Designation to ALLO-715 for Relapsed/Refractory Multiple Myeloma". OncLive. Archived from the original on 2021-07-09. Retrieved 2021-07-01.
  11. ^ Hildreth, Cade (2019-06-12). "AlloVir Secures Latest RMAT Designation for Viralym-M". BioInformant. Retrieved 2024-08-11.
  12. ^ "Angiocrine Bioscience Announces FDA Regenerative Medicine Advanced Therapy (RMAT) Designation Granted to AB-205 (Universal E-CEL® Cell Therapy) to Treat Organ Vascular Niche Injuries for the Prevention of Severe Toxicities in Lymphoma Patients". BioSpace. Retrieved 2021-07-01.
  13. ^ Asterias Biotherapeutics (2017-10-02). "Asterias Announces Two Significant Developments for Spinal Cord Injury Program". GlobeNewswire News Room (Press release). Archived from the original on 2021-07-09. Retrieved 2021-07-01.
  14. ^ Audentes Therapeutics Inc. "Audentes Announces Regenerative Medicine Advanced Therapy (RMAT) Designation Granted by the FDA to AT132 for the Treatment of X-Linked Myotubular Myopathy". www.prnewswire.com (Press release). Archived from the original on 2021-07-09. Retrieved 2021-07-01.
  15. ^ "bluebird bio's LentiGlobin™ for Sickle Cell Disease Gene Therapy (bb1111) Granted Priority Medicines (PRIME) Designation by European Medicines Agency - bluebird bio, Inc". investor.bluebirdbio.com. Archived from the original on 2021-07-09. Retrieved 2021-07-01.
  16. ^ Caladrius Biosciences Inc. (2019-08-07). "Caladrius Biosciences and Cognate BioServices Establish Manufacturing Agreement for Phase 3 Confirmatory Pivotal Clinical Trial of CLBS14 in No-option Refractory Disabling Angina". GlobeNewswire News Room (Press release). Retrieved 2021-07-01.
  17. ^ Capricor Therapeutics Inc. (2019-09-24). "Capricor Therapeutics to Meet with FDA to Discuss CAP-1002 to Treat Duchenne Muscular Dystrophy". GlobeNewswire News Room (Press release). Archived from the original on 2021-07-09. Retrieved 2021-07-01.
  18. ^ "CARsgen Announces Investigational CAR-T Therapy CT053 Granted RMAT Designation by the U.S. FDA for R/R Multiple Myeloma". BioSpace. Archived from the original on 2021-07-09. Retrieved 2021-07-01.
  19. ^ "Cartesian Therapeutics Receives FDA Regenerative Medicine Advanced Therapy (RMAT) Designation for Descartes-08 for the Treatment of Myasthenia Gravis". Cartesian Therapeutics. Archived from the original on 2024-05-23. Retrieved 2024-05-23.
  20. ^ "Cellerant Therapeutics, Inc. Announces FDA Grants Regenerative Medicine Advanced Therapy (RMAT) Designation for romyelocel-L to Prevent Infections During Neutropenia". Cellerant Therapeutic. 2018-07-02. Archived from the original on 2021-07-09. Retrieved 2021-07-01.
  21. ^ Coralea. "Gene-editing therapy CTX001™ is granted RMAT status by FDA for severe β-thalassaemia and SCD". www.ithanet.eu. Archived from the original on 2021-07-09. Retrieved 2021-07-01.
  22. ^ "Duke researcher's drug RVT-802 receives pioneering FDA regenerative medicine designation – Duke OTC". Archived from the original on 2021-07-09. Retrieved 2021-07-01.
  23. ^ ExCellThera (2019-04-23). "ExCellThera's lead technology, ECT-001, receives FDA Regenerative Medicine Advanced Therapy (RMAT) designation". GlobeNewswire News Room (Press release). Archived from the original on 2021-07-09. Retrieved 2021-07-01.
  24. ^ "Castle Creek Biosciences: D-Fi Gene Therapy". Castle Creek Biosciences, Inc. Archived from the original on 2021-07-09. Retrieved 2021-07-01.
  25. ^ Tucker, Nicole (May 8, 2020). "FDA Grants RMAT Designation to Ilixadencel in Metastatic RCC". Targeted Oncology. Retrieved 2021-07-01.
  26. ^ Iovance Biotherapeutics Inc. (2018-10-11). "Iovance Biotherapeutics Reports Results from FDA End of Phase 2 meeting and Provides Updates About the Company's Clinical Program". GlobeNewswire News Room (Press release). Archived from the original on 2021-07-09. Retrieved 2021-07-01.
  27. ^ "Magenta Therapeutics Announces FDA Regenerative Medicine Advanced Therapy (RMAT) Designation Granted to MGTA-456 for the Treatment of Inherited Metabolic Disorders – Magenta Therapeutics". investor.magentatx.com. Archived from the original on 2021-07-09. Retrieved 2021-07-01.
  28. ^ "Medeor Therapeutics' Transplant Immune Tolerance Therapy Receives Regenerative Medicine Advanced Therapy Designation from FDA". www.businesswire.com. 2020-09-22. Archived from the original on 2021-07-09. Retrieved 2021-07-02.
  29. ^ "Mustang Bio Receives Advanced Therapy Medicinal Product Classification from European Medicines Agency for MB-107 Lentiviral Gene Therapy for X-Linked Severe Combined Immunodeficiency". AP NEWS. 2020-04-20. Archived from the original on 2021-07-09. Retrieved 2021-07-02.
  30. ^ "Rocket Pharmaceuticals Receives FDA Regenerative Medicine Advanced Therapy (RMAT) and Fast Track Designations for RP-L102 Gene Therapy for Fanconi Anemia". www.businesswire.com. 2018-11-27. Archived from the original on 2021-07-09. Retrieved 2021-07-02.
  31. ^ Voyager Therapeutics Inc. (2018-06-21). "Voyager Therapeutics Announces FDA Regenerative Medicine Advanced Therapy (RMAT) Designation Granted for VY-AADC for the Treatment of Parkinson's Disease". GlobeNewswire News Room (Press release). Archived from the original on 2021-07-09. Retrieved 2021-07-02.
  32. ^ "Rocket Pharmaceuticals Receives FDA Regenerative Medicine Advanced Therapy Designation for RP-L201 Gene Therapy for Leukocyte Adhesion Deficiency-I". www.businesswire.com. 2021-03-09. Archived from the original on 2021-07-09. Retrieved 2021-07-02.
  33. ^ Orchard Therapeutics (Europe) Limited (2019-07-29). "Orchard Therapeutics Announces FDA Regenerative Medicine Advanced Therapy (RMAT) Designation Granted for OTL-103 for the Treatment of Wiskott-Aldrich Syndrome". GlobeNewswire News Room (Press release). Archived from the original on 2021-07-01. Retrieved 2021-07-02.
  34. ^ "Novartis' Kymriah® Wins Latest FDA RMAT (42 Announced)". BioInformant. 22 April 2020. Archived from the original on 2022-11-27. Retrieved 2024-06-12.
  35. ^ Center for Biologics Evaluation and Research (2021-04-05). "Cumulative CBER Regenerative Medicine Advanced Therapy (RMAT) Designation Requests Received by Fiscal Year". FDA. Archived from the original on 2021-07-26. Retrieved 2021-06-25.

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