Regenerative medicine advanced therapy explained

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]

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) .

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.

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to comply with the requirements for accelerated approval, the RMAT designation and the benefits conferred by it can be withdrawn .

Examples

List of pharmaceuticals designated as RMATs!Name!Designee!Type!Biological target!Therapeutic indication
ED-101[7] Abeona Therapeuticscell therapyCollagen, type VII, alpha 1Recessive dystrophic epidermolysis bullosa
ABO-102[8] Abeona Therapeuticsgene therapySGSHMucopolysaccharidosis Type III (Sanfilippo syndrome)
ADP-A2M4[9] Adaptimmune TherapeuticsSPEAR T-cellsMAGEA4Synovial sarcoma
ALLO-715[10] Allogene Therapeuticsallogeneic CAR-TB-cell maturation antigenRefractory/relapsed multiple myeloma
ALVR-105Viralym-M[11] Allovirallogeneic CAR-TBK 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 Bioscienceallogeneic cord endothelial cellsSevere regiment-related toxicities from conditioning chemotherapy prior to hematopoietic stem cell transplantation in patients with lymphomas
AST-OPC1[13] Asterias Biotherapeuticsallogeneic oligodendrocyte progenitor cellsSpinal cord injuries
AT132[14] Audentes Therapeuticsgene therapyMyotubularin 1X-linked myotubular myopathy
Valoctocogene roxaparvovec(Roctavian,

Valrox)

BioMarin Pharmaceuticalgene therapyF8Haemophilia A
Betibeglogene autotemcel(Lentiglobin)[15] bluebird biogene therapyHemoglobin subunit betaSickle cell disease
Lisocabtagene maraleucel(Breyanzi)Bristol Myers Squibbautologous CAR-TCD19Diffuse large B-cell lymphoma
CLBS14(Ologo)[16] Caladrius Biosciencesautologous cell therapyCD34Refractory angina
CAP-1002[17] Capricor Therapeuticsallogeneic cell therapyDuchenne muscular dystrophy
CT053[18] CARsgen Therapeuticsautologous CAR-TB-cell maturation antigenRefractory or relapsed multiple myeloma
Descartes-08[19] Cartesian Therapeutics, Inc.autologous RNA CAR-TB-cell maturation antigenGeneralized myasthenia gravis
Romyelocel-L[20] Cellerant Therapeuticsallogeneic cell therapySerious bacterial and fungal infections during induction chemotherapy in acute myeloid leukemia
CTX001[21] CRISPR TherapeuticsVertex Pharmaceuticalsgene therapyFetal hemoglobinSickle cell diseaseTransfusion-dependent beta thalassemia
RVT-802[22] Enzyvantallogeneic cell therapyThymus tissueCongenital athymia in DiGeorge syndrome
ECT-001[23] ExCellTheraallogeneic cell therapyHematologic malignancies
FCX-007 (dabocemagene autoficel)[24] FibrocellCastle Creek Biosciencesgene therapyCollagen, type VII, alpha 1Recessive dystrophic epidermolysis bullosa
Ilixadencel[25] Immunicum ABallogeneic cell therapyRenal cell carcinoma
Lifileucel[26] Iovance Biotherapeuticsautologous cell therapyMetastatic melanoma that progresses after an anti-PD-1 treatment
MGTA-456[27] Magenta Therapeuticsallogeneic cell therapyCD34Promoting hematopoietic stem cell transplant engraftment in Hurler syndrome, metachromatic leukodystrophy and Krabbe disease
MDR-101[28] Medeor Therapeuticsallogeneic cell therapyCD34, CD3Prevention of kidney transplant rejection
MB-107[29] Mustang BioSt. Jude Children's Research Hospitalgene therapyCommon gamma chainX-linked severe combined immunodeficiency
RP-L102[30] Rocket Pharmaceuticals Inc.gene therapyFANCAFanconi anemia
VY-AADC[31] Voyager Therapeuticsgene therapyAromatic L-amino acid decarboxylaseParkinson's disease
RP-L201[32] Rocket Pharmaceuticals Inc.gene therapy using autologous CD34+ enriched cellsIntegrin beta 2Leukocyte adhesion deficiency Type I
OTL-103[33] Orchard Therapeuticsgene therapy using autologous cellsWASpWiskott–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.

See also

Notes and References

  1. Web site: Regenerative Medicine Advanced Therapy Designation . Food and Drug Administration . 25 June 2021 . en . 2 August 2021 . https://web.archive.org/web/20210802095320/https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/regenerative-medicine-advanced-therapy-designation . live .
  2. Vaggelas. Annegret. Seimetz. Diane. 2019-05-01. Expediting Drug Development: FDA's New Regenerative Medicine Advanced Therapy Designation. Therapeutic Innovation & Regulatory Science. en. 53. 3. 364–373. 10.1177/2168479018779373. 29895180. 48355647. 2168-4804.
  3. Aronson . J K . Biomarkers and surrogate endpoints . British Journal of Clinical Pharmacology . 2005 . 59 . 5 . 491–494 . 10.1111/j.1365-2125.2005.02435.x . 15842546 . 1884846 .
  4. Web site: Food and Drug Administration . Expedited Programs for Regenerative Medicine Therapies for Serious Conditions: Guidance for Industry . . 25 June 2021 . February 2019 . 13 March 2021 . https://web.archive.org/web/20210313220217/https://www.fda.gov/media/120267/download#page7 . live .
  5. Barlas. Stephen. March 2018. The 21st Century Cures Act: FDA Implementation One Year Later. Pharmacy and Therapeutics. 43. 3. 149–179. 1052-1372. 5821241. 29491696.
  6. Web site: Regulatory intelligence: Update on regenerative medicine advanced therapies designations. 2021-06-25. Endpoints News. en. 2021-06-25. https://web.archive.org/web/20210625210427/https://endpts.com/regulatory-intelligence-update-on-regenerative-medicine-advanced-therapies-designations/. live.
  7. Abeona Therapeutics Inc.. 2018-01-29. Abeona Receives FDA Regenerative Medicine Advanced Therapy Designation for EB-101 Gene Therapy in Epidermolysis Bullosa. 2021-07-01. GlobeNewswire News Room. en. 2021-07-09. https://web.archive.org/web/20210709183150/https://www.globenewswire.com/news-release/2018/01/29/1313576/0/en/Abeona-Receives-FDA-Regenerative-Medicine-Advanced-Therapy-Designation-for-EB-101-Gene-Therapy-in-Epidermolysis-Bullosa.html. live.
  8. Web site: Abeona Announces FDA Grants RMAT Designation to ABO-102 Gene Therapy in MPS IIIA. 2021-07-01. Abeona Therapeutics Inc.. en. 2021-07-09. https://web.archive.org/web/20210709182305/https://investors.abeonatherapeutics.com/press-releases/detail/123/abeona-announces-fda-grants-rmat-designationto-abo-102. live.
  9. 2019-12-11. Regenerative Medicine Advanced Therapy Designation Granted to ADP-A2M4 for Synovial Sarcoma. Journal of Oncology Navigation & Survivorship . en-gb.
  10. Web site: FDA Grants RMAT Designation to ALLO-715 for Relapsed/Refractory Multiple Myeloma. 2021-07-01. OncLive. 2021-07-09. https://web.archive.org/web/20210709182604/https://www.onclive.com/view/fda-grants-rmat-designation-to-allo-715-for-relapsed-refractory-multiple-myeloma. live.
  11. Web site: Hildreth. Cade . AlloVir Secures Latest RMAT Designation for Viralym-M . BioInformant . 2019-06-12 . 2024-08-11.
  12. Web site: 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. 2021-07-01. BioSpace. en-US.
  13. Asterias Biotherapeutics. 2017-10-02. Asterias Announces Two Significant Developments for Spinal Cord Injury Program. 2021-07-01. GlobeNewswire News Room. en. 2021-07-09. https://web.archive.org/web/20210709182418/https://www.globenewswire.com/news-release/2017/10/02/1138619/0/en/Asterias-Announces-Two-Significant-Developments-for-Spinal-Cord-Injury-Program.html. live.
  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. 2021-07-01. www.prnewswire.com. en. 2021-07-09. https://web.archive.org/web/20210709185011/https://www.prnewswire.com/news-releases/audentes-announces-regenerative-medicine-advanced-therapy-rmat-designation-granted-by-the-fda-to-at132-for-the-treatment-of-x-linked-myotubular-myopathy-300699224.html. live.
  15. Web site: bluebird bio's LentiGlobin™ for Sickle Cell Disease Gene Therapy (bb1111) Granted Priority Medicines (PRIME) Designation by European Medicines Agency - bluebird bio, Inc.. 2021-07-01. investor.bluebirdbio.com. en. 2021-07-09. https://web.archive.org/web/20210709182109/https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bios-lentiglobintm-sickle-cell-disease-gene-therapy. live.
  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. 2021-07-01. GlobeNewswire News Room. en.
  17. Capricor Therapeutics Inc.. 2019-09-24. Capricor Therapeutics to Meet with FDA to Discuss CAP-1002 to Treat Duchenne Muscular Dystrophy. 2021-07-01. GlobeNewswire News Room. en. 2021-07-09. https://web.archive.org/web/20210709182531/https://www.globenewswire.com/en/news-release/2019/09/24/1919808/29467/en/Capricor-Therapeutics-to-Meet-with-FDA-to-Discuss-CAP-1002-to-Treat-Duchenne-Muscular-Dystrophy.html. live.
  18. Web site: CARsgen Announces Investigational CAR-T Therapy CT053 Granted RMAT Designation by the U.S. FDA for R/R Multiple Myeloma. 2021-07-01. BioSpace. en-US. 2021-07-09. https://web.archive.org/web/20210709182928/https://www.biospace.com/article/carsgen-announces-investigational-car-t-therapy-ct053-granted-rmat-designation-by-the-u-s-fda-for-r-r-multiple-myeloma/. live.
  19. Web site: Cartesian Therapeutics Receives FDA Regenerative Medicine Advanced Therapy (RMAT) Designation for Descartes-08 for the Treatment of Myasthenia Gravis. 2024-05-23. Cartesian Therapeutics. en-US. 2024-05-23. https://web.archive.org/web/20240523214147/https://ir.cartesiantherapeutics.com/news-releases/news-release-details/cartesian-therapeutics-receives-fda-regenerative-medicine. live.
  20. Web site: 2018-07-02. Cellerant Therapeutics, Inc. Announces FDA Grants Regenerative Medicine Advanced Therapy (RMAT) Designation for romyelocel-L to Prevent Infections During Neutropenia. 2021-07-01. Cellerant Therapeutic. en. 2021-07-09. https://web.archive.org/web/20210709181816/https://www.cellerant.com/investor/press-releases/cellerant-therapeutics-inc-announces-fda-grants-regenerative-medicine-advanced-therapy-rmat-designation-for-romyelocel-l-to-prevent-infections-during-neutropenia/. dead.
  21. Web site: Coralea. Gene-editing therapy CTX001™ is granted RMAT status by FDA for severe β-thalassaemia and SCD. 2021-07-01. www.ithanet.eu. en-gb. 2021-07-09. https://web.archive.org/web/20210709181920/https://www.ithanet.eu/latest-information/news/2998-gene-editing-therapy-ctx001-is-granted-rmat-status-by-fda-for-severe-thalassaemia-and-scd. live.
  22. Web site: Duke researcher's drug RVT-802 receives pioneering FDA regenerative medicine designation – Duke OTC. 2021-07-01. en-US. 2021-07-09. https://web.archive.org/web/20210709182716/https://olv.duke.edu/news/news1/. dead.
  23. ExCellThera. 2019-04-23. ExCellThera's lead technology, ECT-001, receives FDA Regenerative Medicine Advanced Therapy (RMAT) designation. 2021-07-01. GlobeNewswire News Room. en. 2021-07-09. https://web.archive.org/web/20210709182024/https://www.globenewswire.com/news-release/2019/04/23/1807869/0/en/ExCellThera-s-lead-technology-ECT-001-receives-FDA-Regenerative-Medicine-Advanced-Therapy-RMAT-designation.html. live.
  24. Web site: Castle Creek Biosciences: D-Fi Gene Therapy. 2021-07-01. Castle Creek Biosciences, Inc.. 2021-07-09. https://web.archive.org/web/20210709183152/https://castlecreekbio.com/autologous-fibroblast-pipeline/gene-therapy-dystrophic-epidermolysis-bullosa/. live.
  25. Web site: Tucker. Nicole. May 8, 2020. FDA Grants RMAT Designation to Ilixadencel in Metastatic RCC. 2021-07-01. Targeted Oncology.
  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. 2021-07-01. GlobeNewswire News Room. en. 2021-07-09. https://web.archive.org/web/20210709181828/https://www.globenewswire.com/news-release/2018/10/11/1620273/0/en/Iovance-Biotherapeutics-Reports-Results-from-FDA-End-of-Phase-2-meeting-and-Provides-Updates-About-the-Company-s-Clinical-Program.html. live.
  27. Web site: Magenta Therapeutics Announces FDA Regenerative Medicine Advanced Therapy (RMAT) Designation Granted to MGTA-456 for the Treatment of Inherited Metabolic Disorders – Magenta Therapeutics. 2021-07-01. investor.magentatx.com. en. 2021-07-09. https://web.archive.org/web/20210709183107/https://investor.magentatx.com/news-releases/news-release-details/magenta-therapeutics-announces-fda-regenerative-medicine/. live.
  28. Web site: 2020-09-22. Medeor Therapeutics' Transplant Immune Tolerance Therapy Receives Regenerative Medicine Advanced Therapy Designation from FDA. 2021-07-02. www.businesswire.com. en. 2021-07-09. https://web.archive.org/web/20210709181659/https://www.businesswire.com/news/home/20200922005091/en/Medeor-Therapeutics%E2%80%99-Transplant-Immune-Tolerance-Therapy-Receives-Regenerative-Medicine-Advanced-Therapy-Designation-from-FDA. live.
  29. Web site: 2020-04-20. Mustang Bio Receives Advanced Therapy Medicinal Product Classification from European Medicines Agency for MB-107 Lentiviral Gene Therapy for X-Linked Severe Combined Immunodeficiency. 2021-07-02. AP NEWS. en. 2021-07-09. https://web.archive.org/web/20210709182108/https://apnews.com/press-release/Globe%20Newswire/d7067ceb9892b22170428852a1e4d09e. live.
  30. Web site: 2018-11-27. Rocket Pharmaceuticals Receives FDA Regenerative Medicine Advanced Therapy (RMAT) and Fast Track Designations for RP-L102 Gene Therapy for Fanconi Anemia. 2021-07-02. www.businesswire.com. en. 2021-07-09. https://web.archive.org/web/20210709182619/https://www.businesswire.com/news/home/20181127005245/en/Rocket-Pharmaceuticals-Receives-FDA-Regenerative-Medicine-Advanced-Therapy-RMAT-and-Fast-Track-Designations-for-RP-L102-Gene-Therapy-for-Fanconi-Anemia. live.
  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. 2021-07-02. GlobeNewswire News Room. en. 2021-07-09. https://web.archive.org/web/20210709182629/https://www.globenewswire.com/news-release/2018/06/21/1527729/36461/en/Voyager-Therapeutics-Announces-FDA-Regenerative-Medicine-Advanced-Therapy-RMAT-Designation-Granted-for-VY-AADC-for-the-Treatment-of-Parkinson-s-Disease.html. live.
  32. Web site: 2021-03-09. Rocket Pharmaceuticals Receives FDA Regenerative Medicine Advanced Therapy Designation for RP-L201 Gene Therapy for Leukocyte Adhesion Deficiency-I. 2021-07-02. www.businesswire.com. en. 2021-07-09. https://web.archive.org/web/20210709184516/https://www.businesswire.com/news/home/20210309005362/en/Rocket-Pharmaceuticals-Receives-FDA-Regenerative-Medicine-Advanced-Therapy-Designation-for-RP-L201-Gene-Therapy-for-Leukocyte-Adhesion-Deficiency-I. live.
  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. 2021-07-02. GlobeNewswire News Room. en. 2021-07-01. https://web.archive.org/web/20210701215927/https://www.globenewswire.com/news-release/2019/07/29/1892716/0/en/Orchard-Therapeutics-Announces-FDA-Regenerative-Medicine-Advanced-Therapy-RMAT-Designation-Granted-for-OTL-103-for-the-Treatment-of-Wiskott-Aldrich-Syndrome.html. live.
  34. Web site: 2024-06-12. Novartis' Kymriah® Wins Latest FDA RMAT (42 Announced). 22 April 2020. BioInformant. 2022-11-27. https://web.archive.org/web/20221127155904/https://bioinformant.com/novartis-kymriah-rmat/. live.
  35. Center for Biologics Evaluation and Research. 2021-04-05. Cumulative CBER Regenerative Medicine Advanced Therapy (RMAT) Designation Requests Received by Fiscal Year. FDA. en. 2021-06-25. 2021-07-26. https://web.archive.org/web/20210726220622/https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/cumulative-cber-regenerative-medicine-advanced-therapy-rmat-designation-requests-received-fiscal. live.

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