RMAT Designations in Neurology Lead the Way for Gene Therapy Development


Therapies designed to treat neurologic conditions have made up 25% of the submissions to the FDA for a Regenerative Medicine Advanced Therapy designation.

Dr Raj Puri

Raj K. Puri, MD, PhD, the director of the Division of Cellular and Gene Therapies Office of Tissues and Advanced Therapeutics (OTAT) at the FDA

Raj K. Puri, MD, PhD

When the 21st Century Cures Act was signed into law on December 13, 2016, the Regenerative Medicine Advanced Therapy (RMAT) designation offered a new expedited pathway for pharmaceutical developments to gain approval from the FDA.

The pathway exists to facilitate the development and expedite the review of regenerative medicine therapies to treat, modify, reverse, or cure a serious condition and fill an unmet medical need for such conditions. In order to meet the qualifying criteria, a drug must fulfill the following prerequisites:

  1. It is a regenerative medicine therapy
  2. It is intended to treat, modify, reverse, or cure a serious condition
  3. Preliminary clinical evidence indicates that the regenerative medicine therapy has the potential to address unmet medical needs for such condition.

As of November 6, according to the FDA’s own count, 28 therapies have been granted an RMAT designation, with 8 more applications pending. All in all, 80 submissions have been put in front of the agency. The field of neurology has led the way in submissions, with 20 therapies put in front of the FDA.1

Raj K. Puri, MD, PhD, the director of the Division of Cellular and Gene Therapies Office of Tissues and Advanced Therapeutics (OTAT) at the FDA, said at the Society for Immunotherapy of Cancer’s 33rd Annual Meeting, in Washington, DC, that a number—44 to be exact—have been denied the designation due to “administrative reasons, including having an inactive Investigational Drug Application or a lack of preliminary evidence; as well as chemistry, manufacturing, and control reasons; or insufficient preliminary clinical evidence, such as study design issues and inconsistent results.”

The FDA does not announce when a company has been granted an RMAT designation, and currently, only 22 manufacturers have made public that their product received the label. Of those, 7 fall within the field of neurology.


Developer: Asterias Biotherapeutics

Designation granted: October 2, 2017

Treats: Spinal cord injury

Twelve-month data from the phase 1/2a SCiStar study was submitted to the FDA to support the application. That data showed that 67% (4 of 6 patients) of Cohort 2, which consisted of patients with ASIA Impairment Scale [AIS] classification of AIS-A injuries, who were administered 10 million AST-OPC1 cells, had recovered 2 or more motor levels on at least 1 side. Notably, this is more than double the rates of recovery seen in both matched historical controls and published data in a similar population, according to Asterias.2

In July 2018, Asterias announced additional data from the SCiStar study, which included a promising safety profile, with no serious adverse events thus far. As well, 12-month MRI results-to-date for 94% (17 of 18 patients) of Cohorts 2, 3, and 4 subjects showed evidence that AST-OPC1 cells have durably engrafted at the injury site and helped to prevent cavitation. Additionally, all 4 of the subjects in Cohort 5 had MRI scans at 6 months that were consistent with the formation of a tissue matrix at the injury site. At 12 months, all 6 of the subjects in Cohort 3 recovered at least one motor level on at least one side, while 83% (5 of 6 patients) in Cohort 4 experienced the same. All in all, 94% (17 of 18 patients) in Cohorts 2 to 4 recovered 2 or more motor levels on at least 1 side.3


Developer: Athersys

Designation granted: October 5, 2017

Treats: Stroke, other neurologic conditions

Phase 2 data from the MASTERS trial showed that the administration of multipotent adult progenitor cells was safe and well tolerated in 129 patients with acute ischemic stroke, with 99% (64 of 65) of patients in the multipotent adult progenitor cell group compared to 97% (59 of 61) in the placebo group experiencing a treatment-emergent adverse event. Although, there was no significant difference between the group receiving MultiStem and those receiving placebo in global stroke recovery at 90 days (odds ratio, 1.08; 95% CI, 0.55 to 2.09; P = .83).4

Currently, the therapy is set to be assessed in a phase 3 trial, MASTERS 2 (NCT03545607), which will examine the therapy in those who have suffered an acute ischemic stroke in the previous 18 to 36 hours. It is aiming to enroll 300 participants and is estimated to be completed in September 2021.


Developer: Cellvation; Fortress Biotech

Designation granted: November 8, 2017

Treats: Traumatic brain injury

The autologous bone marrow mononuclear cell therapy has shown positive results in a trio of phase 1 trials, which all supported the use of the therapy to treat traumatic brain injury (TBI). In the first trial, Dichotomized Glasgow Outcome Score at 6 months showed 70% with good outcomes and 30% with moderate to severe disability.5 In the second results showed that CEVA101 was associated with a reduction in treatment intensity required to manage intracranial pressure (ICP) associated severity of organ injury and duration of ICP monitoring following severe TBI, as compared to the matched control group. The duration of ICP monitoring was 8.2 ±1.3 days in the CEVA101 group, and 15.6 ±3.5 days (P = .03) in the control group.6 The third trial, a safety assessment, showed that no adverse events were associated with or temporally related to the stem cell harvest or infusion of CEVA101. As well, there were no subject deaths or withdrawals due to adverse events.7

Currently, the therapy is being assessed in 2 phase 2 trials. One study aims to determine the safety and efficacy of CEVA101 on brain structure and neurocognitive functional outcomes after severe traumatic brain injury in children 5 to 17 years of age (NCT01851083). The other aims to determine the safety and efficacy of CEVA101 on brain structure and neurocognitive functional outcomes after severe traumatic brain injury in adults 18 to 55 years of age (NCT02525432).


Developer: Capricor

Designation granted: February 5, 2018

Treats: Duchenne muscular dystrophy

In addition to promising preclinical findings, which showed improved heart function in models of Duchenne muscular dystrophy (DMD), results of the phase 1/2 HOPE-Duchenne trial showed not only 7% improvement in heart scarring, but some improvement in skeletal muscle function in 8 of 9 patients with the most severe disease, compared to none who received standard therapy.8-9

Currently, Capricor is recruiting patients for a phase 2 follow-up trial, HOPE-2 (NCT03406780). With an estimated completion date of April 2020, it is aiming to enroll 84 participants to assess the safety and efficacy of CAP-1002 with a primary end point of change in the mid-level dimension of the Performance of the Upper Limb (PUL) in 12 months.


Developer: Abeona Therapeutics

Designation granted: April 23, 2018

Treats: Mucopolysaccharidosis type IIIA

At the 21st Annual Meeting of the American Society for Gene and Cell Therapy in Chicago, Illinois, data were presented showing a 25.8% reduction of CSF heparan sulfate in cohort 1 (n = 3), a 52.1% reduction in cohort 2 (n = 3), and a 67.1% reduction in cohort 3 (n = 4) at 30 days. At day 180, cohorts 1 to 3 saw reductions of 58.7%, 60.5%, and 83.3%, respectively. At day 360, cohorts 1 and 2 saw respective reductions of 69.3% and 65.7%. Reductions in urine heparan sulfate were demonstrated at day 180, of 29.2% in cohort 1, a 57.6% in cohort 2, and 75% in cohort 3. At the day 360 assessment, it demonstrated 29.2% reduction in cohort 1 and a 45.1% reduction in cohort 2. At the day 540 assessment, it demonstrated a 30% reduction in cohort 1.10

Currently, Abeona is recruiting patients for a phase 1/2 trial (NCT02716246) of the therapy, also known as scAAV9.U1a.hSGSH, in 16 participants with mucopolysaccharidosis (MPS) IIIA. The primary end point is the development of unacceptable toxicity within 2 years. The trial is expected to complete in December 2020.


Developer: Voyager Therapeutics

Designation granted: June 21, 2018

Treats: Parkinson Disease

Phase 1b data showed that the therapy demonstrated durable, dose-dependent, and time-dependent improvement across several measures of motor function, including patients reports, Parkinson rating scales, and activities of daily life, after a single administration. It reduced Parkinson medication use by 14% to 42% across 3 of the patient groups. Moreover, it was found to increase patients’ on-time without dyskinesia from 10.5 hours to 13.5 hours. Coverage of the therapy was 21% of the volume of the putamen with in Cohort 1, 34% in Cohort 2, and 42% in Cohort 3.11 A second phase 1 trial (NCT03065192) assessing safety and efficacy is currently underway, expected to complete in December 2021.

In January 2018, Voyager announced that the FDA granted it clearance to initiate a phase 2/3 clinical trial of the therapy (NCT03562494), which is currently enrolling. The goal for the trial is 42 patients, with several primary end points, including change in patient-rated motor fluctuations, the percentage of coverage of within the putamen at the time of administration, the change in AADC enzyme activity, and several safety measures. The trial is expected to complete in December 2020.


Developer: Audentes

Designation granted: August 21, 2018

Treats: X-Linked Myotubular Myopathy

Early phase, mouse model studies showed promising results for the therapy, with increased expression of the MTM1 gene, as well as improvement in muscle architecture, reversal of muscle hypotrophy, improvement in muscle strength, and an improvement in overall survival.12 After the therapy was granted RMAT designation in August 2018, Audentes announced interim data from ASPIRO, a phase 1/2 trial, which included information from 6 patients. That trial is still ongoing (NCT03199469).

The results showed a 93% (27 points) improvement from baseline in CHOP-INTEND scores for patient 1 and a 42% (19 points) improvement for patient 2 at 48 weeks. It also showed a 47% (17 points) improvement for patient 5 at week 24, and a 33% (13 points) improvement for patient 6 and a 23% (10 points) improvement for patient 7 at week 16. As well, it showed a 53% (19 points) improvement for patient 8 at week 4.13 Since the previous update from Audentes in May 2018, there were no treatment-emergent serious adverse events, and the therapy was well tolerated with a manageable safety profile to date at doses up to 3x1014 vg/kg.


1. Puri RJ. FDA Regulatory Updates: Cell and Gene Therapies. Presented at: Society for Immunotherapy of Cancer’s 33rd Annual Meeting; November 9, 2018; Washington DC.

2. Asterias Announces Two Significant Developments for Spinal Cord Injury Program [press release]. Fremont, CA: Asterias Biotherapeutics; Published October 2, 2017. asteriasbiotherapeutics.com/inv_news_releases_text.php?releaseid=2303887&date=October+02,+2017&title=Asterias+Announces+Two+Significant+Developments+for+Spinal+Cord+Injury+Program. Accessed November 12, 2018.

3. Asterias Provides 12 Month Cohort 3 and 4 Update for its AST-OPC1 Phase 1/2a Clinical Trial in Severe Spinal Cord Injury [press release]. Fremont, CA: Asterias Biotherapeutics; Published July 31, 2018. globenewswire.com/news-release/2018/07/31/1544437/0/en/Asterias-Provides-12-Month-Cohort-3-and-4-Update-for-its-AST-OPC1-Phase-1-2a-Clinical-Trial-in-Severe-Spinal-Cord-Injury.html. Accessed November 12, 2018.

4. Hess DC, Wechsler LR, Clark WM, et al. Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol. 2017;16(5):360-368. doi: 10.1016/S1474-4422(17)30046-7

5. Cox CS, Baumgartner JR, Hartin MT, et al. Autologous bone marrow mononuclear cell therapy for severe traumatic brain injury in children. Neurosurgery. 2011;68(3):588-600. doi: 10.1227/NEU.0b013e318207734c

6. Liao GP, Hartin MT, Hetz RA, et al. Autologous bone marrow mononuclear cells reduce therapeutic intensity for severe traumatic brain injury in children. Pediatr Crit Care Med. 2015;16(3):245-255. doi: 10.1097/PCC.0000000000000324

7. Najar M, Krayem M, Meuleman N, Bron D, Lagneaux L. Mesenchymal stromal cells and toll-like receptor priming: a critical review. Immune Netw. 2017;17(2):89-102. doi: 10.4110/in.2017.17.2.89

8. Aminzadeh MA, Rogers RG, Fournier M, et al. Exosome-mediated benefits of cell therapy in mouse and human models of Duchenne muscular dystrophy. Stem Cell Reports. 2018;10(3):942-955. doi: 10.1016/j.stemcr.2018.01.023

9. Victor RG. HOPE-Duchenne randomized clinical trial. Presented at: American Heart Association’s Scientific Sessions; November 15, 2017; Anaheim, California.

10. Abeona Therapeutics Provides Clinical Update on MPS IIIA Gene Therapy Trial at the 21st Annual ASGCT Meeting [press release]. New York City, New York; Cleveland, Ohio; Abeona Therapeutics; May 18, 2018. globenewswire.com/news-release/2018/05/18/1508887/0/en/Abeona-Therapeutics-Provides-Clinical-Update-on-MPS-IIIA-Gene-Therapy-Trial-at-the-21st-Annual-ASGCT-Meeting.html. Accessed November 12, 2018.

11. Voyager Therapeutics Announces Positive Results from Ongoing Phase 1b Trial of VY-AADC01 for Advanced Parkinson’s Disease [press release]. Cambridge, Massachusetts; Voyager Therapeutics; Published September 6, 2017. globenewswire.com/news-release/2017/09/06/1108225/0/en/Voyager-Therapeutics-Announces-Positive-Results-from-Ongoing-Phase-1b-Trial-of-VY-AADC01-for-Advanced-Parkinson-s-Disease.html. Accessed November 12, 2018.

12. Buj-Bello A, Fougerousse F, Schwab Y, et al. AAV-mediated intramuscular delivery of myotubularin corrects the myotubular myopathy phenotype in targeted murine muscle and suggests a function in plasma membrane homeostasis. Hum Mol Genet. 2008;17(14):2132-2143. doi: 10.1093/hmg/ddn112

13. Audentes Therapeutics Presents New Positive Interim Data from ASPIRO, the Phase 1/2 Clinical Trial of AT132 in Patients with X-linked Myotubular Myopathy, at 23rd International Annual Congress of the World Muscle Society [press release]. San Francisco, CA: Audentes Therapeutics; Published October 5, 2018. prnewswire.com/news-releases/audentes-therapeutics-presents-new-positive-interim-data-from-aspiro-the-phase-12-clinical-trial-of-at132-in-patients-with-x-linked-myotubular-myopathy-at-23rd-international-annual-congress-of-the-world-muscle-society-300725065.html. Accessed November 12, 2018.

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