FDA Issues CRL for Mesoblast's Allogeneic Stem Cell Therapy for SR-Graft-Versus-Host-Disease

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Four years after submitting its initial BLA for remestemcel-L for steroid-refractory acute graft versus host disease, Mesoblast has encountered another hurdle toward possible approval.

Silviu Itescu, MBBS, FRACP, CEO and managing director of Mesoblast

Silviu Itescu, MBBS, FRACP

The FDA has issued another complete response letter (CRL) to Mesoblast for its biologics license application (BLA) for remestemcel-L mesenchymal stromal cell therapy for treating steroid-refractory acute graft versus host disease (SR-aGVHD) in children under the age of 12 years.1

In the CRL, the agency noted that it requires more data to support marketing approval for the allogeneic off-the-shelf cellular medicine. To obtain these data, Mesoblast stated in an announcement that it will conduct a targeted, controlled study in high-risk adults with the greatest mortality in SR-aGVHD, for whom existing therapy has not improved outcomes and 90-day survival remains as low as 20% to 30%. This, the company claimed, is in line with its ongoing strategy that "envisioned a sequenced progression from pediatric to adult SR-aGVHD indications." Adults are the vast majority (up to 80%) of the SR-aGVHD patient population.

“FDA’s inspection of our manufacturing process resulted in no observed concerns, the agency raised no safety issues across more than 1300 patients who have received remestemcel-L to date, and acknowledged improvements to our potency assay," Silviu Itescu, MBBS, FRACP, CEO and managing director of Mesoblast, said in a statement.1 "We remain steadfast in making remestemcel-L available to both children and adults suffering from this devastating disease, and have received substantial clarity in how to bring this much-needed product to these patients”.

Mesoblast noted that it has begun working with leading investigators at various centers of excellence in the United States to establish the adult follow-on study protocol, and will seek alignment with FDA on the trial design for the adult study at a Type A meeting within 45 days.

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Previously, the FDA accepted Mesoblast’s BLA for review in March 2023 after the company resubmitted the application in early February 2022, nearly 4 years after it initiated the rolling submission process for the cell therapy.2,3,4 The company received an earlier CRL in October 2020 that recommended that Mesoblast conduct at least 1 additional randomized, controlled study in adults and/or children to provide further evidence of the effectiveness of remestemcel-L for SR-aGVHD and identified a need for further scientific rationale to demonstrate the relationship of potency measurements to the product’s biologic activity.2,3

Mesoblast later reached an agreement with the FDA that additional data from the phase 3 trial, including survival and biomarkers of in vivo activity, were sufficient in establishing the relevance of in vitro immunomodulatory activity to in vivo clinical effect of the therapy and that the company had an acceptable approach to address chemistry, manufacturing and controls (CMC) issues and submitted these data to the agency.6

The data from the phase 3 trial (NCT02336230) supporting the BLA submission are current as of November 2022 and demonstrated a long-term survival benefit in treated children through 4 years.6 Treated children had an overall survival (OS) rate of 63% at 1 year, 51% at 2 years, and 49% at 4 years (median, 2-3 years) in comparison with control data in children and adults (using best available therapy or ruoxitinib for adults) in which the OS rate ranged from 40% to 49% at 1 year and 25% to 38% at 2 years (median, 6.5-11.1 months). Furthermore, in the therapy’s favor, 88% of these children had severe disease with the highest risk of mortality—defined by either International Bone Marrow Transplant Registry Grade C/D or Glucksberg Grade 3/4—compared with 22% to 68% of patients in control studies having severe disease.

REFERENCES
1. Mesoblast receives complete response from U.S. Food and drug
Administration for biologics license application for steroidrefractory acute graft versus host disease in children. News release. Mesoblast Limited. August 4, 2023. Accessed August 4, 2023. https://investorsmedia.mesoblast.com/static-files/422cd6da-a0b9-49cf-a177-7fd106f111f2
2. FDA Accepts Mesoblast’s Resubmission of the Biologic License Application for Remestemcel-L In Children with Steroid-Refractory Acute Graft Versus Host Disease as a Complete Response and Sets Goal Date of August 2, 2023. News release. Mesoblast Limited. March 8, 2023. Accessed August 2, 2023. https://www.biospace.com/article/releases/fda-accepts-mesoblast-s-resubmission-of-the-biologic-license-application-for-remestemcel-l-in-children-with-steroid-refractory-acute-graft-versus-host-disease-as-a-complete-response-and-sets-goal-date-of-august-2-2023/
3. Mesoblast resubmits biologic license application (BLA) to FDA for Remestemcel-L in children with steroid-refractory acute graft versus host disease (Sr-aGVHD). News release. Mesoblast. February 1, 2023. Accessed August 2, 2023. https://www.globenewswire.com/news-release/2023/01/31/2599031/0/en/Mesoblast-Resubmits-Biologic-License-Application-BLA-to-FDA-for-Remestemcel-L-in-Children-With-Steroid-Refractory-Acute-Graft-Versus-Host-Disease-Sr-aGVHD.html
4. Mesoblast initiates rolling submission of biologics license application (BLA) to U.S. FDA for remestemcel-L in the treatment of acute graft versus host disease. News release. Mesoblast. May 30, 2019. Accessed August 2, 2023. https://investorsmedia.mesoblast.com/static-files/4232b4cb-8942-476b-b002-cda7e3c42cc6
5. Mesoblast receives complete response letter from the FDA for biologics license application for steroid-refractory acute graft versus host disease in children. News release. Mesoblast. October 1, 2020. Accessed August 2, 2023. https://www.asx.com.au/asxpdf/20201002/pdf/44n8xx22956c1c.pdf
6. Mesoblast provides update following meeting with FDA’S OTAT on remestemcel-L for children with acute graft versus host disease. News release. Mesoblast. December 30, 2021. Accessed August 2, 2023. https://investorsmedia.mesoblast.com/static-files/71f7b715-a029-47dc-af8e-8c8f09a4a96f
5. Mesoblast submits new information to FDA IND file in response to items in the CRL to the remestemcel-L BLA for SR-aGVHD. News release. Mesoblast. October 2, 2022. Accessed August 2, 2023. https://www.globenewswire.com/news-release/2022/10/02/2526431/0/en/Mesoblast-Submits-New-Information-to-FDA-IND-File-in-Response-to-Items-in-the-CRL-to-the-Remestemcel-L-BLA-for-SR-aGVHD.html
6. Children treated with remestemcel-L show long-term survival through four years in steroid-refractory acute graft versus host disease (SR-aGVHD). News release. Mesoblast. November 22, 2022. Accessed August 2, 2023. https://investorsmedia.mesoblast.com/static-files/41576351-fa4d-4e1c-93ad-2b822145238f
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