The FDA has informed Mesoblast that the available data from the phase 3 MSB-GVHD001 clinical trial (NCT02336230) is sufficient for the submission of a biologics license application (BLA) for its allogeneic mesenchymal stromal cell therapy, remestemcel-L, for the treatment of children with steroid-refractory acute graft versus host disease (SR-aGVHD).1
The company noted that it plans to submit the BLA in the second quarter of 2024. Mesoblast stated it will attempt to address the remaining product characterization issues prior to the submission.
“We thank the agency for their collaborative approach,” Silviu Itescu, MBBS, FRACP, the chief executive officer of Mesoblast, said in a statement.1 “The responses and guidance from FDA are clear and provide us with a high level of confidence to refile our BLA for remestemcel-L in children with SR-aGVHD.”
The new BLA submission will constitute one of 2 BLA resubmissions for remestemcel-L.2 Mesoblast originally submitted a rolling BLA in May 2019 for remestemcel-L based on MSB-GVHD001 trial data, after which the company received a complete response letter (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.3,4
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Timeline of Events for Remestemcel-L
- May 2019: Mesoblast submits a rolling BLA for remestemcel-L.
- October 2020: Mesoblast receives CRL recommending additional studies and scientific rationale for potency measurements.
- October 2022: Mesoblast agrees with FDA on additional data and CMC issues, and submits new information.
- February 2023: Mesoblast resubmits the BLA for remestemcel-L.
- March 2023: FDA accepts the resubmission for filing.
- August 2023: FDA issues another CRL requiring more data for marketing approval. Mesoblast announces plans for A study in high-risk adults with SR-aGVHD.
- September 2023: Mesoblast reports outcomes from a Type A meeting with the FDA, establishing the path forward.
- March 2024: FDA informs Mesoblast that data from the phase 3 MSB-GVHD001 clinical trial is sufficient for BLA submission for remestemcel-L in children with SR-aGVHD. Mesoblast plans to submit the BLA in the second quarter of 2024.
Mesoblast later met with the FDA at the end of 2021, reaching an agreement 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. It then submitted new information to the agency in October 2022.5
The BLA was resubmitted for the first time in February 2023 with the resubmission accepted for filing by the FDA in March 2023,6,7 although another CRL was issued by the FDA in August 2023.8 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%. In September 2023, Mesoblast announced outcomes from a Type A meeting with the FDA.9
"We had a very productive meeting with the FDA’s review team, allowing us to establish the path forward for potential approval of remestemcel-L in SR-aGVHD,” Itescu said in a September 2023 statement.9 “We are gathering the additional potency assay data required to demonstrate the ability of Mesoblast’s potency assay to show both the product used in the phase 3 trial in children and the product made for commercial release are standardized. In parallel, we are focused on initiating a registration trial in adults in partnership with world-leading investigators at the Blood and Marrow Clinical Trials Network.”
REFERENCES
1. United States Food & Drug Administration (FDA) notifies mesoblast that available clinical data from phase 3 trial appear sufficient to support BLA submission for remestemcel-L in children with steroid refractory acute graft versus host disease (SR-aGVHD). News release. Mesoblast Limited. March 25, 2024. Accessed March 26, 2024. https://investorsmedia.mesoblast.com/static-files/cbb18b5c-3dea-42bf-877d-599dcc242c44
2. Key outcomes from FDA Type A meeting and Mesoblast next steps to achieve RYONCIL approval. News release. Mesoblast. September 21, 2023. Accessed March 26, 2024. https://www.globenewswire.com/news-release/2023/09/21/2746995/0/en/Key-Outcomes-From-FDA-Type-A-Meeting-and-Mesoblast-Next-Steps-to-Achieve-RYONCIL-Approval.html
3. 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 March 26, 2024. Accessed March 26, 2024. https://investorsmedia.mesoblast.com/static-files/4232b4cb-8942-476b-b002-cda7e3c42cc6
4. 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 March 26, 2024. https://www.asx.com.au/asxpdf/20201002/pdf/44n8xx22956c1c.pdf
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 March 26, 2024. 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. 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 March 26, 2024. 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
7. 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 March 26, 2024.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/
8. 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 March 26, 2024. https://investorsmedia.mesoblast.com/static-files/422cd6da-a0b9-49cf-a177-7fd106f111f2
9. Key outcomes from FDA Type A meeting and Mesoblast next steps to achieve RYONCIL approval. News release. Mesoblast. September 21, 2023. Accessed March 26, 2024. https://www.globenewswire.com/news-release/2023/09/21/2746995/0/en/Key-Outcomes-From-FDA-Type-A-Meeting-and-Mesoblast-Next-Steps-to-Achieve-RYONCIL-Approval.html
