BLA Resubmission Accepted by the FDA for Remestemcel-L in Pediatric Steroid-Refractory aGVHD

The resubmission of a biologics license application (BLA) has been accepted by the FDA, which seeks approval of remestemcel-L (Ryoncil) for the treatment of pediatric patients with steroid-refractory acute graft-vs-host-disease (SR-aGVHD).¹

The BLA, which was resubmitted on July 8, 2024, addressed chemistry, manufacturing, and control issues. In March 2024, the FDA also informed Mesoblast, the developer of remestemcel-L, that clinical data from the phase 3 MSB-GVHD001 trial (NCT02336230) were adequate to support another submission.

“We are pleased that FDA has accepted our BLA resubmission for review and look forward to the potential approval of [remestemcel-L] for children with SR-aGVHD,” Silviu Itescu, MBBS, FRACP, chief executive officer of Mesoblast, stated in a news release.

The initial BLA for remestemcel-L received priority review from the FDA in April 2020, based on pooled data from 3 separate trials of 309 pediatric patients with SR-aGVHD.²

Although the FDA’s Oncologic Drugs Advisory Committee voted 8 to 2 in favor of approving remestemcel-L in this indication in August 2020, the FDA issued a complete response letter (CRL) in October 2020, requesting additional data from at least 1 randomized, controlled study in adult and/or pediatric patients with SR-aGVHD.^3,4

In March 2023, the FDA accepted a BLA resubmission seeking the approval of remestemcel-L for pediatric patients with SR-aGVHD; however, the regulatory agency issued another CRL in August 2023, citing the need for more data to support the approval.^5,6

MSB-GVHD001 enrolled 54 pediatric patients with aGVHD who did not respond to steroids. Results showed that remestemcel-L produced an overall response rate (ORR) of 70.4% at day 28 vs the prespecified ORR of 45% (P = .0003), meeting the study’s primary end point. The 100-day overall survival (OS) rate was 87% for patients who achieved a response at day 28 vs 47% for those who did not have a response at day 28 (P = .0001).¹

Additionally, the 28-day ORR was 70% for remestemcel-L compared with 43% in a matched control group of pediatric patients from the Mount Sinai aGVHD International Consortium (MAGIC) who were treated with best available therapy. The respective 100-day OS rates were 74% vs 57%. A propensity-matched study of outcomes in 25 patients treated during the phase 3 trial and 27 patients from a control group derived from the MAGIC database showed that 67% of high-risk pediatric patients treated with remestemcel-L experienced a response at day 28 and were alive after 180 days vs 10% for the control group.

Furthermore, a 4-year survival study conducted by the Center for International Blood and Marrow Transplant Research that included 51 evaluable patients with SR-aGVHD treated during the phase 3 trial showed that the 6-month, 1-year, 2-year, and 4-year OS rates were 67%, 63%, 51%, and 49%, respectively.

MSB-GVHD001 was a single-arm, prospective trial that enrolled pediatric patients between 2 months and 17 years of age with grade B to D aGVHD requiring systemic therapy with corticosteroids. A lack of response to steroids was required, defined as progression within 3 days or no improvement within 7 days.⁷

Patients with grade B aGVHD who had skin-only involvement were excluded. Additionally, patients were not allowed to have received any second-line therapy for aGVHD prior to enrollment.

All enrolled patients received remestemcel-L at 2 x 10⁶ MSCs/kg twice per week for 4 consecutive weeks, with doses given at least 3 days apart and no more than 5 days apart. Eligible patients were then allowed to received remestemcel-L once per week for 4 consecutive weeks, or twice per week for 4 consecutive weeks in the event of an aGVHD flare up.

ORR at day 28 was the trial’s primary end point, and 100-day OS rate was a secondary end point.

References

1. FDA accepts Mesoblast’s biologics license application (BLA) for Ryoncil in children with steroid-refractory acute graft-versus-host disease (SR-aGVHD). News release. Mesoblast Limited. July 23, 2024. Accessed July 23, 2024. https://investorsmedia.mesoblast.com/static-files/9a696437-abbb-4183-822f-9f74c1da5504
2. FDA accepts Mesoblasts biologics license application for Ryoncil and agrees to priority review. News release. Mesoblast Limited. April 1, 2020. Accessed July 23, 2024. https://investorsmedia.mesoblast.com/static-files/1ee6fcd5-de79-4645-bc09-1f1fe8864047
3. Baird K. FDA session on clinical evidence: BLA 125706: Remestemcel-L. August 13, 2020. Accessed July 9, 2024. https://www.fda.gov/media/141131/download
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 Limited. October 2, 2020. Accessed July 9, 2024. https://investorsmedia.mesoblast.com/static-files/1e259fcb-77ba-470c-91af-1c71e5fa32e0
5. 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 7, 2023.
6. Mesoblast receives complete response from US Food and Drug Administration for biologics license application for steroid-refractory acute graft versus host disease in children. News release. August 3, 2023. Accessed July 23, 2024. https://www.globenewswire.com/news-release/2023/08/04/2718706/0/en/Mesoblast-Receives-Complete-Response-From-U-S-Food-and-Drug-Administration-for-Biologics-License-Application-for-Steroid-Refractory-Acute-Graft-Versus-Host-Disease-in-Children.html
7. A prospective study of remestemcel-L, ex-vivo cultured adult human mesenchymal stromal cells, for the treatment of pediatric participants who have failed to respond to steroid treatment for acute graft-versus-host disease (aGVHD). ClinicalTrials.gov. Updated March 17, 2022. Accessed July 10, 2024. https://clinicaltrials.gov/study/NCT02336230