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FDA
The FDA has accepted the resubmission of a biologics license application (BLA) seeking the 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.