FDA Accepts Resubmitted BLA for Remestemcel-L in Pediatric SR-aGVHD

Acceptance of this application follows the resubmission of the BLA for remestemcel-L earlier in July 2024, which was intended to address outstanding Chemistry, Manufacturing, and Control items.

The FDA has accepted a resubmitted biologics license application for remestemcel-L (Ryoncil) as a treatment for pediatric patients with steroid-refractory acute graft-versus-host-disease (SR-aGVHD), according to a press release from the developer, Mesoblast Limited.¹

Acceptance of this application follows the resubmission of the BLA for remestemcel-L earlier in July 2024, which was intended to address outstanding Chemistry, Manufacturing, and Control items.² Resubmission of the application followed a complete response letter (CRL) for remestemcel-L in August 2023.³ The regulatory agency has accepted the resubmitted BLA as a complete response and assigned a Prescription Drug User Fee Act date of January 7, 2025, for remestemcel-L in this population.

“We are pleased that the 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 at Mesoblast, said in the press release.¹

Previously, the FDA issued a complete response letter (CRL) for remestemcel-L in October 2020 and requested further findings from an additional randomized trial to verify the benefits of this agent.⁴ Developers subsequently resubmitted the BLA for remestemcel-L in January 2023, which included data from the phase 3 MSB-GVHD001 study (NCT02336230).⁵ The FDA accepted the resubmission of the BLA based on data from the aforementioned trial in March 2023.⁶

Supporting data for remestemcel-L in pediatric SR-aGVHD came from the phase 3 MSB-GVHD001 trial and phase 3 MSB-GVHD002 (NCT02652130) trial—a follow-up safety extension study.

At day 28, remestemcel-L produced an overall response rate (ORR) of 70.4%, exceeding the pre-specified control value of 45% and meeting the trial’s primary end point (P = .0003).⁷ The rates of survival at day 100 were 87% in patients with a response at day 28 vs 47% in those without (P = .0001).

Investigators also compared the outcomes observed in the phase 3 trial with those of a control group of pediatric patients from the Mount Sinai Acute GVHD International Consortium (MAGIC) who were treated with the best available therapy. On day 28, responses occurred in 70% of those in the phase 3 trial and 43% in the consortium. The respective survival rates at day 100 were 74% vs 57% in each group.

According to findings from a 4-year study by the Center for International Blood and Marrow Transplant Research (CIBMTR), the 6-month survival rate among 51 evaluable patients with SR-aGVHD included in the phase 3 trial was 67%. Additionally, survival occurred in 63% at 1 year, 51% at 2 years, and 49% at 4 years.

Patients enrolled on the single-arm; prospective phase 3 trial were assigned to receive remestemcel-L intravenously at 2 x 10⁶ mesenchymal stem cells (MSC)/kg twice per week for 4 consecutive weeks.⁸

The trial’s primary end point was ORR 28 days after the initiation of the study treatment. Secondary end points included overall survival at 100 days and ORR at 56 days and 100 days after beginning therapy.

Patients 2 months to 17 years old with grade B to D acute GVHD requiring management with corticosteroid systemic therapy were eligible for enrollment on the trial. Having a Karnofsky or Lanksy performance status of 30 or higher, adequate renal function, and progression on prior steroid treatment were additional requirements for enrollment. Those with grade B aGVHD with involvement only in the skin, prior second-line therapy for aGVHD, or prior systemic treatment apart from steroids and prophylactic agents were ineligible to enroll on the trial.

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 24, 2024. https://tinyurl.com/yj5wyx66
2. Mesoblast resubmits biologics license application (BLA) with United States Food & Drug Administration (FDA) for approval of Ryoncil® in children with steroid-refractory acute graft-versus-host disease (SR-aGVHD). News release. Mesoblast Limited. July 9, 2024. Accessed July 24, 2024. https://tinyurl.com/bdjw9y3v
3. 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. News release. Mesoblast Limited. August 3, 2023. Accessed July 24, 2024. bit.ly/3OM2How
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 1, 2020. Accessed July 24, 2024. bit.ly/3l4RjI3
5. 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 Limited. January 31, 2023. Accessed July 10, 2024. yhoo.it/3jvB7Pp
6. 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 July 10, 2024. bit.ly/3ZM6qFi
7. Kurtzberg J, Abdel-Azim H, Carpenter P, et al. A phase 3, single-arm, prospective study of remestemcel-L, ex vivo culture-expanded adult human mesenchymal stromal cells for the treatment of pediatric patients who failed to respond to steroid treatment for acute graft-versus-host disease. Biol Blood Marrow Transplant. 2020;26(5):845-854. doi:10.1016/j.bbmt.2020.01.018.
8. 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. Accessed July 24, 2024. https://tinyurl.com/yc3eena4