The FDA’s Office of Therapeutic Products has accepted a resubmission of the biologics license application (BLA) for remestemcel-L for the treatment of pediatric patients with steroid-refractory, acute graft-vs-host-disease.
The FDA’s Office of Therapeutic Products has accepted a resubmission of the biologics license application (BLA) for remestemcel-L (Ryoncil) for the treatment of pediatric patients with steroid-refractory, acute graft-vs-host-disease (aGVHD).1
The BLA resubmission contained new clinical and biomarker data, including from a propensity matched study of children with high-risk disease, based on the validated MAP biomarker score, comparing outcomes in 25 children from Mesoblast Limited’s single-arm phase 3 MSB-GVHD001 trial (NCT02336230) and 27 control children treated with various biologics, including ruxolitinib (Jakafi), from the Mount Sinai Acute GVHD International Consortium (MAGIC) database.
Findings from the study showed that 67% of high-risk children treated with remestemcel-L responded to treatment within 28 days and were alive after 180 days compared with 10% of patients in both categories in the MAGIC group.
The resubmission of the BLA also included results from a 4-year survival study performed by the Center for International Blood and Marrow Transplant Research in 51 evaluable patients with steroid-refractory aGVHD who were enrolled in the phase 3 trial. This study showed that remestemcel-L elicited durable responses, with 1- and 2-year survival rates of 63% and 51%, respectively, in a group of children with predominantly grade C/D disease (89%), with an expected 2-year survival rate of just 25% to 38% using best available therapy.
Mesoblast Limited, the drug’s developer, said the FDA considered the resubmission to be a complete response, and a target action date of August 2, 2023, has been set under the Prescription Drug User Fee Act (PDUFA).
“Over the last two years we have worked tirelessly to address the issues previously raised by FDA. We look forward to working closely with the agency over the review period with the aim to make remestemcel-L available as a therapy for children suffering from SR-aGVHD,” Silviu Itescu, chief executive of Mesoblast Limited, stated in a news release.
In April 2020, the FDA granted priority review designation to the initial BLA for remestemcel-L for the treatment of pediatric patients with steroid-refractory aGVHD.2 Data from Study 275 (NCT00759018) showed that among 241 children with aGVHD treated with remestemcel-L, the 28-day overall response rate (ORR) was 65.1% (n = 157), including a complete response rate of 14.1% and a partial response rate of 51.3%.3
The ORR at day +28 was 72.9%, 67.1%, and 60.8% for patients with grade B, grade C, and grade D aGVHD, respectively. At day +100, the overall survival (OS) rate was 66.9%. The OS rate through day +100 was significantly higher among patients who had a day +28 response compared with those who did not respond (82.1% vs 38.6%; P < .001).
In August 2020, the FDA’s Oncologic Drugs Advisory Committee voted 8 to 2 in favor of approving remestemcel-L in this setting after discussing whether data from the single-arm MSB-GVHD001 trial was enough to establish the efficacy of the drug.4
However, in October 2020, the FDA issued a complete response letter (CRL) to Mesoblast Limited, requesting additional data from at least 1 randomized, controlled study in adult and/or pediatric patients with steroid-refractory aGVHD.5
In October 2022, the company announced that it had submitted new information to the FDA regarding the items identified in the CRL, and in January 2023, the BLA was formally resubmitted to the regulatory agency.6,7
The company said the resubmitted BLA also contained new analyses of prospectively obtained data relating the validated potency assay, which was used to release product for the phase 3 trial and reflects the primary mechanism of action, as well as new analyses of clinical data obtained prospectively relating to manufacturing changes implemented during product development, prior to the phase 3 study, to progressive increases in potency and to improved survival outcomes of children with steroid-refractory aGVHD treated with remestemcel-L under expanded access.1
The BLA also included new data showing that the validated potency assay has low variability and can adequately demonstrate manufacturing consistency and reproducibility. The company also established a new specification for release of commercial product based on extensive clinical data to provide assurance that future batches of remestemcel-L will have attributes supportive of expected survival outcomes.