Mesoblast is resubmitting its BLA with new CMC, survival, and mechanism of action data on the therapy and phase 3 trial.
Mesoblast has resubmitted a biologics license application (BLA) for remestemcel-L, its mesenchymal stromal cell therapy for treating steroid-refractory acute graft versus host disease (SR-aGVHD) in children, almost 4 years after it had previously initiated a rolling BLA for the therapy.1
“There is an urgent need for a therapy that improves the dismal survival outcome in children with SR-aGVHD” Silviu Itescu, MBBS, FRACP, chief executive officer and managing director, Mesoblast, said in a statement.1 “Our team has worked tirelessly over the past 2 years to provide a comprehensive response to the FDA. We are grateful for the agency’s active dialogue and constructive feedback that will ensure a high bar is met in terms of product consistency and predictability of clinical outcomes.”
Mesoblast had initially submitted a rolling BLA in May 2019 for remestemcel-L based off of phase 3 trial (NCT02336230) 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.2,3
Mesoblast later met with the FDA at the end of 2021 and reached 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.4 The company remained in communication with the FDA and in October 2022, submitted new CMC information to the agency.5
The resubmission includes the new data, which consists of new long-term and durability data from the phase 3 trial through at least 4 years; new efficacy data demonstrating remestemcel-L's benefit in high-risk disease and survival data versus control; new data using the validated potency assay that correlates the therapy’s mechanism of action with its in vivo activity; new CMC data that shows that manufacturing changes to the therapy prior to phase 3 yielded increased efficacy and survivalwith low variability, high consistency, and high reproducibility; and new specifications for a commercial product of the therapy to ensure a consistent therapeutic benefit with the trial product.1 Under remestemcel-L's fast track designation, the BLA resubmission will be reviewed for up to 6 months by the FDA prior to regulatory decision.
The most recent data from the phase 3 trial were released in November 2022 and demonstrated the long-term survival benefit in treated children through 4 years.6 These children had an overall survival (OS) rate of 63% at 1 year, 51% at 2 years, and 49% at 4 years (median, 2-3 years) in comparison to recently published control data in children and adults (using best available therapy or ruoxitinib for adults) in which OS rate was 40-49% at 1 year and 25-38% at 2 years (median, 6.5-11.1 months). The comparison also favors the study cohort, since 88% of these children had severe disease with the highest mortality risk, defined by either IBMTR Grade C/D or Glucksberg Grade 3/4, compared to 22% to 68% of patients in control studies having severe disease.
“These exciting long-term results provide further evidence of remestemcel-L’s potential as a highly effective treatment for SR-aGVHD in children” principal investigator Joanne Kurtzberg, MD, Jerome Harris Distinguished Professor of Pediatrics and Professor of Pathology, Duke University Medical Center, commented on the data.6 “Responses are durable, reducing mortality of this often lethal complication of hematopoietic stem cell transplantation.”