Resubmission of BLA to FDA for remestemcel-L in children with steroid refractory acute graft versus host disease.- Mesoblast Ltd.

Survival outcomes have not improved over the past two decades for the most severe forms of SRaGVHD, a life-threatening complication of an allogeneic bone marrow transplant following treatment for blood cancers and other conditions The lack of any approved treatments for children under 12 means that there is an urgent need for a therapy that improves the dismal survival outcomes. If remestemcelL receives FDA approval, it will be the first allogeneic “off-the-shelf” cellular medicine to be approved in the United States, and the first therapy for children under 12 years old with SR-aGVHD.

The resubmission contains substantial new information as required by FDA in the Complete Response Letter (CRL) received in September 2020 to the BLA for remestemcel-L. Mesoblast has maintained an active dialogue with FDA since receiving the CRL and in October 2022 provided a high-level synopsis of the substantial new information under its Investigational New Drug (IND) application for remestemcel=L. FDA granted remestemcel-L Fast Track designation, a process to facilitate the development and expedited review of therapies for serious conditions that fill unmet medical needs, and Priority Review designation, which is given to drugs that treat a serious condition and provide a significant improvement in safety or effectiveness over existing treatments. The BLA resubmission will have a review period up to six months from filing upon acceptance by FDA.

Mesoblast has responded to the CRL and the further guidance it has received from the FDA and has generated and provided new data and analyses in the resubmission which should provide substantial evidence of remestemcel-L's effectiveness in pediatric SR-aGVHD./p

Specifically, the resubmission contains the following: i. new long-term survival data of children enrolled in the Phase III trial showing durability of treatment effect through at least four years, ii. new data showing remestemcel-L’s treatment benefit in high-risk disease activity and on survival in propensity-matched studies of children in the Phase III trial and controls stratified by validated biomarkers for high-risk disease. iii. new analyses of data obtained prospectively showing that the validated potency assay which was in place and used to release product for the 54-patient Phase III clinical trial measures a key product attribute which reflects the primary mechanism of action of remestemcel-L in children with SR-aGVHD, correlates with the product’s in vivo bioactivity, and predicts overall survival outcomes, iv.new analyses of data obtained prospectively relating manufacturing changes during product development prior to Phase III to progressive increases in potency and to improved survival outcomes in larger studies of remestemcel-L under expanded access in children with SRaGVHD, v. new data showing that the validated potency assay has low variability and can adequately demonstrate manufacturing consistency and reproducibility, and vi. establishment of a new specification for release of commercial product based on extensive clinical data which provides assurance that future batches of remestemcel-L will have attributes supportive of expected survival outcomes.

“There is an urgent need for a therapy that improves the dismal survival outcome in children with SRaGVHD” said Dr. Silviu Itescu, Chief Executive of Mesoblast. “Our team has worked tirelessly over the past two 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.”.

The BLA resubmission also contains results of a 4-year survival study performed by the Center for International Blood and Marrow Transplant Research (CIBMTR) on 51 evaluable patients with SR-aGVHD who were enrolled in the Phase III trial. The results demonstrated durability of the early day 180 survival benefits, with 63% survival at 1 year and 51% at 2 years in a group of children with predominantly grade C/D disease (89%) and with expected 2 year survival of just 25-38% using best available therapy.