FDA Refuses to Approve Mesoblast’s Cell Therapy to Treat Graft-Versus-Host Disease in Children

Rare Daily Staff

The U.S. Food and Drug Administration provided Mesoblast a complete response to its Biologics License Application resubmission for the cell therapy remestemcel-L for the treatment of pediatric steroid-refractory acute graft versus host disease and requires more data to support marketing approval.

To obtain the data required, Mesoblast will conduct a targeted, controlled study in the highest-risk adults with the greatest mortality. The company saod this adult study is in line with its overall commercial strategy, which envisioned a sequenced progression from pediatric to adult steroid-refractory acute graft versus host disease (SR-aGVHD) indications. Adults comprise 80 percent of the SR-aGVHD market.

“FDA’s inspection of our manufacturing process resulted in no observed concerns, the agency raised no safety issues across more than 1,300 patients who have received remestemcel-L to date, and acknowledged improvements to our potency assay,” said Mesoblast CEO Silviu Itescu. “We remain steadfast in making remestemcel-L available to both children and adults suffering from this devastating disease and have received substantial clarity in how to bring this much-needed product to these patients.”

Acute graft versus host disease (aGVHD) occurs in approximately 50 percent of patients who receive an allogeneic bone marrow transplant. Over 30,000 patients worldwide undergo an allogeneic BMT annually, primarily during treatment for blood cancers, including about 20 percent in pediatric patients. First-line treatment involves systemic corticosteroids. A significant proportion of patients have severe disease that is refractory to steroids. SR-aGVHD is associated with mortality as high as 90 percent and significant extended hospital stay costs.

Mesoblast intends to enroll adult patients at highest mortality risk with SR-aGVHD where existing therapy has not improved outcomes and 90-day survival remains as low as 20-30 percent. Mesoblast has generated pilot data through its emergency IND program in adults showing a survival benefit with remestemcel-L in this target population. Mesoblast has already been working with leading investigators at various U.S. centers of excellence to establish the adult follow-on study protocol, potentially utilizing established clinical trials networks. The company will seek alignment with FDA on the trial design for the adult study at a Type A meeting within 45 days.

Prior to the resubmission, FDA guided Mesoblast to resolve outstanding chemistry, manufacturing, and controls issues before initiating any additional clinical trial. FDA completed the Pre-License Inspection (PLI) of the manufacturing facility, did not issue any Form 483, and found no objectionable conditions. In addition, FDA acknowledged in the resubmission review that changes implemented appear to improve assay performance relative to the original version of the assay used in the pediatric phase 3 trial.

Mesoblast has successfully met the pre-specified primary endpoint, prospectively agreed with FDA, of a single-arm phase 3 trial in 54 children with SR-aGvHD. While the Oncologic Drugs Advisory Committee of FDA in August 2020 voted 9:1 in favor of remestemcel-L’s efficacy in a pediatric patient population, in September 2020 FDA recommended further steps be undertaken to obtain approval. The application resubmission of January 2023 included long-term follow-up data from the phase 3 trial by the Center for International Blood and Marrow Transplant Research showing 50 percent survival through more than 4 years of follow-up for remestemcel-L treated patients in the phase 3 trial for whom less than 20 percent survival at two years was expected based on disease severity. The resubmission also included a post-hoc propensity matched study showing six-month survival was 67 percent with remestemcel-L vs 10 percent with other unapproved therapies in highest-risk patients as identified using the Mount Sinai Acute GVHD International Consortium. These pediatric data provide further support for use of remestemcel-L in the proposed study in high-risk adults with SR-aGVHD.

Photo: Silviu Itescu, CEO of Mesoblast