FDA Receives BLA Resubmission of Remestemcel-L for Pediatric SR-aGVHD

A biologics license application (BLA) for the approval of remestemcel-L (Ryoncil) has been resubmitted to the FDA for the treatment of children with steroid-refractory acute graft-vs-host disease (SR-aGVHD).¹

"Remestemcel-L suppresses activity of allo-reactive T cells that are causing a hyperinflammatory state and attacking various tissue in GVHD. I have seen remestemcel-L cure children with acute GvHD who have failed to respond to all standard therapies. I sincerely hope that this BLA is approved by the FDA with this resubmission," Joanne Kurtzberg, MD, professor of pediatrics and pathology, director of Marcus Center for Cellular Cures, Pediatric Blood and Marrow Transplant Program, and Carolinas Cord Blood Bank, and co-director, of Stem Cell Transplant Laboratory Duke University Medical Center, told Targeted Oncology^TM.

The original BLA submission was supported by findings from the single-arm phase 3 GVHD001/002 clinical trial as well as 2 randomized phase 3 studies, and a post-hoc analysis. Outcomes of 309 children with SR-aGVHD were contained in this BLA and showed consistent treatment responses and survival across these 3 trials.

In the phase 3, single-arm, multicenter GVHD001/002 trial, the objective response rate (ORR) at day 28 served as the primary end point of the study and results were deemed positive if the ORR was above 45%.²

Findings showed that treatment with remestemcel-L led to a 69.1% ORR at day 28 (95% CI, 55.2%-80.9%). This included a 29.1% complete response (CR) rate and a 40.0% partial response (PR) rate. The median duration of response reported was 70.5 days, and there was an ORR of 74% among patients with standard-risk disease and 37% among those with high-risk disease.

Positive responses were also observed in the randomized trial data as the second study reviewed was the phase 2 280 clinical trial which evaluated the standard-of-care plus placebo vs remestemcel-L in 260 patients. According to the study results, 33 patients did not respond to steroids by day 7 and patients achieved a CR rate of 42% (95% CI, 26%-61%) at day 35 of the study.

Data were then reviewed by the FDAs Oncologic Drugs Advisory Committee where they ultimately voted in favor 9:1 that the data available at the time support the efficacy of remestemcel-L in pediatric patients with SR-aGVHD.

Then in September 2020, the FDA issued a complete response letter regarding the first BLA for remestemcel-L, identifying a need for further scientific rationale that demonstrates the relationship of potency measurements to the biologic activity of this agent.³

With this resubmission comes new information as required by the FDA, including new long-term survival data of patients enrolled in the phase 3 GVHD001/002 clinical trial (NCT02652130). Findings included in this BLA show the durability of the treatment effect through 4 years or more, the treatment benefit in patients with high-risk disease and on survival in propensity-matched studies, and that the validated potency assay has low variability and can demonstrate consistency and reproducibility for manufacturing.¹

In a new analysis of data, the validated potency assay, which was used to release product for the phase 3 trial of 54 patients, reflected the primary mechanism of action of remestemcel-L in this pediatric patient population with SR-aGVHD, correlated with the in vivo bioactivity of the agent, and predicted overall survival outcomes.

Further, the BLA resubmission includes additional clinical and biomarker data from a propensity-matched study of children with high-risk disease, based on the validated MAP biomarker score. The study assessed outcomes in 25 patients from a phase 3 trial and 27 children in the control group from the Mount Sinai Acute GvHD International Consortium (MAGIC) who were treated with various biologics, including ruxolitinib (Jakafi).

In this study, 67% of high-risk children treated given remestemcel-L responded positively to treatment within 28 days. Patients were alive after 180 days vs only 10% in the MAGIC group.

Results of a 4-year survival study performed by the Center for International Blood and Marrow Transplant Research (CIBMTR) were also included in the submission. Fifty-one evaluable patients with SR-aGVHD were a part of the phase 3 trial, and results showed durability of the early day 180 survival benefits. There was a 63% survival rate at 1 year and 51% at 2 years for patients with predominantly grade C/D disease (89%) who had an expected 2-year survival of just 25%-38% using best available therapy.

Overall, there has been a lack of treatment options for patients with SR-aGVHD. Over the past 2 decades, survival outcomes have not improved for this patient population, demonstrating the large unmet need for more approved treatment options.

If remestemcel-L is granted approval by the FDA, it will be the first allogeneic “off-the-shelf” cellular medicine to be approved in the United States for pediatric patients under 12 years old with SR-aGVHD.

“There is an urgent need for a therapy that improves the dismal survival outcome in children with SR-aGVHD” said Silviu Itescu, MD, chief executive of Mesoblast, in the press release. “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.”

REFERENCE:

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 February 1, 2023. https://bit.ly/3HPASZ8

ODAC Briefing Document: Session on clinical evidence (PM session). FDA. August 13, 2020. Accessed February 1, 2023. https://bit.ly/2XXf725

Mesoblast receives complete response letter from the FDA for biologics license application for steroid-refractory acute graft versus host disease in children. News Release. October 2, 2020. Accessed February 1, 2023. https://bit.ly/34hNMtQ