FDA in Favor of Remestemcel-L for Pediatric GVHD


The FDA’s Oncologic Drugs Advisory Committee voted in favor of approving remestemcel-L for the treatment of children with steroid-refractory acute graft-versus-host disease.

FDA in Favor of Remestemcel-L for Pediatric GVHD

FDA in Favor of Remestemcel-L for Pediatric GVHD

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted in favor of approving remestemcel-L (Ryoncil) for the treatment of children with steroid-refractory acute graft-versus-host disease (SR-aGVHD).1

The FDA previously scheduled the hearing to discuss data supporting a biologics license application (BLA) for remestemcel-L for use in this setting. Specifically, the panel sought to discuss issues associated with the characterization and critical quality attributes of the agent as they relate to clinical effectiveness and examine clinical trial data included in the BLA.

"Based upon the available data, I do believe this agent has efficacy in the disease in question," Jorge A. Garcia, MD, FACP, of Case Western Reserve University, said. "Do I believe it's better than any other existing agent? I don't know. Do I believe it's a safe agent? I do. Do I believe, with 15 years of experience, no overlapping side effects in a disease setting where there's clearly an unmet need, I think that agent has shown some efficacy.

The hearing followed by a April 2020 priority review designation granted to the BLA.

In the single-arm Study GVD001/002 phase 3 trial, a total of 55 children were enrolled across 20 centers throughout the United States. Investigators examined remestemcel-L as a first-line treatment in children who did not respond to steroids for aGHVD. The primary end point of the trial was overall response rate (ORR) at day 28.

Results showed that the ORR at day 28 was 69.1% in the full analysis set (95% CI, 55.2-80.9); the complete response (CR) rate at that time point was 29.1% and the partial response (PR) rate was 40.0%.2,3

“Despite the positive outcome of this trial, the clinical meaningfulness is unclear in the setting of the uncertainties and limitations in determining the null for this population,” noted Kristin Baird, MD, medical officer at the FDA, during the regulatory agency’s presentation on the clinical evidence with the drug.

Moreover, the median duration of response (DOR) of day-28 ORR was found to differ between the analysis submitted by Mesoblast Limited, the drug developer, and the FDA analysis. The applicant-defined DOR with remestemcel-L was a median of 70.5 days versus the FDA-defined ORR of 54 days.

In the randomized, double-blind, placebo-controlled, phase 3 Study 280, a total of 27 patients were enrolled to the pediatric subgroup, which included both adult and pediatric patients with with grade B to D SR-aGVHD.4 In this trial, standard of care plus remestemcel-L was compared with standard of care plus placebo; 14 patients were randomized to the investigational arm and 13 patients were enrolled to the control arm. The primary end point of the trial was CR at 28 days duration or more.

Results showed a day-28 ORR of 64.3% (95% CI, 35.1-87.2) in those who received standard of care plus remestemcel-L versus 38.5% (95% CI, 13.9-68.4) in those who were given standard of care plus placebo.

Lastly, remestemcel-L was also examined in the single-arm Study 275 in a total of 241 pediatric patients with grade B to D SR-aGVHD who had been enrolled at 50 sites spanning 8 countries. Thirty percent of participants had grade C disease and 50% had grade D disease. The mean patient age was 9.6 years and 60% of patients were white; the majority of participants, or 61%, were male. The primary end point of this trial was day-28 ORR.

Results showed a day-28 ORR of 65.1% (95% CI, 58.8-71.1) in those who received remestemcel-L; this was comprised of a CR rate of 14.1% and a PR rate of 51.3%. The day-28 ORR proved to be even higher in those with grade B and C disease, at 72.9% and 67.1%, respectively, compared with 60.8% in patients with grade D disease.

The issues with doing a cross-trial comparison are three-fold, according to Baird: Study 280 and 275 permitted new salvage therapy for aGVHD, small numbers of patients were analyzed, and the subgroup analysis from Study 280 was not particularly persuasive, showing a large confidence interval.

An additional randomized, double-blind, placebo-controlled, multicenter phase 3 trial was also done in adult patients with newly diagnosed grade B to D SR-aGVHD. In this trial, remestemcel-L plus steroids (n = 97) was compared with steroids plus placebo (n = 95), and the primary end point was CR at 28 days duration or more.

Results from this trial showed that the day-28 ORR in the remestemcel-L/steroids arm was 60% (95% CI, 49.3-69.6) versus 61% (95% CI, 50.5-70.9) in the steroids/placebo arm. The day-28 CR and PR rates in the investigational arm were 41% and 19%, respectively, versus 49% and 12%, respectively, in the placebo arm.

“No treatment effect was identified in the randomized trials,” noted Baird, “and the ORR in the remestemcel treatment arms ranged from 54% to 70% with wide confidence intervals.”

Baird concluded by reiterating that the primary end point results for Study GVD001/002 were statistically significant and the response measured was durable; moreover, the study data were consistent across subgroups, as well as secondary efficacy end points. However, the 2 randomized trials, Study 265 and 280, did not demonstrate a treatment effect with the agent when re-analyzed using the day-28 ORR efficacy end point.

"I believe that the drug has activity and even although I was 51% for voting yes, versus 49%, I was persuaded by the clinical...argument that it may not be possible to do a randomized trial and I'm also hopeful that the sponsor will try to address some of the concerns [brought up by the panel in the future]," Susan Halabi, PhD, of Duke Cancer Institute, noted.


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

2. Baird K. FDA session on clinical evidence: BLA 125706: Remestemcel-L. August 13, 2020. Accessed August 13, 2020. https://bit.ly/3fR3Syp.

Clinical outcomes using Ryoncil (remestemcel-L) in children and adults with severe inflammatory graft versus host disease published in three articles in Biology of Blood and Marrow Transplantation. News release. Mesoblast Limited; May 25, 2020. Accessed August 13, 2020. https://bit.ly/2ZNvrnb.

3. Kurtzberg J, Prockop S, Chaudhury S, et al. Study 275: updated expanded access program for remestemcel-L in steroid-refractory acute graft-versus-host disease in children. Biol Blood Marrow Transplant. 2020;26(5):855-864. doi:10.1016/j.bbmt.2020.01.026

This article was originally published on OncLive as, "FDA Panel Supports Remestemcel-L for Pediatric Steroid-Refractory Acute GVHD."

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