FDA Issues Complete Response Letter for Remestemcel-L for Pediatric Steroid-Refractory Acute GVHD

The FDA has issued a complete response letter (CRL) to Mesoblast Limited regarding a biologics license application (BLA) for remestemcel-L (Ryoncil), recommending that at least 1 additional randomized, controlled study be conducted in adult and/or pediatric patients to provide further evidence of the efficacy of the agent in steroid-refractory acute graft-versus-host disease (SR-aGVHD).¹

In August 2020, the regulatory agency’s Oncologic Drugs Advisory Committee (ODAC) reviewed findings supporting the BLA for remestemcel-L for use in this setting. During this hearing, they discussed issues associated with the characterization and clinical quality attributes of the agent as they relate to clinical effectiveness and examined clinical trial data included in the BLA. The ODAC committee voted 8 to 2 in favor of approving the agent.

The regenerative medicine company plans to request a Type A meeting with the FDA within the next 30 days to discuss the potential of an accelerated approval with a post-approval condition for another clinical trial, as no other agents are approved for this life-threatening condition in patients under 12 years of age.

“The phase 3 trial results showed that remestemcel-L provides a meaningful treatment for children with SR-aGVHD who have a very dismal prognosis,” Joanne Kurtzberg, MD, Jerome Harris Distinguished Professor of Pediatrics, director of the Pediatric Blood and Marrow Transplant Program, and co-director of the Stem Cell Transplant Laboratory at Duke University Medical Center, stated in a press release. “I look forward to having this much-needed therapy available to our patients.”

In the single-arm Study GVD001/002 phase 3 trial, investigators examined remestemcel-L as a first-line treatment in a total of 55 pediatric patients 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 an ORR of 69.1% at day 28 in the full analysis set (95% CI, 55.2-80.9). Moreover, the day-28 complete response (CR) rate was 29.1%, while the partial response (PR) rate was 40.0%.^2,3 The median duration of response (DOR) of day-28 ORR differed between the analysis submitted by Mesoblast and the FDA analysis. The applicant-defined DOR with the agent was a median of 70.5 days compared with 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 grade B to D SR-aGVHD.⁴ In this trial, standard treatment plus remestemcel-L was examined against standard treatment plus placebo. Here, a total of 14 patients were randomized to the investigational, while 13 patients were enrolled to the control arm. The primary end point of the trial was CR at 28 days duration or longer.

Results demonstrated a day-28 ORR of 64.3% (95% CI, 35.1-87.2) in the standard treatment/remestemcel-L arm compared with 38.5% (95% CI, 13.9-68.4) in the standard treatment/placebo arm.

Remestemcel-L was also evaluated in the single-arm Study 275 in 241 pediatric patients with grade B to D SR-aGVHD; these patients had been enrolled at 50 sites across 8 countries. Thirty percent of study participants had grade C disease and half had grade D disease. The mean patient age was 9.6 years and the majority, or 60%, of participants were white. Sixty-one percent of patients were male. The primary end point of this trial was day-28 ORR.

Results demonstrated that the day-28 ORR was 65.1% (95% CI, 58.8-71.1) in patients who received remestemcel-L; this included a CR rate of 14.1% and a PR rate of 51.3%. The day-28 ORR was even higher in those with grade B disease, at 72.9%, and those with grade C disease, at 67.1%, versus the 60.8% observed in those with grade D disease.

Additionally, an ongoing randomized, controlled phase 3 trial is examining the agent in up to 300 adult patients who are ventilator dependent and have moderate to severe acute respiratory distress syndrome (ARDS) from coronavirus disease 2019 (COVID-19). A second interim analysis from the trial is anticipated in early November 2020, and patient enrollment is expected to be completed the following month, in December 2020. The primary end point of the trial is reduction of all-cause mortality within 30 days of randomization.

The FDA stated the need for additional scientific rationale to showcase the relationship of potency measurements to the agent’s biologic activity, according to Mesoblast. To this end, assays will continue to undergo refinement to supply that rationale for the use of the agent in severe inflammatory diseases that have high risk of mortality, including SR-aGVHD and ARDS associated with COVID-19.

“We are working tirelessly to bring remestemcel-L to patients with life-threatening inflammatory conditions, including SR-aGVHD and COVID-19 ARDS, Silviu Itescu, MBBS, FRACP, added in the release.

References:

1. 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 October 2, 2020. https://bit.ly/2GsGGKI.
2. Baird K. FDA session on clinical evidence: BLA 125706: Remestemcel-L. August 13, 2020. Accessed August 13, 2020. https://bit.ly/3fR3Syp.
3. 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.
4. 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