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

The FDA has issued a Complete Response Letter to the Biologics License Application (BLA) for remestemcel-L (Ryoncil) for the treatment of pediatric patients with steroid-refractory acute-graft-versus-host disease (SR-aGVHD), according to a press release from Mesoblast, developer of the drug.¹

Despite the Oncologic Drugs Advisory Committee’s 9:1 vote in favor of an approval of remestemcel-L, the FDA recommends at least 1 more randomized, controlled trial be conducted in adult and/or pediatric patients with SR-aGVHD to provide further evidence for the approval of this agent. Within 30 days, the company is expected to urgently request a Type A meeting with the FDA to discuss potential accelerated approval with a post-approval condition for an additional study.

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

The company is currently conducting a randomized, controlled phase 3 study of remestemcel-L in up to 300 ventilator-dependent adult patients with moderate to severe respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19). The Independent Data Safety Monitoring Board is expected to conduct a second interim analysis on the study in early November 2020, and the study should complete patient enrollment in December. COVID-19 ARDS is an inflammatory disease with a similar profile to what has been observed in children with SR-GVHD, and this is the primary cause of death in COVID-19 infection. The primary end point of the study is reduction of all-cause mortality within 30 days of randomization.

In the Complete Response Letter, the FDA also identified a need for further scientific rationale that demonstrate the relationship of potency measurements to the biologic activity of this agent. The assays used to measure potency of the drug will continue to be refined to provide further scientific rationale for the use of remestemcel-L as treatment of severe inflammatory diseases with high mortality risk like SR-aGVHD and COVID-19 ARDS.

The BLA was supported by findings from a single-arm phase 3 GVHD001/002 clinical trial (NCT02652130) and 2 randomized phase 3 studies, as well as a post-hoc analysis. Together, this dataset included 448 patients, in which they all received remestemcel-L in 8 infusions at 2 x 106 cells/kg over 4 weeks.²

In the multicenter GVHD001/002 study, the primary end point was the objective response rate (ORR) at day 28, which was deemed positive if the ORR was above 45% per the study’s protocol. A total of 55 patients were evaluated in this study.

The ORR was 69.1% by day 28 (95% CI, 55.2%-90.9%), with a complete response (CR) rate of 29.1% and a partial response (PR) rate of 40.0%. The median duration of response was 70.5 days, according to the FDA analysis at day 54.

In the 2 randomized studies, remestemcel-L also demonstrated positive responses. In the first study, 260 patients were randomized to receive the standard of care with either remestemcel-L or placebo. The primary end point was the percentage of patients with a CR lasting at least 28 days. The ORR in this study was 74% among those with standard-risk disease and 37% among those high-risk disease.

The second study evaluated the same primary end point in a total of 193 patients who were randomized to receive steroids with either remestemcel-L or placebo. This trial included adult patients with a new aGVHD of grade B through D. Overall, 33 patients did not respond to steroids by day 7. The CR rate was 42% (95% CI, 26%-61%) at day 35.

These findings were previously presented during the 2020 Transplantation & Cellular Therapy Meetings. The mean age of patients in this dataset was 8.9 years, and 82% of patients had aGVHD of grade C or D, based on the International Bone Marrow Transplant Registry criteria. Additionally, 46% of our patients had grafts from the bone marrow, 20% from mobilized blood, and 31% from cord blood.³

At day 28, the ORR was 66%, which included CRs in 18% and PRs in 48%. The ORR among those with grade C or D disease at baseline was 65%.

The survival rate was 68% at day 100, and the day 28 ORR strongly predicted survival at day 100 in 84% of responders versus 39% in non-responders. This association was consistent across aGVHD grades. The day 28 ORR was also strongly predicted with day 180 survival in 83% of responders remaining alive.

Infusion-related adverse events (AEs) were not observed with remestemcel-L infusions. The most common treatment-emergent serious AEs included infections (28%) and respiratory-related events (18%), which were considered related to the underlying disease or aGVHD. Six percent of AEs were possibly related to remestemcel-L, according to investigators.

_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/34hNMtQ}

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

_{3. Kurstzberg J, Martin PJ, Prockop SE, et al. Aggregate Results of Remestemcel-L Treatment for Steroid-Refractory Acute Graft-Versus-Host Disease in Pediatric Patients. Presented at: 2020 Transplantation & Cellular Therapy Meetings; February 19-23, 2020; Orlando, FL. Abstract LBA12.}