ODAC Votes Yes to FDA Approval of Remestemcel-L in Pediatric Steroid-Refractory Acute Graft-Versus-Host Disease

The Oncologic Drugs Advisory Committee (ODAC) of the FDA voted 9 to 1 in favor of the approval of remestemcel-L (Ryoncil), an allogeneic cell therapy, for the treatment of children with steroid-refractory acute graft-versus-host disease (SR-aGVHD). A Biologics License Application (BLA) for remestemcel-L under this indication was granted in April and given a Prescription Drug Fee User Act target action date of September 30, 2020.¹

The ODAC hearing was held to review the data backing the BLA. The key topics of discussion during the hearing were the clinical trial protocols and the efficacy of remestemcel-L SR-aGVHD as observed in these studies.

In the BLA, the developer of remestemcel-L shared results from 3 different clinical trials, including one single-arm study (GVHD001/002) and 2 randomized, double-blind, placebo-controlled phase 3 clinical trials of remestemcel-L used as treatment of aGVHD, as well as post hoc analyses. As a whole, the dataset included information from 448 patients. In all studies, patients received remestemcel-L as 8 intravenous infusions at 2 x 10⁶ cells/kg over 4 weeks.²

Subjects assessed in these clinical trials had a mean age of 8.9 years and 82% had aGVHD grade C or D, based on the International Bone Marrow Transplant Registry criteria. In 46% of patients, grafts were from the bone marrow, while in 20%, grafts were from mobilized blood in 20%, and grafts were from cord blood in 31% of patients.

GVHD001/002 is a phase 3 single-arm, multicenter clinical trial of 55 patients. The study evaluated the objective response rate (ORR) at day 28 as the primary end points. Per the study’s protocol, results were positive if the ORR was above 45%.¹

According to the results submitted, treatment with remestemcel-L led to a 69.1% ORR at day 28 (95% CI, 55.2%-80.9%), which 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, according to the drug developer and 54 days, according to the FDA analysis.

Positive responses also carried over in the randomized trial data. The second study reviewed was the phase 2 280 clinical trial of 260 patients randomized to receive standard of care plus placebo compared with standard of care plus remestemcel-L. The primary end point of the trial was the percentage of patients with a CR lasting at least 28 days.

The results showed an ORR of 74% among patients with standard-risk disease and 37% among those with high-risk disease.

The ODAC board also reviewed the phase 3 265 clinical trial, which studied adults with a new aGVHD grade B through D. A total of 193 patients were enrolled in the study and randomized to receive steroids plus placebo versus steroids plus remestemcel-L. The primary end point was the number of patients with a CR lasting 28 days or more.

According to the results of this study, 33 patients did not response to steroids by day 7. This group of patients achieved a CR rate of 42% (95% CI, 26%-61%) at day 35 of the study.

Additional research was reviewed during the hearing but deemed not applicable for consideration in the potential approval of remestemcel-L as treatment of SR-aGVHD.

Currently, the only agent with FDA approval for the treatment of SR-aGVHD is ruxolitinib (Jakafi), which was granted approval in May of 2019, based on results from the REACH-1 clinical trial (NCT02953678). To date, the best ORR at day 28 observed with ruxolitinib is 57.1%, and with 69.1% ORR at day 28 observed with remestemcel-L, it was suggested that remestemcel-L could improve outcome overall in this patient population if approved by the FDA.

_References:

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

_{2. FDA Accepts Mesoblasts Biologics License Application for Ryoncil and Agrees to Priority Review. News release. Mesoblast Limited. April 1, 2020. Accessed August 13, 2020. https://yhoo.it/2X2Qphg}