Cell Therapy for GVHD in Kids Faces Uncertain Fate in FDA Panel Review – MedPage Today

WASHINGTON -- An FDA advisory panel on Thursday will decide whether to recommend approval of the investigational cellular therapy remestemcel-L for treating children with graft-versus-host disease (GVHD) following stem cell transplantation.

No drugs are currently approved for the treatment of steroid-refractory acute GVHD in children under age 12, and the Oncologic Drugs Advisory Committee (ODAC) will be asked to vote on whether the available data support remestemcel-L's efficacy for pediatric patients with steroid-refractory acute GVHD.

In a morning session, ODAC will review issues surrounding the manufacturing of remestemcel-L, which is described by sponsor Mesoblast as a product "comprising culture-expanded mesenchymal stem cells [MSCs] derived from the bone marrow of an unrelated donor."

Patients with GVHD experience sustained systemic immune activation, and remestemcel-L's proposed mechanism of action is the reduction of these inflammatory processes mediated by the immunomodulatory bioactivity of MSCs.

ODAC will be tasked with evaluating whether an assay developed by Mesoblast can adequately determine that the drug's potency remains consistent from lot to lot, and with proposing and discussing other measures for ensuring its adequate safety and effectiveness.

"The issue of reliable prediction of biological activity is particularly challenging for MSCs," noted FDA staff in briefing documents for the morning session. "Substantial functional heterogeneity has been observed between MSC batches derived from different donors and expanded using different tissue culture conditions or duration."

In the afternoon, the clinical efficacy data in pediatric patients with acute steroid-refractory GVHD will take center stage, though negative results from past trials of remestemcel-L in adults is also on the agenda.

Primary support for the sponsor's application comes from a single-arm trial (Protocol MSB-GVHD001), which from 2015 to 2017 enrolled 55 pediatric patients in the U.S. with acute steroid-refractory GVHD (grades B-D). Over 8 weeks, patients received a median of 10 doses of intravenous remestemcel-L (106 cells/kg infusion), and some required further treatment for "flares."

The study met its primary endpoint, with 69.1% of patients treated with remestemcel-L achieving an objective response at day 28 (95% CI 55.2%-80.9%), including complete responses in 29.1% and partial responses in 40.0%. The median duration of response was 54 days. Long-term data from the trial left FDA staff wanting.

Common adverse events included infections (grade 3/4 in 19%), gastrointestinal toxicities, and respiratory complications. No deaths were deemed treatment related, with GVHD, relapse, and infections being the leading causes of death among treated patients.

Although the study met its primary endpoint, which had the assumption of a 45% overall response rate as its null hypothesis, FDA staff questioned the method for determining this benchmark and whether MSB-GVHD001 offers a definitive answer.

"It is unclear whether this one single-arm trial provides evidence of clinical benefit," agency staff wrote in briefing documents for the afternoon session. "Furthermore, it is unclear if the durability of response requires continued infusions of remestemcel-L."

Past trials may doom the therapy's fortunes as well, as remestemcel-L twice failed as a treatment for GVHD in phase III trials (Protocols 280 and 265), though the latter was restricted to adults with newly-diagnosed acute GVHD, and both were conducted over a decade ago.

In Protocol 280, adding remestemcel-L to standard of care in a trial of mostly adults did not improve response rates versus placebo. Among the subgroup of pediatric patients in this trial (n=27), the response rate at 28 days was 64.3% (95% CI 35.1%-87.2%) with remestemcel-L plus standard salvage treatments, as compared to 38.5% for the placebo arm (95% CI 13.9%-68.4%).

Similarly, among 241 kids with acute steroid-refractory GVHD in Protocol 275, an expanded access cohort, 65.1% had an objective response (95% CI 58.8%-71.1%) with remestemcel-L plus standard salvage treatments, but FDA staff cautioned that this was not a well-controlled trial.

Before their vote, ODAC members will be asked to weigh the strengths and weaknesses of the single-arm trial, and discuss whether the randomized trials should have any bearing on the current application or if further trials are warranted for the present application.

Last Updated August 12, 2020

Ian Ingram joined MedPage Today in 2018 as Deputy Managing Editor, and covers oncology for the site.

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Cell Therapy for GVHD in Kids Faces Uncertain Fate in FDA Panel Review - MedPage Today