Press "Enter" to skip to content

GVHD Cell Therapy for Kids Gets ODAC Backing

An FDA advisory panel was mostly convinced that remestemcel-L, an investigational cellular therapy, would be a safe and effective treatment for acute graft-versus-host disease (GVHD) in children with no other approved options.

In an 8-2 vote, the Oncologic Drugs Advisory Committee (ODAC) determined that the available evidence supports remestemcel-L’s efficacy in pediatric patients with steroid-refractory acute GVHD. Panel members also appeared to back the product’s safety in their remarks, but they weren’t asked to vote on it formally.

Steroids are standard first-line treatment for acute GVHD, but 30%-60% of patients fail to respond, and survival outcomes are poor, with no second-line drugs currently approved in children under 12 years of age.

As described by sponsor Mesoblast, remestemcel-L is an off-the-shelf cellular product that uses culture-expanded mesenchymal stem cells (MSCs) isolated from the bone marrow of healthy unrelated adults. A single donor can provide enough cells to treat more than 400 patients, according to a company representative.

GVHD is a life-threatening complication of stem cell transplantation that causes sustained and systemic immune activation in patients. Remestemcel-L’s proposed — but unproven — mechanism of action is the reduction of these inflammatory processes mediated by the immunomodulatory bioactivity of MSCs.

During a morning session, concerns from ODAC members centered largely on whether remestemcel-L’s potency could be consistently assured from lot to lot, given the potential for donor variability, and whether assays developed by Mesoblast could accurately determine such potency in the absence of a clearly understood mechanism of action.

Some committee members were at a loss on guidance for improving confidence in the final product.

“With a complex and somewhat unclear mechanism of action it’s really difficult to think about how you would want to see the potency determined, and what mechanism characteristics you would want to see tested,” said Christian Hinrichs, MD, of the National Cancer Institute in Bethesda, Maryland.

Pamela Robey, PhD, of the National Institute of Neurological Disorders and Stroke, also in Bethesda, recommended that each lot of cells have a transcriptomic profile associated with it. “It would come in extremely handy for future evaluations and also address the issue of lot-to-lot variability,” she said.

Primary support for the sponsor’s application came 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). The majority of patients had higher-grade disease (C/D) and about two-thirds had high-risk biomarkers. Over 8 weeks, patients received a median of 10 doses of intravenous remestemcel-L (2 × 106 cells/kg infusion), with some responders receiving further treatment for GVHD 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%. The median duration of response was 54 days, according to the FDA.

Survival at days 100 and 180 were 74% and 69%, respectively. Prior studies in GVHD have shown response at day 28 to be associated with long-term survival.

But FDA staff raised concerns over the study’s primary endpoint, which had the assumption of a 45% overall response rate as its null hypothesis based on prior pediatric cohorts showing day-28 response rates of 24%-43% with standard care alone or with placebo.

Agency staff pointed to other studies in children with steroid-refractory acute GVHD demonstrating response rates of 67%-82% using other investigational agents, including infliximab (Remicade).

Nancy Bunin, MD, of the University of Pennsylvania, wasn’t convinced that remestemcel-L was better for gut GVHD than infliximab, which is commonly used.

“If a randomized trial were to be considered, I would confine it to gut GVHD and consider infliximab as the other arm,” said Bunin.

Randomized, placebo-controlled trials in this patient population are unlikely to be feasible, with site investigators potentially unwilling to risk putting patients on placebo.

Further complicating the efficacy evaluation for remestemcel-L were two negative phase III trials conducted over a decade ago. These were conducted primarily in adults; one trial was in newly-diagnosed disease.

Mesoblast said newer manufacturing processes introduced during an earlier study involving 241 kids with acute steroid-refractory GVHD (Protocol 275) have made remestemcel-L more potent by increasing concentrations of tumor necrosis factor receptor 1 (TNFR1), which are correlated with better patient outcomes. In the trial, those treated using the newer process showed numerically higher response rates (70% vs 63%), and improved survival at 100 days (75% vs 58%, P=0.0026), according to the sponsor.

Safety was less contentious for panel members, with broad agreement that the therapy appeared relatively safe in children. Common adverse events in MSB-GVHD001 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.

Although the FDA is not required to follow its advisory committees’ recommendations, it typically does.

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