While the FDA’s Oncologic Drugs Advisory Committee (ODAC) shared some of the agency’s concerns about uncertainties surrounding Mesoblast Ltd.’s Ryoncil (remestemcel-L), it initially voted 8-2 Aug. 13 that the mesenchymal stromal cell (MSC) product showed evidence of efficacy as a treatment for steroid-refractory acute graft-vs.-host disease (GVHD) in children. But when it came time for the members to explain their votes, one of the members changed her no vote to a yes, giving the MSC therapy a 9-1 tally.*

The vote was a welcome relief for the Melbourne, Australia-based company, which saw its stock tumble more than 30% Monday following the FDA’s release of its briefing documents for the adcom.

If the FDA follows ODAC’s lead, Ryoncil would be the first FDA-approved GVHD treatment for children younger than 12 and the first MSC product approved in the U.S. Despite the vote, approval is still far from certain.

Divided into two separate sessions, each with its own public hearing and discussion questions, the ODAC meeting pitted the FDA’s desire to cross all the trial “T’s” and dot all the scientific “I’s” against a significant unmet need and parents’ tearful testimony of how the off-the-shelf therapy, through compassionate use, saved their children from unimaginable suffering and possible death.

In opening the meeting, Wilson Bryan, director of the Office of Tissues and Advanced Therapies at the FDA’s Center for Biologics Evaluation and Research, set the agency’s negative tone, saying, “We have substantial concerns regarding this application.” The biggest concerns had to do with uncertainties about the therapy’s mechanism of action, potential variability in an off-the-shelf cell therapy and the lack of a randomized control trial (RCT).

While the FDA asked for advice on requiring another study, pediatric specialists presenting for Mesoblast and testifying in the public hearings stressed the urgency of getting the therapy approved to meet the unmet medical need. Incyte Corp.’s Jakafi (ruxolitinib) has been approved to treat GVHD in adults, but it can’t be used in young children because of its side effects. So not only is there no approved treatment for children younger than 12, there is no standard of care using an off-label therapy, said Joanne Kurtzberg, director of the pediatric blood and marrow transplant program at Duke University School of Medicine and a principal investigator in Mesoblast’s 001 pediatric study.

Kurtzberg said she has been using remestemcel-L for more than a decade with good results. Because of that experience and the positive results she’s seen with the therapy, Kurtzberg argued against requiring a controlled study, saying she and other clinicians wouldn’t risk putting their young patients into a control arm when remestemcel-L works so well. She pointed out that without the therapy, the survival rate for children with GVHD who don’t respond to steroids is 35%.

Given Kurtzberg’s remarks, panelist Mark Walters, director of blood and marrow transplantation at the University of California San Francisco, questioned the feasibility of requiring Mesoblast to conduct an RCT. Such a study would be ethical, Walters said, but it wouldn’t be practical because the already established belief in the therapy’s efficacy would create a barrier to getting trial participation.

Mesoblast’s product has been in development for more than 15 years and has been available through compassionate use. Although previous trials in adult populations failed to meet their endpoint, no safety signals were sounded. That left the FDA questioning the efficacy that was revealed in the latest study – a single-arm trial that showed a 70% overall response rate at day 28 and overall survival of 74% at day 100.

The response rate far exceeded the 45% null hypothesis Mesoblast set based on historic controls. However, the FDA questioned the null hypothesis and the lack of a control in the trial. It also brought up the past failures, even though Mesoblast pointed out the previous trials were conducted with an earlier iteration of the therapy. Since then, it has optimized its processes, increasing the potency of the product.

The company already is in the process of planning another study in adults, this time using the new and improved therapy.

With hundreds of MSC products in clinical trials in the U.S., the FDA likely will tread cautiously as it enters this relatively new field. Bryan noted that several MSC therapies are being illegally marketed in the U.S. even though they haven’t been shown to be safe or effective. While the field of cell therapy has the potential to meet many unmet needs, it must be reached through scientific rigor, he stressed.

MSCs and all cell therapies are highly complex products, so chemistry, manufacturing and control issues can be particularly challenging, Bryan said. If Ryoncil is approved, Mesoblast must be able to ensure that every lot has the same safety and efficacy as those seen in the trials, he added.

*Story was updated to reflect the changed vote, which occurred after the virtual adcom had disconnected.

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