Brainstorm Cell Therapeutics got the FDA advisory committee meeting it asked for but not the outcome it wanted. After a full day of presentations and testimonials, the panel of outside experts on Wednesday evening voted against recommending regulatory approval of the company’s experimental stem cell therapy for amyotrophic lateral sclerosis, or ALS.

The committee was specifically asked to vote on the question of whether the data Brainstorm presented for its therapy, called NurOwn, demonstrate substantial effectiveness for the treatment of mild-to-moderate ALS. Of the 19 eligible voting members, 17 voted “no,” one voted “yes,” and one abstained.

NurOwn is made from a patient’s own stem cells. Brainstorm specifically looks for mesenchymal stem cells, which the company says release growth factors—proteins that stimulate growth. Brainstorm produces NurOwn by isolating mesenchymal stem cells from a patient sample, then multiplying those cells in a lab. Administered as an injection into the spine, the treatment is intended to support neurons and improve neurological function.

Committee members largely expressed skepticism about Brainstorm’s clinical data, raising questions about whether trial results show that the therapy is doing what the company says it is doing. Panelists also expressed concerns about the therapy’s safety considering that there were more fatalities in the study drug group versus the placebo arm. That was one of the concerns of Andrew Buckley, an ALS patient who served on the committee as a patient representative and temporary voting member. In explaining his “no” vote, Buckley said he weighed whether NurOwn was safe and effective.

“I didn’t find it was effective,” he said. “It seemed to me there was more evidence to the contrary. As to the issue of safety, it seems to me it’s not as safe as maybe the sponsor would like it to be, given the number of deaths in the NurOwn group versus the control group.”

Some of the committee’s concerns and questions about NurOwn were raised previously. The therapy failed its double-blind, placebo-controlled Phase 3 study in 2020, an outcome the company acknowledged. But Brainstorm pointed to a post-hoc analysis of a subgroup of patients in which it said there was an increase in growth factors and a decrease in the signs of neurodegeneration and neuroinflammation. The FDA in 2021 told Brainstorm that the clinical data do not support an interpretation of patient benefit, but added that it would work with company on another clinical trial.

Rather than conduct another clinical trial, Brainstorm went ahead and filed an application seeking FDA approval. Last November, the agency refused to review it, telling the company it was incomplete. Refuse-to-file letters are a more formal way of informing a company that a drug needs another clinical trial, but Brainstorm still did not take that step. Instead, the company asked the FDA to review the application under a procedure called “file over protest.” Taking that step returned NurOwn to active review, and the FDA said it would convene an advisory committee meeting to discuss the application. Those moves led to Wednesday’s meeting.

Committee member Mark Tuszynski, professor of neurosciences and director of the Translational Neuroscience Institute at the University of California San Diego, said it’s unclear to him whether growth factors produced by NurOwn are penetrating the spinal cord to provide a treatment effect. If a therapy does not achieve substantial boost in growth factor levels in a clinical trial, there is little evidence that those growth factors are reaching the intended destination. Tuszynski said in his view, NurOwn’s mechanism “is more of a hypothesis than a proven bit of data.”

The abstention was from Nirali Shah, head of the hematologic malignancies section of the pediatric oncology branch of the National Cancer Institute, who said a fair amount of conflicting information was presented. She believes that “something is there,” but she does not know if it fits the regulatory platform available and it’s unclear what would be needed of a mesenchymal stem cell therapy to be approved.

Kathleen O’Sullivan-Fortin, the founder of ALD Connect, a nonprofit organization that brings together stakeholders in the adrenoleukodstrophy (ALD) community, cast the lone vote backing NurOwn. She said the basis of her support were the reports of improvements in some patients. O’Sullivan-Fortin added that the seriousness of a disease that brings imminent certain death provides “unique circumstances for us to exercise flexibility.”

The testimonies of those who have ALS and are looking for additional treatment options were acknowledged by committee members, including Michael Gold, chief medical officer of neuroscience drug developer Neumora Therapeutics and the committee’s acting industry representative. But Gold expressed caution about placing too much weight on anecdotal data, adding that the committee needs to be objective and data driven. Wendy London, an associate professor of pediatrics at Harvard Medical School, said the trial was not designed to detect a treatment effect in a post-hoc, subgroup analysis. She added that in a future trial, the company could add a secondary endpoint measuring quality of life changes that capture some of the anecdotal evidence of a treatment effect.

Caleb Alexander, professor of epidemiology and medicine at Johns Hopkins University’s Bloomberg School of Public Health, said the NurOwn data were hard to interpret and did not suggest efficacy, adding that Brainstorm’s application relies on a single study in which the results did not show efficacy. He acknowledged that there’s precedent for the FDA approving drugs based on a single pivotal study.

“Although there are some unfortunate examples, I think if you look at the majority of examples where FDA used a single trial, it’s been with very strong evidence to support the approvals,” Alexander said.

The FDA is not required to follow the votes of its advisory committees, but it does take committee discussions into account in its decisions. Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, concluded the meeting by acknowledging the patient testimony, adding that the agency will review the comments to the docket and the transcript of the advisory committee meeting.

“The FDA does hear the tremendous need here for effective therapies in this space, and that’s not lost on us,” Marks said.

Image: koto_feja, Getty Images