FDA Panel Rejects Experimental Stem Cell Therapy for ALS

Kelli Whitlock Burton

September 27, 2023

An experimental stem cell therapy for the treatment of mild to moderate amyotrophic lateral sclerosis (ALS) received a resounding rejection today from a US Food and Drug Administration (FDA) advisory panel that cited efficacy, safety, and product manufacturing concerns.

The 17-1 vote (with one abstention) against approval by members of the FDA's Peripheral and Central Nervous System Drugs Advisory Committee followed the release earlier this week of a negative FDA review that characterized the company's Biologics License Application (BLA) for approval as "scientifically incomplete" and "grossly deficient."

The therapy, debamestrocel (NurOwn; BrainStorm Cell Therapeutics), uses mesenchymal stem cells harvested from patients' own bone marrow that are engineered to secrete neurotrophic factors, proteins important for the survival and function of neurons. The manipulated stem cells are then injected into a patient's spine.

More than 1200 people tuned into the 8-hour livestream of the hearing, which featured public testimony from more than a dozen individuals, including impassioned pleas from patients with ALS, their physicians, and their caregivers who urged the panel to support the therapy's approval.

Ultimately, the panel denied the company's BLA, ruling that evidence from phase 2 and 3 trials failed to demonstrate the therapy's efficacy and raised safety concerns after more patients in the treatment group died during the study.

"We have a single study at the dose and formulation that's been proposed, and it unfortunately didn't achieve evidence of efficacy for either the primary or secondary endpoints," said committee member Caleb Alexander, MD, a professor of epidemiology and medicine at Johns Hopkins University, Baltimore, Maryland, who voted against approval.

"Guidance may allow for the approval of a product based on a single pivotal trial plus confirmatory evidence but not a trial that's not successful in demonstration of efficacy," Alexander added.

Lack of Efficacy

BrainStorm's BLA application is based on data from four clinical studies, but only one — a phase 3 randomized controlled trial — measured efficacy of the recommended dosage. Conducted at six US sites, the trial included 189 patients with ALS who received at least one treatment of NurOwn or a placebo.

After 28 weeks, there was no significant difference between groups in response rates (32.6% with NurOwn vs 27.7% with placebo; P = .45) or in improvements on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), which reflects motor impairment and functional deterioration in patients with ALS (P = .69).

BrainStorm's representatives attempted to make the case for efficacy based on an analysis of data from a prespecified subgroup of 58 patients whose disease was not as advanced.

Those findings also showed no significant differences between the groups in terms of treatment response, but the company argued that the results were muddied by an issue with the scale used to measure disease progression that's known as a "floor effect."

A floor effect happens when a patient's score on a specific measure of physical function is low, and the scale can no longer accurately capture disease progression.

"When the trial originally read out, the most straightforward decision for the company was to walk away from ALS," Stacy Lindborg, PhD, co-chief executive officer of BrainStorm, told the committee. "In fact, like the FDA, we originally looked at this as a failed trial."

Analysis of the subgroup shed new light on the findings, Lindborg said, offering "nominally significant" findings. The analysis also prompted BrainStorm to amend their BLA to change the therapy's indication from treatment for ALS to treatment for mild to moderate ALS.

"We saw that more participants with NurOwn compared to placebo had a large clinical response and 2 points of function preserved across the NurOwn treatment arm, both of which are highly clinically meaningful," Lindborg said. "These results are not by chance, but a direct effect of NurOwn."

Those claims were refuted by FDA reviewers, who found no evidence of a floor effect and challenged whether a subgroup analysis would have been enough to justify an approval.

"Analyses of subgroups in the context of a negative study cannot provide evidence of effectiveness," said Rosa Sherafat-Kazemzadeh, MD, clinical team leader in the FDA's Office of Clinical Evaluation.

Path to the Hearing

NurOwn was granted orphan drug status from the FDA in 2011 and fast-track status in 2014. A regulatory timeline from the FDA shows meetings with the manufacturer going back to 2016, with at least six meetings to discuss the agency's concerns about the company's trial design.

In a February 2021 meeting, the FDA warned BrainStorm that study data did not demonstrate efficacy and expressed concern over the higher mortality in the treatment group. Of the 13 deaths during the study, 10 had received NurOwn, which the agency said indicated a lack of survival benefit that deserves further study.

Reviewers also cited issues with product manufacturing, calling the company's BLA application "grossly deficient to ensure adequate product quality."

After that meeting, the FDA recommended BrainStorm file a new BLA that addressed the agency's concerns. BrainStorm chose instead to move forward with the original BLA in September 2022. The FDA rejected it in November.

In February 2023, the company requested the application be filed over protest, adding exploratory post hoc subgroup analysis of clinical data, exploratory analysis of biomarker data, and additional manufacturing information.

Then, just 5 days before today's hearing, the company modified the proposed indication from treatment of ALS to treatment of mild to moderate ALS.

Danger of 'False Hope'

In addition to more than 1900 written comments submitted in advance of the hearing, the committee also heard from 15 individuals during the public comment period. Most speakers were patients with ALS or their caregivers who testified, sometimes tearfully, about the impact of the disease and the benefits some received from NurOwn as participants in the phase 3 trial.

Testimony from patients deserves equal weight to other evidence the committee provided to the committee, said Andrea Goodman, MSW, MPH, chief executive officer of I AM ALS, who testified during the public hearing.

"People living with ALS are the authority on what constitutes a meaningful effect on their health and quality of life," Goodman said. "Keep them foremost in mind as you make your decision."

Those on the committee who voted against the application were quick to acknowledge the lack of effective treatments for ALS and the hardship patients and caregivers face. However, "[p]atients and families need hope, but providing false hope can be ethically problematic," said committee member Lisa Lee, PhD, associate vice president for research and innovation and director of the Division of Scholarly Integrity and Research Compliance, Virginia Tech University, Blacksburg, Virginia. "False hope is provided when the probability of a positive outcome is overestimated, and I think that seems to be the case here."

The FDA's final decision on the drug is due later this year.

Kelli Whitlock Burton is a reporter for Medscape Medical News covering neurology and psychiatry.

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