NEW YORK – An advisory committee for the US Food and Drug Administration on Wednesday was nearly unanimous in its view that BrainStorm Cell Therapeutics' investigational stem cell therapy NurOwn (debamestrocel) doesn't appear to be effective in treating amyotrophic lateral sclerosis (ALS) based on data submitted by the firm.
In a 17-to-1 vote, members of the FDA's Cellular, Tissue, and Gene Therapies Advisory Committee agreed that BrainStorm didn't provide enough evidence of NurOwn's efficacy in treating mild-to-moderate ALS, in spite of impassioned testimonials from patients and families. One committee member abstained from the vote.
"The discussion in today's advisory committee meeting, and the heart-rending testimony of those living with ALS and their loved ones, underscores not only the need for regulatory flexibility but also for continuing research in the field," BrainStorm President and CEO Chaim Lebovits said in a statement after the meeting. "The people of BrainStorm will do everything in our power to fulfill the obligation we deeply feel we owe to the ALS community, and in the coming weeks we will explore all options available to us."
BrainStorm's NurOwn technology produces autologous multipotent stem cells derived from bone marrow. These stem cells are induced to secrete high levels of neurotrophic factors, proteins that support neuronal growth and survival, which the company believes can slow progression of the rare neurodegenerative illness, also known as Lou Gehrig's disease.
The negative vote from the advisory committee is another strike against BrainStorm's hope of achieving regulatory approval for NurOwn. Ahead of the advisory panel's meeting on Monday, the FDA released a briefing document, in which its reviewers expressed "major concerns" over the supplemental retrospective analyses provided by the company, post hoc analyses of the prospective Phase III clinical trial that failed to show benefit. The reviewers said the available data on the drug provided "little confidence on which to base regulatory decisions" but felt it may help generate hypotheses for future clinical trials.
"There continues to be an urgent need for treatment," Celia Witten, deputy director of the FDA's Center for Biologics Evaluation and Research (CBER), said during the meeting. "Unfortunately, both the Phase II and the Phase III randomized, double-blind, placebo-controlled studies conducted as part of the applicant's development program for this product failed to show efficacy."
Recommendations from the FDA's advisory committees are nonbinding, but the agency usually follows the advice of its independent expert panels.
NurOwn has been mired in controversy. BrainStorm submitted a biologics license application (BLA) seeking approval for the drug as a treatment for ALS a year ago, but the FDA in November 2022 refused to accept the submission after determining that the data did not demonstrate substantial evidence of effectiveness for NurOwn and that the "grossly deficient" manufacturing information did not ensure product quality.
BrainStorm requested that CBER accept its BLA and provided additional retrospective analyses and biomarker results. The FDA resumed its BLA review of the drug in February, and last week, the company modified NurOwn's proposed indication as a treatment for ALS in mild to moderate forms of the disease.
BrainStorm's BLA included data from multiple clinical trials; however, only one study — a Phase III randomized, double-blind trial with 196 participants — evaluated the administration of the drug with the intended route and dose interval. The pivotal Phase III trial did not show that NurOwn slowed disease progression in the treated group compared to the placebo group based on the widely used Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Moreover, when the study was complete, survival was worse among treated patients.
None of the deaths were related to the treatment, Kirk Taylor, BrainStorm's executive VP and chief medical officer, said during the meeting. BrainStorm further argued that the trial failed because it is difficult to measure disease progression in patients with advanced disease, and subsequently, it conducted its own analyses of Phase III data, homing in on patients with mild or moderate disease.
In these retrospective analyses on unblinded data, NurOwn-treated patients on average retained two more points of function on ALSFRS-R compared to the placebo group. Based on this, BrainStorm concluded that its drug slowed disease progression in ALS patients who had not progressed to advanced disease.
According to the company, patients treated with NurOwn also experienced reductions in cerebrospinal fluid biomarkers linked to neuroinflammation and neurodegeneration when compared to the placebo group, including neurofilament light chain (NfL) — the biomarker on which the FDA granted Biogen accelerated approval for the ALS drug Qalsody (tofersen). Twenty weeks after starting treatment, NurOwn-treated patients had about an 8.9 percent reduction in NfL levels compared to the placebo group.
Many who spoke in favor of NurOwn's data highlighted recent comments from FDA officials about the agency's willingness to be more flexible when shepherding investigational rare disease treatments through the regulatory process.
Kathleen O'Sullivan-Fortin, the consumer representative on the committee and founder of the nonprofit ALD Connect, was the singular vote in support of NurOwn. After the vote, she expressed frustration when describing her reasoning in favor of the drug. "I think it is very clear that I include data that no one else considers as real data," she said, referring to patient experiences and family testimonials from the public. "There's no bigger risk than imminent, certain death from ALS, and these are unique and desperate circumstances that would require us to exercise flexibility."
Anthony Windebank, a professor and faculty development chair at the Mayo Clinic's neurology department, pointed out that the FDA approved Qalsody based on Phase III data demonstrating reductions in NfL, even though the drug failed to significantly improve patients' physical functions and meet the primary endpoint in that study.
"Given the unmet need that remains, I hope that the FDA will continue to exercise the broadest flexibility in applying the statutory standards for this life-threatening disease," said Windebank, who was a principal investigator on several NurOwn trials. Speaking during BrainStorm's presentation, Windebank added that he would prescribe NurOwn to his ALS patients, since he believes it is a safe and promising therapy. "We can't afford to lose a potentially valuable treatment simply because of complex data."
In the briefing document, FDA reviewers flagged that around 50 percent of biomarker measurements at week 20, the last time point in the Phase III trial for biomarker sample collection, were missing. BrainStorm attributed the missing data to hospital restrictions on patients coming into facilities during the COVID-19 pandemic.
Agency reviewers were also unconvinced that there was a clear association between NfL and clinical benefit. NurOwn-treated patients with a greater reduction in NfL levels appeared to experience a greater loss of function based on a decline in ALSFRS-R scores, which is the opposite of what FDA reviewers would have expected.
Ultimately, FDA reviewers said they found BrainStorm's purported findings of treatment benefit for patients with mild-to-moderate ALS spurious and not valid.
"Subgroup analyses following overall nonsignificant tests in the overall population must always be interpreted with caution," they wrote. "The applicant may conduct additional well-controlled clinical [study or studies] in subjects with high baseline ALSFRS-R to assess the efficacy and safety of [mesenchymal stromal cells secreting neurotrophic factors]; however, exploratory subgroup analysis data from the completed Phase III study cannot serve as evidence of effectiveness."
Nearly all comments during the open public hearing portion of the meeting were from ALS patients and family members urging the committee to vote in favor of the drug.
Madi Bailey, whose stepfather died from ALS in 2018, advocated for NurOwn's approval, emphasizing how the drug has reportedly enabled patients to retain more points on the ALSFRS-R functional rating scale. "One point could have meant that my mother got to spend more time with my stepdad as his wife and not as his nurse and caregiver. One more point could have meant that my children had the chance to learn more about the world from [his] shoulders before his speech became too slurred to understand and his arms were too weak to hold them," she said. "Every point matters."
Ajay Sampat, an ALS patient and an associate clinical professor of neurology at UC Davis School of Medicine, said he found the Phase III data on NurOwn's ability to preserve function compelling and would feel comfortable taking the drug himself and recommending it to his patients. "Please don't discount the human experience in this horrific disease," he said. "There is no risk worse than a certain death from a 100 percent fatal condition."
Not all public commenters agreed that the drug should be approved.
Given the failed study results, "patients should have the option of being in a free clinical trial or [receiving] expanded access, but it would be unconscionable for patients to pay for this unproven treatment," said Diana Zuckerman, president of the National Center for Health Research. "The patients who died on this treatment are not here today, and I want to represent those patients' results, which haven't gotten much attention so far."
Committee members seemed to well understand that their task is to advise whether the FDA should approve NurOwn based on the available safety and efficacy data, while taking into consideration the unmet need for new ALS treatments and the emotional pleas from patients and family members dealing with an incurable disease.
"We need to be very, very guarded about the weight that we put on [anecdotes]. … Multiple anecdotes is not the same thing as data," said Michael Gold, chief medical officer of Neumora Therapeutics and a temporary nonvoting member on the committee acting as an industry representative. He noted that it's important to keep in mind that patients who don't benefit from a drug are less likely to offer testimonials. "We have to be objective, and we have to be data-driven," Gold said.
Lisa Lee, associate VP for research and innovation at Virginia Tech and a temporary voting member on the committee, added, "There is absolutely no doubt that ALS is a devastating disease and that there's an urgent need for treatments that are effective. We heard from our public commenters; patients and families need hope. But providing false hope can be ethically problematic, and 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 is expected to issue a decision on BrainStorm's BLA by Dec. 8.