The FDA’s briefing documents found that BrainStorm’s BLA submission for its investigational cell therapy for ALS did not demonstrate evidence of effectiveness and that the manufacturing data was “grossly deficient.”
Pictured: FDA Headquarters/iStock, Grandbrothers
Update, Sept. 25, all new information:
The FDA noted in its briefing documents that a total of 13 deaths occurred during the post-treatment follow-up phase of BrainStorm’s Phase III trial, with 10 deaths in the NurOwn treatment group compared to three in the placebo group.
In its own briefing documents, also posted on Monday, BrainStorm reported 16 deaths in the Phase III trial—10 in the NurOwn group compared to six in the placebo group. The company attributed the majority of these deaths to disease progression, which the FDA said “seems reasonable based on available information.” However, the regulator continued, no autopsy reports were submitted and with limited information, “it is challenging to assess whether MSC-NTF played an active role in these deaths,” and that the early change in overall survival in patients treated with NurOwn “is of serious concern.”
BrainStorm declined to comment further to a BioSpace query. A spokesperson said that as a public company, BrainStorm is now “in a quiet period” until after the Cellular, Tissues and Gene Therapies Advisory Committee [CTGTAC] votes on Wednesday.
In briefing documents published Monday, ahead of Wednesday’s advisory committee meeting for BrainStorm Cell Therapeutics’ ALS hopeful NurOwn (debamestrocel), the FDA took issue with the cell therapy’s manufacturing plan and said the company failed to demonstrate substantial evidence of efficacy in its Biologics License Application.
In the documents, FDA staffers said that upon initial receipt of the BLA, the agency determined it was “scientifically incomplete” to demonstrate effectiveness, while the manufacturing information it received was “grossly deficient” to ensure adequate quality of the product. These factors led the FDA to issue the Israel- and New York–based company a Refuse to File letter in November 2022. BrainStorm leveraged the FDA’s File Over Protest procedure to file the BLA anyway and was granted an advisory committee meeting in March 2023.
The FDA noted in the documents that the Phase III trial of NurOwn—a cell therapy made up of mesenchymal stromal cells secreting neurotrophic factors (MSC-NTF)—failed to demonstrate efficacy in its primary and all secondary endpoints.
“Although the agency has potential issues with the quality and safety of this product, at [Wednesday’s} advisory committee meeting, FDA is seeking to obtain input from the committee as to whether the available data can be considered to constitute substantial evidence of effectiveness to support regulatory approval of MSC-NTF for treatment of ALS,” the regulator wrote in the adcomm briefing documents.
NurOwn did hit the primary treatment response endpoint, with 34.7% of patients achieving an improvement of 1.5 points per month on the ALS Functional Rating Scale – Revised (ALSFRS-R), according to BrainStorm in a press release issued in November 2022. However, the FDA’s documents state that just 32.6% of patients met the responder criteria compared to 27.7% in the placebo group. One problem for BrainStorm has been that this placebo response exceeds those of others observed in contemporary ALS trials.
BrainStorm has claimed that this result is due to a “floor effect,” which occurs when ALSFRS-R total scores plateau over time, meaning that further deterioration of function cannot be measured. To demonstrate this, the company conducted an analysis separating patients who hit zero on the scale from those who did not. This analysis showed that treatment with NurOwn preserved more than two points on the ALSFRS-R after 28 weeks. In the briefing documents, however, the FDA attests that no floor effect was demonstrated in the analysis and that a floor effect “would not be expected in the assessment of survival or biomarkers.”
The FDA’s documents also note that survival in the Phase III study was worse at its completion for subjects who received NurOwn. “A total of 13 deaths occurred during the post-treatment follow up (28 weeks ± 5 days) with ten deaths (10/95) in the MSC-NTF group and three deaths (3/94) in the placebo group,” the reviewers wrote.
Regulatory Flexibility
The briefing documents also point to the FDA’s willingness to show regulatory flexibility in ALS, which is 100% fatal, typically claiming the lives of its victims in two to five years.
BrainStorm co-CEO Stacy Lindborg also noted this in an interview with BioSpace, saying that the FDA has shown flexibility in all the ALS therapies it has approved. “When you look back, certainly you have products where approvals have come after the trials have missed their primary endpoints, in some instances where post hoc analyses have been conducted,” she said.
In July 2023, BrainStorm buttressed NurOwn’s case with biomarker data showing that treatment with the therapy increases levels of neuroprotective biomarkers. NurOwn also led to a significant decline in markers of neurodegeneration including neurofilament light chain (NfL), concentrations of which spike in response to damage to neurons. Biogen won approval earlier this year for tofersen in (SOD1)-ALS based largely on the drug’s effect on NfL.
Jonathan S. Katz, ALS clinic director at Forbes Norris MDA/ALS Research and Treatment Center at California Pacific Medical Center/Sutter Medical Center and a lead site investigator for NurOwn’s Phase III trial, called BrainStorm’s sub-analysis “legitimate.”
“It’s a good question [BrainStorm is] asking about the floor effect,” Katz told BioSpace. He said that while it is “true” the company should have been able to show a response even with the floor effect, “we don’t have that many drugs that work in ALS, and there are legitimate reasons to think that this trial hit the floor effect because of its design and that the design might have gotten it into some trouble.” Katz said that in an ideal world where money wasn’t an issue, BrainStorm would repeat the trial but acknowledged resource constraints.
Speaking to BioSpace ahead of the adcomm, Brian Wallach, co-founder of the patient advocacy group I AM ALS, said that he believes approval of NurOwn is “merited by the science and data that the company has shared with the public and with the FDA.” Wallach, who suffers from the disease, said he has seen people living with ALS who are part of the extended trial and have ALSFRS scores “all over the map” see real benefit from NurOwn. “For some of them, it has halted their progression and for others, it has actually been able to help them regain some function. This is not something you see in a disease like ALS given how heterogeneous it is.”
Closing out the executive summary section, the FDA wrote that it “recognizes the urgent unmet need for additional effective treatments for ALS. At the same time, the critical statutory requirements for approval of drugs and biologics include substantial evidence of effectiveness and evidence of safety, and demonstration of adequate product quality.”
Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Follow her on LinkedIn and X @chicat08.
