The Food and Drug Administration (FDA) has expressed grave reservations about an investigational amyotrophic lateral sclerosis (ALS) treatment called debamestrocel — also known as MSC-NTF or NurOwn — developed by BrainStorm Cell Therapeutics. With an advisory committee meeting scheduled for this week, the FDA has deemed the drug’s application as scientifically incomplete and lacking evidence of effectiveness, as well as suffering from manufacturing deficiencies. This article explores the concerns raised by FDA reviewers and the implications for BrainStorm’s experimental treatment.
Upon receiving the application for approval, the FDA identified several significant shortcomings in the submission. According to briefing documents prepared for the advisory committee meeting, the application lacked substantial evidence of effectiveness and had grossly deficient manufacturing information. In particular, there were issues with missing or incomplete validation of methods and a lack of data demonstrating manufacturing consistency. Consequently, the FDA refused to file the submission and conveyed these deficiencies to BrainStorm in a letter.
In response to the FDA’s concerns, BrainStorm provided additional retrospective analyses and biomarker results. The company performed additional testing and analysis to address the deficiencies pointed out by the FDA. During the advisory committee meeting, the FDA’s Cellular, Tissue, and Gene Therapy Advisory Committee will scrutinize BrainStorm’s data to determine if it meets the agency’s standard of substantial evidence of effectiveness for approval.
MSC-NTF is an autologous cell-based therapy designed to secrete neurotrophic factors (NTFs) that are crucial for nerve survival and function. However, the FDA maintains that the mechanism of action for the drug is unclear. BrainStorm hypothesizes that by secreting NTFs, their therapy could potentially slow down the progression of ALS in patients. The treatment process involves extracting cells from the patient’s bone marrow through aspiration, followed by repeated intrathecal administration.
The MSC-NTF clinical development program consisted of four studies. The first two studies were single-arm, open-label, early-phase studies. The phase II trial involved ALS patients receiving a single intrathecal injection and 24 intramuscular injections. Finally, the phase III study was a randomized, double-blind, placebo-controlled study where patients received three intrathecal injections, one every eight weeks.
The pivotal phase III trial, which was the only one to evaluate MSC-NTF using its intended route and dose interval, did not achieve its primary endpoint. The FDA noted that only 33% of patients in the MSC-NTF group and 28% in the placebo group met clinical response criteria at 28 weeks. The survival rate was also worse for the MSC-NTF group, with 10 deaths compared to three deaths in the placebo group. Although some biomarker data suggested potential benefit, there was a significant amount of missing data for all biomarkers at the designated time point for analysis.
Despite the inconsistent results, BrainStorm maintained in its pre-meeting briefing documents that the evidence showed NurOwn had a consistent and clinically meaningful treatment effect across a wide range of ALS patients. They also pointed to significant results across multiple biomarkers. However, the ALS Association, which generally supports new ALS treatments, expressed skepticism. The association stated that the testimonials they had seen online did not align with the data shared by BrainStorm or published in peer-reviewed publications. The organization emphasized the need for an independent review before taking a position on the approval of NurOwn.
On Wednesday, BrainStorm will present its case before a panel of FDA advisors, who will spend the day reviewing the clinical, statistical, and biomarker data related to MSC-NTF. If the advisory committee determines that the data does not provide sufficient evidence of effectiveness, they will discuss potential trial designs that could address these concerns. It’s important to note that the advisory committee meeting will solely focus on clinical data and not on the product’s manufacturing and control processes, as those issues have yet to be resolved. The FDA will only issue a final determination on MSC-NTF after considering input from the advisory committee process and completing all necessary reviews.
The FDA’s serious concerns about BrainStorm Cell Therapeutics’ investigational ALS treatment, MSC-NTF, highlight significant deficiencies in the drug’s application for approval. The lack of substantial evidence of effectiveness and manufacturing deficiencies identified by FDA reviewers raise doubts about the treatment’s safety and efficacy. BrainStorm’s response and subsequent additional analyses will be evaluated by the FDA advisory committee to determine if the data meets the necessary standards for approval. The outcome of the advisory committee’s review will have far-reaching implications for the future of MSC-NTF and its potential as a therapy for ALS.