FDA reviewers voiced serious concerns about the investigational amyotrophic lateral sclerosis (ALS) treatment debamestrocel -- mesenchymal stromal cells secreting neurotrophic factors, also known as MSC-NTF, or NurOwn -- from BrainStorm Cell Therapeutics ahead of an this week.
When the FDA first received the drug's application for approval, it determined the submission was "scientifically incomplete to demonstrate substantial evidence of effectiveness, and that the manufacturing information was grossly deficient to ensure adequate product quality," the agency said in prepared before the Wednesday meeting.
The application had missing or incomplete validation of methods and a lack of data demonstrating manufacturing consistency, FDA reviewers wrote. The agency refused to file the submission and detailed these deficiencies in a letter to BrainStorm, which filed the application over protest. The company subsequently provided additional retrospective analyses and biomarker results.
On Wednesday, the FDA's Cellular, Tissue, and Gene Therapy Advisory Committee will meet to discuss whether BrainStorm's data meet the agency's standard of substantial evidence of effectiveness for approval.
MSC-NTF is an autologous cell-based therapy intended to secrete NTFs, which are important for nerve survival and function. The FDA maintains that the drug's mechanism is unclear, but BrainStorm hypothesizes that by secreting NTFs, its therapy could slow disease progression in patients with ALS.
Treatment requires initial bone marrow aspiration from the patient to obtain the cells to produce the product, followed by repeated intrathecal administration.
The MSC-NTF clinical development program consisted of four studies -- two single-arm, open-label, early-phase studies; a phase II trial where ALS patients received a one-time administration of a single intrathecal injection and 24 intramuscular injections; and a phase III randomized, double-blind, placebo-controlled study in which patients received a total of three intrathecal injections, one every 8 weeks.
The pivotal phase III trial -- the only one to evaluate MSC-NTF using both its intended route and dose interval -- , with 33% of patients in the MSC-NTF group and 28% in the placebo group meeting clinical response criteria at 28 weeks (P=0.45).
The phase III study randomized 98 ALS patients to MSC-NTF and 98 to placebo. Survival was worse at study completion for people who received MSC-NTF (10 deaths vs three deaths for the placebo group), the FDA noted. Some biomarker data suggested benefit, but "there was a large amount of missing data for all biomarkers at week 20 (~50%), the last time point for biomarker sample collection and the focused time point for biomarker analyses," the agency said.
Analysis of a prespecified subgroup suggested that MSC-NTF participants with less severe disease may have retained more function compared with placebo, but the findings were not statistically significant.
Nonetheless, BrainStorm maintained in , "the totality of evidence shows that NurOwn has a consistent and clinically meaningful treatment effect across a broad range of patients with ALS, which is further supported by significant results across multiple biomarkers."
The ALS Association, which often takes a supportive position on new ALS treatments, noted the "amazing testimonials we have seen online with us or has been published in peer-reviewed publications."
"We have an obligation to the community we serve to be vigilant and data-driven, and our approach has served the ALS community well in recent FDA reviews," the group added. "Until we have the opportunity to conduct an independent review, we cannot take a position for or against approval of NurOwn."
BrainStorm will make its case Wednesday before a , who will spend the day reviewing the MSC-NTF data. If the group decides the data did not show substantial effectiveness evidence, it will discuss potential designs for a trial that can. The meeting will focus on clinical, statistical, and biomarker data only, not the product manufacturing and control processes since those issues aren't resolved.
The FDA said it will not issue a final determination about MSC-NTF until input from the advisory committee process has been considered and all reviews have been finalized. The agency doesn't have to follow the advice of the committee, but it often does.